TY  - JOUR
AU  - Novković, Mirjana
AU  - Banović Đeri, Bojana
AU  - RistivojeviĆ, Bojan
AU  - Knežević, Aleksandra
AU  - Janković, Marko
AU  - Tanasić, Vanja
AU  - Radojičić, Verica
AU  - Keckarević, Dusan
AU  - Vidanović, Dejan
AU  - Tešović, Bojana
AU  - Skakić, Anita
AU  - Tolinački, Maja
AU  - Morić, Ivana
AU  - Đorđević, Valentina
PY  - 2024
UR  - https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1332276
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2327
AB  - The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, has been evolving rapidly causing emergence of new variants and health uncertainties. Monitoring the evolution of the virus was of the utmost importance for public health interventions and the development of national and global mitigation strategies. Here, we report national data on the emergence of new variants, their distribution, and dynamics in a 3-year study conducted from March 2020 to the end of January 2023 in the Republic of Serbia. Nasopharyngeal and oropharyngeal swabs from 2,398 COVID-19-positive patients were collected and sequenced using three different next generation technologies: Oxford Nanopore, Ion Torrent, and DNBSeq. In the subset of 2,107 SARS-CoV-2 sequences which met the quality requirements, detection of mutations, assignment to SARS-CoV-2 lineages, and phylogenetic analysis were performed. During the 3-year period, we detected three variants of concern, namely, Alpha (5.6%), Delta (7.4%), and Omicron (70.3%) and one variant of interest—Omicron recombinant “Kraken” (XBB1.5) (<1%), whereas 16.8% of the samples belonged to other SARS-CoV-2 (sub)lineages. The detected SARS-CoV-2 (sub)lineages resulted in eight COVID-19 pandemic waves in Serbia, which correspond to the pandemic waves reported in Europe and the United States. Wave dynamics in Serbia showed the most resemblance with the profile of pandemic waves in southern Europe, consistent with the southeastern European location of Serbia. The samples were assigned to sixteen SARS-CoV-2 Nextstrain clades: 20A, 20B, 20C, 20D, 20E, 20G, 20I, 21J, 21K, 21L, 22A, 22B, 22C, 22D, 22E, and 22F and six different Omicron recombinants (XZ, XAZ, XAS, XBB, XBF, and XBK). The 10 most common mutations detected in the coding and untranslated regions of the SARS-CoV-2 genomes included four mutations affecting the spike protein (S:D614G, S:T478K, S:P681H, and S:S477N) and one mutation at each of the following positions: 5′-untranslated region (5’UTR:241); N protein (N:RG203KR); NSP3 protein (NSP3:F106F); NSP4 protein (NSP4:T492I); NSP6 protein (NSP6: S106/G107/F108 - triple deletion), and NSP12b protein (NSP12b:P314L). This national-level study is the most comprehensive in terms of sequencing and genomic surveillance of SARS-CoV-2 during the pandemic in Serbia, highlighting the importance of establishing and maintaining good national practice for monitoring SARS-CoV-2 and other viruses circulating worldwide.
AB  - The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, has been evolving rapidly causing emergence of new variants and health uncertainties. Monitoring the evolution of the virus was of the utmost importance for public health interventions and the development of national and global mitigation strategies. Here, we report national data on the emergence of new variants, their distribution, and dynamics in a 3-year study conducted from March 2020 to the end of January 2023 in the Republic of Serbia. Nasopharyngeal and oropharyngeal swabs from 2,398 COVID-19- positive patients were collected and sequenced using three different next generation technologies: Oxford Nanopore, Ion Torrent, and DNBSeq. In the subset of 2,107 SARS-CoV-2 sequences which met the quality requirements, detection of mutations, assignment to SARS-CoV-2 lineages, and phylogenetic analysis were performed. During the 3-year period, we detected three variants of concern, namely, Alpha (5.6%), Delta (7.4%), and Omicron (70.3%) and one variant of interest—Omicron recombinant “Kraken” (XBB1.5) (<1%), whereas 16.8% of the samples belonged to other SARS-CoV-2 (sub)lineages. The detected SARS-CoV-2 (sub)lineages resulted in eight COVID-19 pandemic waves in Serbia, which correspond to the pandemic waves reported in Europe and the United States. Wave dynamics in Serbia showed the most resemblance with the profile of pandemic waves in southern Europe, consistent with the southeastern European location of Serbia. The samples were assigned to sixteen SARS-CoV-2 Nextstrain clades: 20A, 20B, 20C, 20D, 20E, 20G, 20I, 21J, 21K, 21L, 22A, 22B, 22C, 22D, 22E, and 22F and six different Omicron recombinants (XZ, XAZ, XAS, XBB, XBF, and XBK). The 10 most common mutations detected in the coding and untranslated regions of the SARS-CoV-2 genomes included four mutations affecting the spike protein (S:D614G, S:T478K, S:P681H, and S:S477N) and one mutation at each of the following positions: 5′-untranslated region (5’UTR:241); N protein (N:RG203KR); NSP3 protein (NSP3:F106F); NSP4 protein (NSP4:T492I); NSP6 protein (NSP6: S106/G107/F108 - triple deletion), and NSP12b protein (NSP12b:P314L). This national-level study is the most comprehensive in terms of sequencing and genomic surveillance of SARS-CoV-2 during the pandemic in Serbia, highlighting the importance of establishing and maintaining good national practice for monitoring SARS-CoV-2 and other viruses circulating worldwide.
PB  - Frontiers
T2  - Frontiers in Microbiology
T2  - Frontiers in Microbiology
T1  - Genome sequence diversity of SARS-CoV-2 in Serbia: insights gained from a 3-year pandemic study
VL  - 15
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2327
ER  - 

@article{
author = "Novković, Mirjana and Banović Đeri, Bojana and RistivojeviĆ, Bojan and Knežević, Aleksandra and Janković, Marko and Tanasić, Vanja and Radojičić, Verica and Keckarević, Dusan and Vidanović, Dejan and Tešović, Bojana and Skakić, Anita and Tolinački, Maja and Morić, Ivana and Đorđević, Valentina",
year = "2024",
abstract = "The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, has been evolving rapidly causing emergence of new variants and health uncertainties. Monitoring the evolution of the virus was of the utmost importance for public health interventions and the development of national and global mitigation strategies. Here, we report national data on the emergence of new variants, their distribution, and dynamics in a 3-year study conducted from March 2020 to the end of January 2023 in the Republic of Serbia. Nasopharyngeal and oropharyngeal swabs from 2,398 COVID-19-positive patients were collected and sequenced using three different next generation technologies: Oxford Nanopore, Ion Torrent, and DNBSeq. In the subset of 2,107 SARS-CoV-2 sequences which met the quality requirements, detection of mutations, assignment to SARS-CoV-2 lineages, and phylogenetic analysis were performed. During the 3-year period, we detected three variants of concern, namely, Alpha (5.6%), Delta (7.4%), and Omicron (70.3%) and one variant of interest—Omicron recombinant “Kraken” (XBB1.5) (<1%), whereas 16.8% of the samples belonged to other SARS-CoV-2 (sub)lineages. The detected SARS-CoV-2 (sub)lineages resulted in eight COVID-19 pandemic waves in Serbia, which correspond to the pandemic waves reported in Europe and the United States. Wave dynamics in Serbia showed the most resemblance with the profile of pandemic waves in southern Europe, consistent with the southeastern European location of Serbia. The samples were assigned to sixteen SARS-CoV-2 Nextstrain clades: 20A, 20B, 20C, 20D, 20E, 20G, 20I, 21J, 21K, 21L, 22A, 22B, 22C, 22D, 22E, and 22F and six different Omicron recombinants (XZ, XAZ, XAS, XBB, XBF, and XBK). The 10 most common mutations detected in the coding and untranslated regions of the SARS-CoV-2 genomes included four mutations affecting the spike protein (S:D614G, S:T478K, S:P681H, and S:S477N) and one mutation at each of the following positions: 5′-untranslated region (5’UTR:241); N protein (N:RG203KR); NSP3 protein (NSP3:F106F); NSP4 protein (NSP4:T492I); NSP6 protein (NSP6: S106/G107/F108 - triple deletion), and NSP12b protein (NSP12b:P314L). This national-level study is the most comprehensive in terms of sequencing and genomic surveillance of SARS-CoV-2 during the pandemic in Serbia, highlighting the importance of establishing and maintaining good national practice for monitoring SARS-CoV-2 and other viruses circulating worldwide., The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, has been evolving rapidly causing emergence of new variants and health uncertainties. Monitoring the evolution of the virus was of the utmost importance for public health interventions and the development of national and global mitigation strategies. Here, we report national data on the emergence of new variants, their distribution, and dynamics in a 3-year study conducted from March 2020 to the end of January 2023 in the Republic of Serbia. Nasopharyngeal and oropharyngeal swabs from 2,398 COVID-19- positive patients were collected and sequenced using three different next generation technologies: Oxford Nanopore, Ion Torrent, and DNBSeq. In the subset of 2,107 SARS-CoV-2 sequences which met the quality requirements, detection of mutations, assignment to SARS-CoV-2 lineages, and phylogenetic analysis were performed. During the 3-year period, we detected three variants of concern, namely, Alpha (5.6%), Delta (7.4%), and Omicron (70.3%) and one variant of interest—Omicron recombinant “Kraken” (XBB1.5) (<1%), whereas 16.8% of the samples belonged to other SARS-CoV-2 (sub)lineages. The detected SARS-CoV-2 (sub)lineages resulted in eight COVID-19 pandemic waves in Serbia, which correspond to the pandemic waves reported in Europe and the United States. Wave dynamics in Serbia showed the most resemblance with the profile of pandemic waves in southern Europe, consistent with the southeastern European location of Serbia. The samples were assigned to sixteen SARS-CoV-2 Nextstrain clades: 20A, 20B, 20C, 20D, 20E, 20G, 20I, 21J, 21K, 21L, 22A, 22B, 22C, 22D, 22E, and 22F and six different Omicron recombinants (XZ, XAZ, XAS, XBB, XBF, and XBK). The 10 most common mutations detected in the coding and untranslated regions of the SARS-CoV-2 genomes included four mutations affecting the spike protein (S:D614G, S:T478K, S:P681H, and S:S477N) and one mutation at each of the following positions: 5′-untranslated region (5’UTR:241); N protein (N:RG203KR); NSP3 protein (NSP3:F106F); NSP4 protein (NSP4:T492I); NSP6 protein (NSP6: S106/G107/F108 - triple deletion), and NSP12b protein (NSP12b:P314L). This national-level study is the most comprehensive in terms of sequencing and genomic surveillance of SARS-CoV-2 during the pandemic in Serbia, highlighting the importance of establishing and maintaining good national practice for monitoring SARS-CoV-2 and other viruses circulating worldwide.",
publisher = "Frontiers",
journal = "Frontiers in Microbiology, Frontiers in Microbiology",
title = "Genome sequence diversity of SARS-CoV-2 in Serbia: insights gained from a 3-year pandemic study",
volume = "15",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2327"
}

Novković, M., Banović Đeri, B., RistivojeviĆ, B., Knežević, A., Janković, M., Tanasić, V., Radojičić, V., Keckarević, D., Vidanović, D., Tešović, B., Skakić, A., Tolinački, M., Morić, I.,& Đorđević, V.. (2024). Genome sequence diversity of SARS-CoV-2 in Serbia: insights gained from a 3-year pandemic study. in Frontiers in Microbiology
Frontiers., 15.
https://hdl.handle.net/21.15107/rcub_imagine_2327

Novković M, Banović Đeri B, RistivojeviĆ B, Knežević A, Janković M, Tanasić V, Radojičić V, Keckarević D, Vidanović D, Tešović B, Skakić A, Tolinački M, Morić I, Đorđević V. Genome sequence diversity of SARS-CoV-2 in Serbia: insights gained from a 3-year pandemic study. in Frontiers in Microbiology. 2024;15.
https://hdl.handle.net/21.15107/rcub_imagine_2327 .

Novković, Mirjana, Banović Đeri, Bojana, RistivojeviĆ, Bojan, Knežević, Aleksandra, Janković, Marko, Tanasić, Vanja, Radojičić, Verica, Keckarević, Dusan, Vidanović, Dejan, Tešović, Bojana, Skakić, Anita, Tolinački, Maja, Morić, Ivana, Đorđević, Valentina, "Genome sequence diversity of SARS-CoV-2 in Serbia: insights gained from a 3-year pandemic study" in Frontiers in Microbiology, 15 (2024),
https://hdl.handle.net/21.15107/rcub_imagine_2327 .

TY  - JOUR
AU  - Jelovac, Marina
AU  - Kotur, Nikola
AU  - Ristivojević, Bojan
AU  - Pavlović, Djordje
AU  - Spasovski, Vesna
AU  - Damjanov, Nemanja
AU  - Pavlović, Sonja
AU  - Zukić, Branka
PY  - 2023
UR  - https://www.mdpi.com/1422-0067/24/10/8538
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1859
AB  - Systemic sclerosis (SSc) is a rare connective tissue disorder with highest morbidity and mortality among rheumatologic diseases. Disease progression is highly heterogeneous between patients, implying a strong need for individualization of therapy. Four pharmacogenetic variants, namely TPMT rs1800460, TPMT rs1142345, MTHFR rs1801133 and SLCO1B1 rs4149056 were tested for association with severe disease outcomes in 102 patients with SSc from Serbia treated either with immunosuppressants azathioprine (AZA) and methotrexate (MTX) or with other types of medications. Genotyping was performed using PCR-RFLP and direct Sanger sequencing. R software was used for statistical analysis and development of polygenic risk score (PRS) model. Association was found between MTHFR rs1801133 and higher risk for elevated systolic pressure in all patients except those prescribed with MTX, and higher risk for kidney insufficiency in patients prescribed with other types of drugs. In patients treated with MTX, variant SLCO1B1 rs4149056 was protective against kidney insufficiency. For patients receiving MTX a trend was shown for having a higher PRS rank and elevated systolic pressure. Our results open a door wide for more extensive research on pharmacogenomics markers in patients with SSc. Altogether, pharmacogenomics markers could predict the outcome of patients with SSc and help in prevention of adverse drug reactions.
T2  - International Journal of Molecular Sciences
T2  - International Journal of Molecular Sciences
T1  - Can Pharmacogenetic Variants in TPMT, MTHFR and SLCO1B1 Genes Be Used as Potential Markers of Outcome Prediction in Systemic Sclerosis Patients?
IS  - 10
SP  - 8538
VL  - 24
DO  - 10.3390/ijms24108538
ER  - 

@article{
author = "Jelovac, Marina and Kotur, Nikola and Ristivojević, Bojan and Pavlović, Djordje and Spasovski, Vesna and Damjanov, Nemanja and Pavlović, Sonja and Zukić, Branka",
year = "2023",
abstract = "Systemic sclerosis (SSc) is a rare connective tissue disorder with highest morbidity and mortality among rheumatologic diseases. Disease progression is highly heterogeneous between patients, implying a strong need for individualization of therapy. Four pharmacogenetic variants, namely TPMT rs1800460, TPMT rs1142345, MTHFR rs1801133 and SLCO1B1 rs4149056 were tested for association with severe disease outcomes in 102 patients with SSc from Serbia treated either with immunosuppressants azathioprine (AZA) and methotrexate (MTX) or with other types of medications. Genotyping was performed using PCR-RFLP and direct Sanger sequencing. R software was used for statistical analysis and development of polygenic risk score (PRS) model. Association was found between MTHFR rs1801133 and higher risk for elevated systolic pressure in all patients except those prescribed with MTX, and higher risk for kidney insufficiency in patients prescribed with other types of drugs. In patients treated with MTX, variant SLCO1B1 rs4149056 was protective against kidney insufficiency. For patients receiving MTX a trend was shown for having a higher PRS rank and elevated systolic pressure. Our results open a door wide for more extensive research on pharmacogenomics markers in patients with SSc. Altogether, pharmacogenomics markers could predict the outcome of patients with SSc and help in prevention of adverse drug reactions.",
journal = "International Journal of Molecular Sciences, International Journal of Molecular Sciences",
title = "Can Pharmacogenetic Variants in TPMT, MTHFR and SLCO1B1 Genes Be Used as Potential Markers of Outcome Prediction in Systemic Sclerosis Patients?",
number = "10",
pages = "8538",
volume = "24",
doi = "10.3390/ijms24108538"
}

Jelovac, M., Kotur, N., Ristivojević, B., Pavlović, D., Spasovski, V., Damjanov, N., Pavlović, S.,& Zukić, B.. (2023). Can Pharmacogenetic Variants in TPMT, MTHFR and SLCO1B1 Genes Be Used as Potential Markers of Outcome Prediction in Systemic Sclerosis Patients?. in International Journal of Molecular Sciences, 24(10), 8538.
https://doi.org/10.3390/ijms24108538

Jelovac M, Kotur N, Ristivojević B, Pavlović D, Spasovski V, Damjanov N, Pavlović S, Zukić B. Can Pharmacogenetic Variants in TPMT, MTHFR and SLCO1B1 Genes Be Used as Potential Markers of Outcome Prediction in Systemic Sclerosis Patients?. in International Journal of Molecular Sciences. 2023;24(10):8538.
doi:10.3390/ijms24108538 .

Jelovac, Marina, Kotur, Nikola, Ristivojević, Bojan, Pavlović, Djordje, Spasovski, Vesna, Damjanov, Nemanja, Pavlović, Sonja, Zukić, Branka, "Can Pharmacogenetic Variants in TPMT, MTHFR and SLCO1B1 Genes Be Used as Potential Markers of Outcome Prediction in Systemic Sclerosis Patients?" in International Journal of Molecular Sciences, 24, no. 10 (2023):8538,
https://doi.org/10.3390/ijms24108538 . .

TY  - CONF
AU  - Zečević, Marko
AU  - Kotur, Nikola
AU  - Ristivojević, Bojan
AU  - Gašić, Vladimir
AU  - Zukić, Branka
AU  - Pavlović, Sonja
AU  - Stanković, Biljana
PY  - 2023
UR  - https://belbi.bg.ac.rs/
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2029
AB  - Host genetics, an important contributor to the COVID-19 clinical susceptibility and severity,
currently is the focus of multiple genome-wide association studies (GWAS) in populations
affected by the pandemic. This is the first study from Serbia that performed a GWAS of
COVID-19 outcomes to identify genetic risk markers of disease severity. A group of 128
hospitalized COVID-19 patients from the Serbian population was enrolled in the study.
We conducted a GWAS comparing (1) patients with pneumonia (n = 80) against patients
without pneumonia (n = 48), and (2) severe (n = 34) against mild disease (n = 48) patients,
using a genotyping array followed by imputation of missing genotypes. We have detected
a significant signal associated with COVID-19 related pneumonia at locus 13q21.33, with
a peak residing upstream of the gene KLHL1 (p = 1.91 × 10−8). Our study also replicated
a previously reported COVID-19 risk locus at 3p21.31, identifying lead variants in SACM1L
and LZTFL1 genes suggestively associated with pneumonia (p = 7.54 × 10−6) and
severe COVID-19 (p = 6.88 × 10−7), respectively. Suggestive association with COVID-19
pneumonia has also been observed at chromosomes 5p15.33 (IRX, NDUFS6,MRPL36, p
= 2.81 × 10−6), 5q11.2 (ESM1, p = 6.59 × 10−6), and 9p23 (TYRP1,LURAP1L, p = 8.69 ×
10−6). The genes located in or near the risk loci are expressed in neural or lung tissues, and
have been previously associated with respiratory diseases such as asthma and COVID-19
or reported as differentially expressed in COVID-19 gene expression profiling studies.
Our results revealed novel risk loci for pneumonia and severe COVID-19 disease which
could contribute to a better understanding of the COVID-19 host genetics in different
populations.
PB  - Belgrade : Institute of molecular genetics and genetic engineering
C3  - 4th Belgrade Bioinformatics Conference
T1  - Genome-wide association analysis for severe COVID-19 in Serbian population
EP  - 84
SP  - 84
VL  - 4
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2029
ER  - 

@conference{
author = "Zečević, Marko and Kotur, Nikola and Ristivojević, Bojan and Gašić, Vladimir and Zukić, Branka and Pavlović, Sonja and Stanković, Biljana",
year = "2023",
abstract = "Host genetics, an important contributor to the COVID-19 clinical susceptibility and severity,
currently is the focus of multiple genome-wide association studies (GWAS) in populations
affected by the pandemic. This is the first study from Serbia that performed a GWAS of
COVID-19 outcomes to identify genetic risk markers of disease severity. A group of 128
hospitalized COVID-19 patients from the Serbian population was enrolled in the study.
We conducted a GWAS comparing (1) patients with pneumonia (n = 80) against patients
without pneumonia (n = 48), and (2) severe (n = 34) against mild disease (n = 48) patients,
using a genotyping array followed by imputation of missing genotypes. We have detected
a significant signal associated with COVID-19 related pneumonia at locus 13q21.33, with
a peak residing upstream of the gene KLHL1 (p = 1.91 × 10−8). Our study also replicated
a previously reported COVID-19 risk locus at 3p21.31, identifying lead variants in SACM1L
and LZTFL1 genes suggestively associated with pneumonia (p = 7.54 × 10−6) and
severe COVID-19 (p = 6.88 × 10−7), respectively. Suggestive association with COVID-19
pneumonia has also been observed at chromosomes 5p15.33 (IRX, NDUFS6,MRPL36, p
= 2.81 × 10−6), 5q11.2 (ESM1, p = 6.59 × 10−6), and 9p23 (TYRP1,LURAP1L, p = 8.69 ×
10−6). The genes located in or near the risk loci are expressed in neural or lung tissues, and
have been previously associated with respiratory diseases such as asthma and COVID-19
or reported as differentially expressed in COVID-19 gene expression profiling studies.
Our results revealed novel risk loci for pneumonia and severe COVID-19 disease which
could contribute to a better understanding of the COVID-19 host genetics in different
populations.",
publisher = "Belgrade : Institute of molecular genetics and genetic engineering",
journal = "4th Belgrade Bioinformatics Conference",
title = "Genome-wide association analysis for severe COVID-19 in Serbian population",
pages = "84-84",
volume = "4",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2029"
}

Zečević, M., Kotur, N., Ristivojević, B., Gašić, V., Zukić, B., Pavlović, S.,& Stanković, B.. (2023). Genome-wide association analysis for severe COVID-19 in Serbian population. in 4th Belgrade Bioinformatics Conference
Belgrade : Institute of molecular genetics and genetic engineering., 4, 84-84.
https://hdl.handle.net/21.15107/rcub_imagine_2029

Zečević M, Kotur N, Ristivojević B, Gašić V, Zukić B, Pavlović S, Stanković B. Genome-wide association analysis for severe COVID-19 in Serbian population. in 4th Belgrade Bioinformatics Conference. 2023;4:84-84.
https://hdl.handle.net/21.15107/rcub_imagine_2029 .

Zečević, Marko, Kotur, Nikola, Ristivojević, Bojan, Gašić, Vladimir, Zukić, Branka, Pavlović, Sonja, Stanković, Biljana, "Genome-wide association analysis for severe COVID-19 in Serbian population" in 4th Belgrade Bioinformatics Conference, 4 (2023):84-84,
https://hdl.handle.net/21.15107/rcub_imagine_2029 .

TY  - CONF
AU  - Ristivojević, Bojan
AU  - Kotur, Nikola
AU  - Tošić, Nataša
AU  - Stanković, Biljana
AU  - Gašić, Vladimir
AU  - Pavlović, Đorđe
AU  - Jelovac, Marina
AU  - Milošević, Goran
AU  - Pavlović, Sonja
AU  - Zukić, Branka
PY  - 2023
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2128
AB  - Introduction: The NUDT15 is new pharmacogene of importance for 6-mercaptopurine therapy, given to
children with acute lymphoblastic leukemia (ALL). The association ofside effectsin children with variants
in NUDT15 are well established in Asian populations, yet the relevance ofthis pharmacogene in European
populationsremainslargely unexplored. The aim of thisstudy wasto identify pharmacogenetic variants
in coding and neighbouring regions of NUDT15 gene and analyse if the expression levels of NUDT15 can
predict the occurence of side effects of 6-mercaptopurine during the maintenance therapy in children
with ALL of Serbian origin.
Methods: The genotyping of coding and neighbouring regions of NUDT15 gene was performed using
PCR and Sangersequencing based technology in 48 children with ALL. NUDT15 expression was analyzed
in mononuclear cells of 24 ALL patients at diagnosis and 6 healthy controls by qRT-PCR, and association
with surogate markers was assessed using adequate statistical methodology.
Results: The genotypig revealed the presence of 5 variantsin NUDT15 (NUDT15(NM_018283.4):c.36A>C,
NUDT15(NM_018283.4):c.158+117C>T,NUDT15(NM_018283.4):c.158+174G>A,NUDT15(NM_018283.4):c.159-
91G>A,NUDT15(NM_018283.4):c.*7G>A), none of them with effects on the expression or the function of
NUDT15 protein. There was no statistically significant association between the expression of NUDT15 at
diagnosis and the surogate markers of side effects (number of episodes of leukopenia (p=0.821), number of weeks without therapy (p=0.507), number of weeks with lower dose (p=0.434), average doses
(p=0.374)) of 6-mercaptopurine during the maintenance therapy.
Conclusion: Presently, NUDT15 cannot be used as a pharmacogene in predicting the toxicity of 6-mercaptopurine terapy in children with ALL in Serbia.
PB  - Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade
C3  - CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
T1  - NUDT15 as potential marker for pharmacogenetic-guided 6-mercaptopurine therapy in children with acute lymphoblastic leukemia in Serbia
EP  - 81
SP  - 81
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2128
ER  - 

@conference{
author = "Ristivojević, Bojan and Kotur, Nikola and Tošić, Nataša and Stanković, Biljana and Gašić, Vladimir and Pavlović, Đorđe and Jelovac, Marina and Milošević, Goran and Pavlović, Sonja and Zukić, Branka",
year = "2023",
abstract = "Introduction: The NUDT15 is new pharmacogene of importance for 6-mercaptopurine therapy, given to
children with acute lymphoblastic leukemia (ALL). The association ofside effectsin children with variants
in NUDT15 are well established in Asian populations, yet the relevance ofthis pharmacogene in European
populationsremainslargely unexplored. The aim of thisstudy wasto identify pharmacogenetic variants
in coding and neighbouring regions of NUDT15 gene and analyse if the expression levels of NUDT15 can
predict the occurence of side effects of 6-mercaptopurine during the maintenance therapy in children
with ALL of Serbian origin.
Methods: The genotyping of coding and neighbouring regions of NUDT15 gene was performed using
PCR and Sangersequencing based technology in 48 children with ALL. NUDT15 expression was analyzed
in mononuclear cells of 24 ALL patients at diagnosis and 6 healthy controls by qRT-PCR, and association
with surogate markers was assessed using adequate statistical methodology.
Results: The genotypig revealed the presence of 5 variantsin NUDT15 (NUDT15(NM_018283.4):c.36A>C,
NUDT15(NM_018283.4):c.158+117C>T,NUDT15(NM_018283.4):c.158+174G>A,NUDT15(NM_018283.4):c.159-
91G>A,NUDT15(NM_018283.4):c.*7G>A), none of them with effects on the expression or the function of
NUDT15 protein. There was no statistically significant association between the expression of NUDT15 at
diagnosis and the surogate markers of side effects (number of episodes of leukopenia (p=0.821), number of weeks without therapy (p=0.507), number of weeks with lower dose (p=0.434), average doses
(p=0.374)) of 6-mercaptopurine during the maintenance therapy.
Conclusion: Presently, NUDT15 cannot be used as a pharmacogene in predicting the toxicity of 6-mercaptopurine terapy in children with ALL in Serbia.",
publisher = "Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade",
journal = "CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia",
title = "NUDT15 as potential marker for pharmacogenetic-guided 6-mercaptopurine therapy in children with acute lymphoblastic leukemia in Serbia",
pages = "81-81",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2128"
}

Ristivojević, B., Kotur, N., Tošić, N., Stanković, B., Gašić, V., Pavlović, Đ., Jelovac, M., Milošević, G., Pavlović, S.,& Zukić, B.. (2023). NUDT15 as potential marker for pharmacogenetic-guided 6-mercaptopurine therapy in children with acute lymphoblastic leukemia in Serbia. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade., 81-81.
https://hdl.handle.net/21.15107/rcub_imagine_2128

Ristivojević B, Kotur N, Tošić N, Stanković B, Gašić V, Pavlović Đ, Jelovac M, Milošević G, Pavlović S, Zukić B. NUDT15 as potential marker for pharmacogenetic-guided 6-mercaptopurine therapy in children with acute lymphoblastic leukemia in Serbia. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia. 2023;:81-81.
https://hdl.handle.net/21.15107/rcub_imagine_2128 .

Ristivojević, Bojan, Kotur, Nikola, Tošić, Nataša, Stanković, Biljana, Gašić, Vladimir, Pavlović, Đorđe, Jelovac, Marina, Milošević, Goran, Pavlović, Sonja, Zukić, Branka, "NUDT15 as potential marker for pharmacogenetic-guided 6-mercaptopurine therapy in children with acute lymphoblastic leukemia in Serbia" in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia (2023):81-81,
https://hdl.handle.net/21.15107/rcub_imagine_2128 .

TY  - CONF
AU  - Gašić, Vladimir
AU  - Kotur, Nikola
AU  - Stanković, Biljana
AU  - Pavlović, Đorđe
AU  - Jelovac, Marina
AU  - Perić, Jelena
AU  - Ristivojević, Bojan
AU  - Pavlović, Sonja
AU  - Zukić, Branka
PY  - 2023
UR  - https://belbi.bg.ac.rs/
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2040
AB  - Acute lymphoblastic leukemia (ALL) is the most common childhood neoplasm. Side
effects of therapy occur in 75% of patients and 1-3% of patients have a lethal outcome due
to treatment. More efficient treatment of pediatric ALL has been developed by avoiding
drug adverse effects included in the treatment protocols. Therefore, implementation of
pharmacogenomics is paramount in pediatric ALL treatment. Next generation sequencing
(NGS) contributed to discovery of novel genetic markers, potential candidates for targeted
therapy and predictors of efficacy and toxicity of drugs.
We aimed to discover novel potential pharmacogenomic markers in pediatric ALL.
DNA samples from bone marrow of 17 pediatric ALL patients were analyzed using
the platform TruSeq Amplicon – Cancer Panel (Ilumina) for somatic mutations in 48
oncogenes. DNA samples from blood of 100 individuals, using the platform TruSightOne
(Ilumina), were analyzed for germinative mutations. An in-house virtual panel for GC
response markers was designed. Predicting the effects of novel variants was performed
using the SIFT, PolyPhen-2 and PROVEAN software tools. For protein structure stability
and modeling we used STRUM method and i-TASSER server.
In the NGS study of somatic mutations in pediatric ALL, 9 novel variants have been
identified. Bioinformatic analysis has shown that STK11 c.1023G>T and ERBB2 c.2341C>T
possess potential as pharmacogenomic markers, therefore, they are candidates for
molecular targeted therapy. In the exome sequencing study, according to the prediction
algorithms, 3 new potential markers in pharmacogenes related to GC response have been
identified, ABCB1 c.947A>G, NCOA3 rs138733364 and TBX21 rs14059812.
Using NGS analysis and prediction algorithms, we have detected 2 novel somatic mutations,
candidates for targeted molecular therapy, as well as 3 novel germinative variants,
potential pharmacogenomic markers of GC response in pediatric ALL. Pharmacogenomic
profiling of each pediatric ALL patient is indispensable for new therapy approaches and it
could lead to better outcomes.
PB  - Belgrade : Institute of molecular genetics and genetic engineering
C3  - 4th Belgrade Bioinformatics Conference
T1  - In Silico analysis and prediction of novel pharmacogenomic markers of pediatric ALL treatment
EP  - 95
SP  - 95
VL  - 4
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2040
ER  - 

@conference{
author = "Gašić, Vladimir and Kotur, Nikola and Stanković, Biljana and Pavlović, Đorđe and Jelovac, Marina and Perić, Jelena and Ristivojević, Bojan and Pavlović, Sonja and Zukić, Branka",
year = "2023",
abstract = "Acute lymphoblastic leukemia (ALL) is the most common childhood neoplasm. Side
effects of therapy occur in 75% of patients and 1-3% of patients have a lethal outcome due
to treatment. More efficient treatment of pediatric ALL has been developed by avoiding
drug adverse effects included in the treatment protocols. Therefore, implementation of
pharmacogenomics is paramount in pediatric ALL treatment. Next generation sequencing
(NGS) contributed to discovery of novel genetic markers, potential candidates for targeted
therapy and predictors of efficacy and toxicity of drugs.
We aimed to discover novel potential pharmacogenomic markers in pediatric ALL.
DNA samples from bone marrow of 17 pediatric ALL patients were analyzed using
the platform TruSeq Amplicon – Cancer Panel (Ilumina) for somatic mutations in 48
oncogenes. DNA samples from blood of 100 individuals, using the platform TruSightOne
(Ilumina), were analyzed for germinative mutations. An in-house virtual panel for GC
response markers was designed. Predicting the effects of novel variants was performed
using the SIFT, PolyPhen-2 and PROVEAN software tools. For protein structure stability
and modeling we used STRUM method and i-TASSER server.
In the NGS study of somatic mutations in pediatric ALL, 9 novel variants have been
identified. Bioinformatic analysis has shown that STK11 c.1023G>T and ERBB2 c.2341C>T
possess potential as pharmacogenomic markers, therefore, they are candidates for
molecular targeted therapy. In the exome sequencing study, according to the prediction
algorithms, 3 new potential markers in pharmacogenes related to GC response have been
identified, ABCB1 c.947A>G, NCOA3 rs138733364 and TBX21 rs14059812.
Using NGS analysis and prediction algorithms, we have detected 2 novel somatic mutations,
candidates for targeted molecular therapy, as well as 3 novel germinative variants,
potential pharmacogenomic markers of GC response in pediatric ALL. Pharmacogenomic
profiling of each pediatric ALL patient is indispensable for new therapy approaches and it
could lead to better outcomes.",
publisher = "Belgrade : Institute of molecular genetics and genetic engineering",
journal = "4th Belgrade Bioinformatics Conference",
title = "In Silico analysis and prediction of novel pharmacogenomic markers of pediatric ALL treatment",
pages = "95-95",
volume = "4",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2040"
}

Gašić, V., Kotur, N., Stanković, B., Pavlović, Đ., Jelovac, M., Perić, J., Ristivojević, B., Pavlović, S.,& Zukić, B.. (2023). In Silico analysis and prediction of novel pharmacogenomic markers of pediatric ALL treatment. in 4th Belgrade Bioinformatics Conference
Belgrade : Institute of molecular genetics and genetic engineering., 4, 95-95.
https://hdl.handle.net/21.15107/rcub_imagine_2040

Gašić V, Kotur N, Stanković B, Pavlović Đ, Jelovac M, Perić J, Ristivojević B, Pavlović S, Zukić B. In Silico analysis and prediction of novel pharmacogenomic markers of pediatric ALL treatment. in 4th Belgrade Bioinformatics Conference. 2023;4:95-95.
https://hdl.handle.net/21.15107/rcub_imagine_2040 .

Gašić, Vladimir, Kotur, Nikola, Stanković, Biljana, Pavlović, Đorđe, Jelovac, Marina, Perić, Jelena, Ristivojević, Bojan, Pavlović, Sonja, Zukić, Branka, "In Silico analysis and prediction of novel pharmacogenomic markers of pediatric ALL treatment" in 4th Belgrade Bioinformatics Conference, 4 (2023):95-95,
https://hdl.handle.net/21.15107/rcub_imagine_2040 .

TY  - CONF
AU  - Kotur, Nikola
AU  - Skakić, Anita
AU  - Klaassen, Kristel
AU  - Gašić, Vladimir
AU  - Jelovac, Marina
AU  - Ristivojević, Bojan
AU  - Zukić, Branka
AU  - Pavlović, Sonja
AU  - Stanković, Biljana
PY  - 2023
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1904
AB  - COVID-19 pandemic has proved to be an unrelenting health threat for more than a year now. The
emerging amount of data indicates that vitamin D could be important for clinical presentation of
COVID-19. Here, we investigated association of genetic variants related to the altered level and
bioavailability of vitamin D with clinical severity of COVID-19. We analyzed variants in genes
significant for the status of vitamin D (DHCR7/NADSYN1 rs12785878, GC rs2282679, and CYP2R1
rs10741657), and vitamin D effect (VDR rs2228570) in 120 Serbian adult and pediatric COVID-19
patients using allelic discrimination. Furthermore, we carried out comparative population genetic
analysis among European and other worldwide populations to investigate variation in allelic
frequencies of selected variants. The results showed that DHCR7/NADSYN rs12785878 and CYP2R1
rs10741657 variants were associated with severe COVID-19 in adults (p = 0.03, p = 0.017,
respectively); carriers of DHCR7/NADSYN TG+GG and CYP2R1 GG genotypes had 0.21 and 5.9 the
odds for developing severe disease, OR 0.21 (0.05–0.9) and OR 5.9 (1.4–25.2), respectively. There
were no associations between selected genetic variants and disease severity in pediatric patients.
Comparative population genetic analysis revealed that Serbian population had the lowest frequency of
CYP2R1 rs10741657 G allele compared to other non-Finish Europeans (0.58 compared to 0.69 and
0.66 in Spanish and Italian population, respectively), suggesting that other populations should also
investigate the relationship of CYP2R1 variant and the COVID-19 disease course. The results of the
study indicated that vitamin D related genetic variants were implicated in severe COVID-19 in adults.
This could direct prevention strategies based on population specific nutrigenetic profiles.
PB  - Sarajevo : Institute for Genetic Engineering and Biotechnology, University of Sarajevo
C3  - Genetics & Applications
T1  - Covid-19 disease severity associated with vitamin d related genetic Variants
IS  - 2 (Special edition
SP  - 144
VL  - 7
UR  - https://hdl.handle.net/21.15107/rcub_imagine_1904
ER  - 

@conference{
author = "Kotur, Nikola and Skakić, Anita and Klaassen, Kristel and Gašić, Vladimir and Jelovac, Marina and Ristivojević, Bojan and Zukić, Branka and Pavlović, Sonja and Stanković, Biljana",
year = "2023",
abstract = "COVID-19 pandemic has proved to be an unrelenting health threat for more than a year now. The
emerging amount of data indicates that vitamin D could be important for clinical presentation of
COVID-19. Here, we investigated association of genetic variants related to the altered level and
bioavailability of vitamin D with clinical severity of COVID-19. We analyzed variants in genes
significant for the status of vitamin D (DHCR7/NADSYN1 rs12785878, GC rs2282679, and CYP2R1
rs10741657), and vitamin D effect (VDR rs2228570) in 120 Serbian adult and pediatric COVID-19
patients using allelic discrimination. Furthermore, we carried out comparative population genetic
analysis among European and other worldwide populations to investigate variation in allelic
frequencies of selected variants. The results showed that DHCR7/NADSYN rs12785878 and CYP2R1
rs10741657 variants were associated with severe COVID-19 in adults (p = 0.03, p = 0.017,
respectively); carriers of DHCR7/NADSYN TG+GG and CYP2R1 GG genotypes had 0.21 and 5.9 the
odds for developing severe disease, OR 0.21 (0.05–0.9) and OR 5.9 (1.4–25.2), respectively. There
were no associations between selected genetic variants and disease severity in pediatric patients.
Comparative population genetic analysis revealed that Serbian population had the lowest frequency of
CYP2R1 rs10741657 G allele compared to other non-Finish Europeans (0.58 compared to 0.69 and
0.66 in Spanish and Italian population, respectively), suggesting that other populations should also
investigate the relationship of CYP2R1 variant and the COVID-19 disease course. The results of the
study indicated that vitamin D related genetic variants were implicated in severe COVID-19 in adults.
This could direct prevention strategies based on population specific nutrigenetic profiles.",
publisher = "Sarajevo : Institute for Genetic Engineering and Biotechnology, University of Sarajevo",
journal = "Genetics & Applications",
title = "Covid-19 disease severity associated with vitamin d related genetic Variants",
number = "2 (Special edition",
pages = "144",
volume = "7",
url = "https://hdl.handle.net/21.15107/rcub_imagine_1904"
}

Kotur, N., Skakić, A., Klaassen, K., Gašić, V., Jelovac, M., Ristivojević, B., Zukić, B., Pavlović, S.,& Stanković, B.. (2023). Covid-19 disease severity associated with vitamin d related genetic Variants. in Genetics & Applications
Sarajevo : Institute for Genetic Engineering and Biotechnology, University of Sarajevo., 7(2 (Special edition), 144.
https://hdl.handle.net/21.15107/rcub_imagine_1904

Kotur N, Skakić A, Klaassen K, Gašić V, Jelovac M, Ristivojević B, Zukić B, Pavlović S, Stanković B. Covid-19 disease severity associated with vitamin d related genetic Variants. in Genetics & Applications. 2023;7(2 (Special edition):144.
https://hdl.handle.net/21.15107/rcub_imagine_1904 .

Kotur, Nikola, Skakić, Anita, Klaassen, Kristel, Gašić, Vladimir, Jelovac, Marina, Ristivojević, Bojan, Zukić, Branka, Pavlović, Sonja, Stanković, Biljana, "Covid-19 disease severity associated with vitamin d related genetic Variants" in Genetics & Applications, 7, no. 2 (Special edition (2023):144,
https://hdl.handle.net/21.15107/rcub_imagine_1904 .

TY  - CONF
AU  - Jelovac, Marina
AU  - Kotur, Nikola
AU  - Ristivojević, Bojan
AU  - Pavlović, Đorđe
AU  - Spasovski, Vesna
AU  - Damjanov, Nemanja
AU  - Pavlović, Sonja
AU  - Zukić, Branka
PY  - 2023
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2119
AB  - Introduction: Systemic sclerosis(SSc) is a rare autoimmune disorder that affects connective tissues and
hasthe highest morbidity and mortality among rheumatologic diseases. Clinical presentations as well as
disease progression are highly heterogeneous between patients, implying a strong need for individualization of therapy.
Methods: Four pharmacogenetic variants, namely TPMT rs1800460, TPMT rs1142345, MTHFR rs1801133
and SLCO1B1 rs4149056 were tested for association with severe disease outcomes in 102 patients with
SSc from Serbia treated either with immunosuppressants azathioprine (AZA) and methotrexate (MTX) or
with other types of medications. Genotyping was performed using PCR-RFLP and direct Sanger sequencing. R software was used for statistical analysis and development of polygenic risk score (PRS)
model.
Results: Association wasfound between MTHFR rs1801133 and higher risk for elevated systolic pressure
in all patients except those prescribed with MTX, and higher risk for kidney insufficiency in patients prescribed with other types of drugs. In patients treated with MTX, variant SLCO1B1 rs4149056 was protective against kidney insufficiency. For patients receiving MTX a trend was shown for having a higher PRS
rank and elevated systolic pressure.
Conclusion: Our results open a door wide for more extensive research on pharmacogenomics markers
in patients with SSc. Altogether, pharmacogenomics markers could predict the outcome of patients with
SSc and help in prevention of adverse drug reactions
PB  - Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade
C3  - CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
T1  - Can pharmacogenetic variants in TPMT, MTHFR and SLCO1B1 genes be used as potential markers of outcome prediction in systemic sclerosis patients?
EP  - 64
SP  - 64
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2119
ER  - 

@conference{
author = "Jelovac, Marina and Kotur, Nikola and Ristivojević, Bojan and Pavlović, Đorđe and Spasovski, Vesna and Damjanov, Nemanja and Pavlović, Sonja and Zukić, Branka",
year = "2023",
abstract = "Introduction: Systemic sclerosis(SSc) is a rare autoimmune disorder that affects connective tissues and
hasthe highest morbidity and mortality among rheumatologic diseases. Clinical presentations as well as
disease progression are highly heterogeneous between patients, implying a strong need for individualization of therapy.
Methods: Four pharmacogenetic variants, namely TPMT rs1800460, TPMT rs1142345, MTHFR rs1801133
and SLCO1B1 rs4149056 were tested for association with severe disease outcomes in 102 patients with
SSc from Serbia treated either with immunosuppressants azathioprine (AZA) and methotrexate (MTX) or
with other types of medications. Genotyping was performed using PCR-RFLP and direct Sanger sequencing. R software was used for statistical analysis and development of polygenic risk score (PRS)
model.
Results: Association wasfound between MTHFR rs1801133 and higher risk for elevated systolic pressure
in all patients except those prescribed with MTX, and higher risk for kidney insufficiency in patients prescribed with other types of drugs. In patients treated with MTX, variant SLCO1B1 rs4149056 was protective against kidney insufficiency. For patients receiving MTX a trend was shown for having a higher PRS
rank and elevated systolic pressure.
Conclusion: Our results open a door wide for more extensive research on pharmacogenomics markers
in patients with SSc. Altogether, pharmacogenomics markers could predict the outcome of patients with
SSc and help in prevention of adverse drug reactions",
publisher = "Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade",
journal = "CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia",
title = "Can pharmacogenetic variants in TPMT, MTHFR and SLCO1B1 genes be used as potential markers of outcome prediction in systemic sclerosis patients?",
pages = "64-64",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2119"
}

Jelovac, M., Kotur, N., Ristivojević, B., Pavlović, Đ., Spasovski, V., Damjanov, N., Pavlović, S.,& Zukić, B.. (2023). Can pharmacogenetic variants in TPMT, MTHFR and SLCO1B1 genes be used as potential markers of outcome prediction in systemic sclerosis patients?. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade., 64-64.
https://hdl.handle.net/21.15107/rcub_imagine_2119

Jelovac M, Kotur N, Ristivojević B, Pavlović Đ, Spasovski V, Damjanov N, Pavlović S, Zukić B. Can pharmacogenetic variants in TPMT, MTHFR and SLCO1B1 genes be used as potential markers of outcome prediction in systemic sclerosis patients?. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia. 2023;:64-64.
https://hdl.handle.net/21.15107/rcub_imagine_2119 .

Jelovac, Marina, Kotur, Nikola, Ristivojević, Bojan, Pavlović, Đorđe, Spasovski, Vesna, Damjanov, Nemanja, Pavlović, Sonja, Zukić, Branka, "Can pharmacogenetic variants in TPMT, MTHFR and SLCO1B1 genes be used as potential markers of outcome prediction in systemic sclerosis patients?" in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia (2023):64-64,
https://hdl.handle.net/21.15107/rcub_imagine_2119 .

TY  - CONF
AU  - Ristivojević, Bojan
AU  - Kotur, Nikola
AU  - Stanković, Biljana
AU  - Gašić, Vladimir
AU  - Pavlović, Đorđe
AU  - Jelovac, Marina
AU  - Pavlović, Sonja
AU  - Zukić, Branka
PY  - 2023
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1902
AB  - Vincristine (VCR) is one of the key drugs in current treatment protocols for pediatric acute
lymphoblastic leukemia (ALL). By destabilization of microtubules, VCR arrests cells in metaphase,
inducing apoptosis of malignant cells. VCR also causes axonal degradation and impairment of axonal
transport, which leads to vincristine-induced peripheral neuropathy (VIPN). The aim of this study was
to determine if the selected genetic variants are associated with the development of VIPN in ALL
children treated with VCR in Serbia. This study also aimed to discover candidate pharmacogenomic
markers of VIPN in Serbian population. PCR and sequencing-based methodology was used to detect
variants in following genes: CYP3А5 (rs776746), CEP72 (rs924607), ACTG1 (rs1135989), MIR3117
(rs12402181) and MIR4481 (rs7896283). Statistical analyses were performed for investigation of their
association with VIPN in 56 pediatric ALL patients. Population VCR pharmacogenomics analysis of 17
pharmacogenes from in-house next-generation sequencing data was also done. Data on allele frequency
distribution for European population were extracted from public databases. During the treatment,
17.86% of patients developed VIPN. Association analyses have shown that none of the investigated
genetic variants contributed to the occurrence of VIPN in our study group. Population
pharmacogenomics study didn’t reveal valid candidate pharmacovariants for the occurrence of VIPN.
Our results suggested that pre-emptive pharmacogenetic testing for VCR is not applicable. More
comprehensive approaches are needed to identify panel of genes that could explain the VIPN
development after VCR administration in ALL patients. Utilizing better designed GWAS studies and
more robust artificial intelligence-based tools would provide a panel of pharmacogenes for pre-emptive
tests of VIPN to individualize therapy for ALL in children.
PB  - Sarajevo : Institute for Genetic Engineering and Biotechnology, University of Sarajevo
C3  - Genetics & Applications
T1  - The pharmacogenomics of vincristine-induced peripheral neuropathy in pediatric acute lymphoblastic leukemia patients in Serbia
IS  - 2 (Special edition)
SP  - 109
VL  - 7
UR  - https://hdl.handle.net/21.15107/rcub_imagine_1902
ER  - 

@conference{
author = "Ristivojević, Bojan and Kotur, Nikola and Stanković, Biljana and Gašić, Vladimir and Pavlović, Đorđe and Jelovac, Marina and Pavlović, Sonja and Zukić, Branka",
year = "2023",
abstract = "Vincristine (VCR) is one of the key drugs in current treatment protocols for pediatric acute
lymphoblastic leukemia (ALL). By destabilization of microtubules, VCR arrests cells in metaphase,
inducing apoptosis of malignant cells. VCR also causes axonal degradation and impairment of axonal
transport, which leads to vincristine-induced peripheral neuropathy (VIPN). The aim of this study was
to determine if the selected genetic variants are associated with the development of VIPN in ALL
children treated with VCR in Serbia. This study also aimed to discover candidate pharmacogenomic
markers of VIPN in Serbian population. PCR and sequencing-based methodology was used to detect
variants in following genes: CYP3А5 (rs776746), CEP72 (rs924607), ACTG1 (rs1135989), MIR3117
(rs12402181) and MIR4481 (rs7896283). Statistical analyses were performed for investigation of their
association with VIPN in 56 pediatric ALL patients. Population VCR pharmacogenomics analysis of 17
pharmacogenes from in-house next-generation sequencing data was also done. Data on allele frequency
distribution for European population were extracted from public databases. During the treatment,
17.86% of patients developed VIPN. Association analyses have shown that none of the investigated
genetic variants contributed to the occurrence of VIPN in our study group. Population
pharmacogenomics study didn’t reveal valid candidate pharmacovariants for the occurrence of VIPN.
Our results suggested that pre-emptive pharmacogenetic testing for VCR is not applicable. More
comprehensive approaches are needed to identify panel of genes that could explain the VIPN
development after VCR administration in ALL patients. Utilizing better designed GWAS studies and
more robust artificial intelligence-based tools would provide a panel of pharmacogenes for pre-emptive
tests of VIPN to individualize therapy for ALL in children.",
publisher = "Sarajevo : Institute for Genetic Engineering and Biotechnology, University of Sarajevo",
journal = "Genetics & Applications",
title = "The pharmacogenomics of vincristine-induced peripheral neuropathy in pediatric acute lymphoblastic leukemia patients in Serbia",
number = "2 (Special edition)",
pages = "109",
volume = "7",
url = "https://hdl.handle.net/21.15107/rcub_imagine_1902"
}

Ristivojević, B., Kotur, N., Stanković, B., Gašić, V., Pavlović, Đ., Jelovac, M., Pavlović, S.,& Zukić, B.. (2023). The pharmacogenomics of vincristine-induced peripheral neuropathy in pediatric acute lymphoblastic leukemia patients in Serbia. in Genetics & Applications
Sarajevo : Institute for Genetic Engineering and Biotechnology, University of Sarajevo., 7(2 (Special edition)), 109.
https://hdl.handle.net/21.15107/rcub_imagine_1902

Ristivojević B, Kotur N, Stanković B, Gašić V, Pavlović Đ, Jelovac M, Pavlović S, Zukić B. The pharmacogenomics of vincristine-induced peripheral neuropathy in pediatric acute lymphoblastic leukemia patients in Serbia. in Genetics & Applications. 2023;7(2 (Special edition)):109.
https://hdl.handle.net/21.15107/rcub_imagine_1902 .

Ristivojević, Bojan, Kotur, Nikola, Stanković, Biljana, Gašić, Vladimir, Pavlović, Đorđe, Jelovac, Marina, Pavlović, Sonja, Zukić, Branka, "The pharmacogenomics of vincristine-induced peripheral neuropathy in pediatric acute lymphoblastic leukemia patients in Serbia" in Genetics & Applications, 7, no. 2 (Special edition) (2023):109,
https://hdl.handle.net/21.15107/rcub_imagine_1902 .

TY  - JOUR
AU  - Ristivojević, Bojan
AU  - Kotur, Nikola
AU  - Stanković, Biljana
AU  - Gašić, Vladimir
AU  - Lazić, Jelena
AU  - Pavlović, Sonja
AU  - Zukić, Branka
PY  - 2022
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1569
AB  - Uvod/Cilj Vinkristin je jedan od ključnih lekova u protokolima lečenja dečje akutne limfoblastne leukemije (ALL). Vinkristin dovodi do destabilizacije mikrotubula, čime se ćelija zaustavlja u metafazi i indukuje apoptoza. Takođe dovodi do degradacije aksona i poremećaja aksonskog transporta, uzrokujući vinkristinom indukovanu perifernu neuropatiju (VIPN). Cilj ove studije bio je da istraži povezanost pet varijanti u farmakogenima uključenim u metabolizam vinkristina kod dece obolele od ALL koja su razvila VIPN, u Srbiji. Takođe, cilj nam je bio da otkrijemo kandidate za nove farmakogenomske markere VIPN-a u srpskoj populaciji. Metode Detekcija varijanti gena CYP3A5, CEP72, ACTG1, MIR3117 i MIR4481 izvedena je metodologijom zasnovanom na PCR-u i sekvenciranju. Statističkim metodama je ispitana njihova asocijacija sa VIPN-om kod 56 pedijatrijskih bolesnika obolelih od ALL. Urađena je i populaciona vinkristin farmakogenomska analiza 17 farmakogena iz postojećih podataka dobijenih sekvenciranjem nove generacije u srpskoj populaciji. Podaci o distribuciji frekvencija alela za evropsko stanovništvo preuzeti su iz javnih baza podataka. Rezultati Tokom lečenja, 17,86% bolesnika je razvilo VIPN. Asocijativne analize pokazale su da nijedna genetička varijanta nije bila povezana sa VIPN-om u našoj studiji. Naše populaciono farmakogenomsko istraživanje nije otkrilo validne farmakovarijante za VIPN. Naši rezultati ne preporučuju preventivno farmakogenetičko ispitivanje vinkristina u Srbiji. Zaključak Potreban je sveobuhvatniji pristup kako bi se identifikovao panel gena kojim bi se mogao objasniti razvoj VIPN-a posle primene vinkristina kod pedijatrijskih bolesnika obolelih od ALL. Bolje osmišljene studije asocijacija na nivou genoma (GWAS) i robusniji alati koji koriste veštačku inteligenciju doveli bi do dizajniranja panela farmakogena za preventivno testiranje predispozicije za razvoj VIPN-a, doprinoseći individualizaciji i unapređenju terapije dece obolele od ALL.
AB  - Introduction/Objective Vincristine (VCR) is one of the key drugs in current treatment protocols for pediatric acute lymphoblastic leukemia (ALL). By destabilizing microtubules, VCR arrests cells in metaphase, inducing apoptosis of malignant cells. VCR also causes axonal degradation and impairment of axonal transport, which leads to VCR-induced peripheral neuropathy (VIPN). This study aimed to investigate the association of five variants in pharmacogenes involved in VCR metabolism with VIPN in Serbian ALL children. We also wanted to discover candidate pharmacogenomic markers of VIPN in Serbian population. Methods PCR and sequencing-based methodology was used to detect variants in CYP3A5, CEP72, ACTG1, MIR3117, and MIR4481 genes. Statistical analyses were performed for investigating their association with VIPN in 56 pediatric ALL patients. Population VCR pharmacogenomics analysis of 17 pharmacogenes from in-house next-generation sequencing data was also done. Data on allele frequency distribution for the European population were extracted from public databases. Results During the treatment, 17.86% of patients developed VIPN. Association analyses have shown that none of the genetic variants contributed to the occurrence of VIPN in our study. Population pharmacogenomics study did not reveal valid candidate pharmacovariants for VIPN. Our results suggested that pre-emptive pharmacogenetic testing for VCR is not applicable presently. Conclusion More comprehensive approaches are needed to identify the panel of genes that could explain the VIPN development after VCR administration in ALL patients. Utilizing better designed genome-wide association studies and more robust artificial intelligence-based tools would provide a panel of pharmacogenes for pre-emptive tests of VIPN to individualize therapy for ALL in children.
PB  - Srpsko lekarsko društvo, Beograd
T2  - Srpski arhiv za celokupno lekarstvo
T1  - Farmakogenomika vinkristinom indukovane periferne neuropatije kod dece sa akutnom limfoblastnom leukemijom u Srbiji - iskustvo jednog centra
T1  - The pharmacogenomics of vincristine-induced peripheral neuropathy in pediatric acute lymphoblastic leukemia patients in Serbia: A single center experience
EP  - 58
IS  - 1-2
SP  - 53
VL  - 150
DO  - 10.2298/SARH210813099R
ER  - 

@article{
author = "Ristivojević, Bojan and Kotur, Nikola and Stanković, Biljana and Gašić, Vladimir and Lazić, Jelena and Pavlović, Sonja and Zukić, Branka",
year = "2022",
abstract = "Uvod/Cilj Vinkristin je jedan od ključnih lekova u protokolima lečenja dečje akutne limfoblastne leukemije (ALL). Vinkristin dovodi do destabilizacije mikrotubula, čime se ćelija zaustavlja u metafazi i indukuje apoptoza. Takođe dovodi do degradacije aksona i poremećaja aksonskog transporta, uzrokujući vinkristinom indukovanu perifernu neuropatiju (VIPN). Cilj ove studije bio je da istraži povezanost pet varijanti u farmakogenima uključenim u metabolizam vinkristina kod dece obolele od ALL koja su razvila VIPN, u Srbiji. Takođe, cilj nam je bio da otkrijemo kandidate za nove farmakogenomske markere VIPN-a u srpskoj populaciji. Metode Detekcija varijanti gena CYP3A5, CEP72, ACTG1, MIR3117 i MIR4481 izvedena je metodologijom zasnovanom na PCR-u i sekvenciranju. Statističkim metodama je ispitana njihova asocijacija sa VIPN-om kod 56 pedijatrijskih bolesnika obolelih od ALL. Urađena je i populaciona vinkristin farmakogenomska analiza 17 farmakogena iz postojećih podataka dobijenih sekvenciranjem nove generacije u srpskoj populaciji. Podaci o distribuciji frekvencija alela za evropsko stanovništvo preuzeti su iz javnih baza podataka. Rezultati Tokom lečenja, 17,86% bolesnika je razvilo VIPN. Asocijativne analize pokazale su da nijedna genetička varijanta nije bila povezana sa VIPN-om u našoj studiji. Naše populaciono farmakogenomsko istraživanje nije otkrilo validne farmakovarijante za VIPN. Naši rezultati ne preporučuju preventivno farmakogenetičko ispitivanje vinkristina u Srbiji. Zaključak Potreban je sveobuhvatniji pristup kako bi se identifikovao panel gena kojim bi se mogao objasniti razvoj VIPN-a posle primene vinkristina kod pedijatrijskih bolesnika obolelih od ALL. Bolje osmišljene studije asocijacija na nivou genoma (GWAS) i robusniji alati koji koriste veštačku inteligenciju doveli bi do dizajniranja panela farmakogena za preventivno testiranje predispozicije za razvoj VIPN-a, doprinoseći individualizaciji i unapređenju terapije dece obolele od ALL., Introduction/Objective Vincristine (VCR) is one of the key drugs in current treatment protocols for pediatric acute lymphoblastic leukemia (ALL). By destabilizing microtubules, VCR arrests cells in metaphase, inducing apoptosis of malignant cells. VCR also causes axonal degradation and impairment of axonal transport, which leads to VCR-induced peripheral neuropathy (VIPN). This study aimed to investigate the association of five variants in pharmacogenes involved in VCR metabolism with VIPN in Serbian ALL children. We also wanted to discover candidate pharmacogenomic markers of VIPN in Serbian population. Methods PCR and sequencing-based methodology was used to detect variants in CYP3A5, CEP72, ACTG1, MIR3117, and MIR4481 genes. Statistical analyses were performed for investigating their association with VIPN in 56 pediatric ALL patients. Population VCR pharmacogenomics analysis of 17 pharmacogenes from in-house next-generation sequencing data was also done. Data on allele frequency distribution for the European population were extracted from public databases. Results During the treatment, 17.86% of patients developed VIPN. Association analyses have shown that none of the genetic variants contributed to the occurrence of VIPN in our study. Population pharmacogenomics study did not reveal valid candidate pharmacovariants for VIPN. Our results suggested that pre-emptive pharmacogenetic testing for VCR is not applicable presently. Conclusion More comprehensive approaches are needed to identify the panel of genes that could explain the VIPN development after VCR administration in ALL patients. Utilizing better designed genome-wide association studies and more robust artificial intelligence-based tools would provide a panel of pharmacogenes for pre-emptive tests of VIPN to individualize therapy for ALL in children.",
publisher = "Srpsko lekarsko društvo, Beograd",
journal = "Srpski arhiv za celokupno lekarstvo",
title = "Farmakogenomika vinkristinom indukovane periferne neuropatije kod dece sa akutnom limfoblastnom leukemijom u Srbiji - iskustvo jednog centra, The pharmacogenomics of vincristine-induced peripheral neuropathy in pediatric acute lymphoblastic leukemia patients in Serbia: A single center experience",
pages = "58-53",
number = "1-2",
volume = "150",
doi = "10.2298/SARH210813099R"
}

Ristivojević, B., Kotur, N., Stanković, B., Gašić, V., Lazić, J., Pavlović, S.,& Zukić, B.. (2022). Farmakogenomika vinkristinom indukovane periferne neuropatije kod dece sa akutnom limfoblastnom leukemijom u Srbiji - iskustvo jednog centra. in Srpski arhiv za celokupno lekarstvo
Srpsko lekarsko društvo, Beograd., 150(1-2), 53-58.
https://doi.org/10.2298/SARH210813099R

Ristivojević B, Kotur N, Stanković B, Gašić V, Lazić J, Pavlović S, Zukić B. Farmakogenomika vinkristinom indukovane periferne neuropatije kod dece sa akutnom limfoblastnom leukemijom u Srbiji - iskustvo jednog centra. in Srpski arhiv za celokupno lekarstvo. 2022;150(1-2):53-58.
doi:10.2298/SARH210813099R .

Ristivojević, Bojan, Kotur, Nikola, Stanković, Biljana, Gašić, Vladimir, Lazić, Jelena, Pavlović, Sonja, Zukić, Branka, "Farmakogenomika vinkristinom indukovane periferne neuropatije kod dece sa akutnom limfoblastnom leukemijom u Srbiji - iskustvo jednog centra" in Srpski arhiv za celokupno lekarstvo, 150, no. 1-2 (2022):53-58,
https://doi.org/10.2298/SARH210813099R . .

TY  - JOUR
AU  - Zecević, Marko
AU  - Kotur, Nikola
AU  - Ristivojević, Bojan
AU  - Gašić, Vladimir
AU  - Skodrić-Trifunović, Vesna
AU  - Stjepanović, Mihailo
AU  - Stevanović, Goran
AU  - Lavadinović, Lidija
AU  - Zukić, Branka
AU  - Pavlović, Sonja
AU  - Stanković, Biljana
PY  - 2022
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1515
AB  - Host genetics, an important contributor to the COVID-19 clinical susceptibility and severity, currently is the focus of multiple genome-wide association studies (GWAS) in populations affected by the pandemic. This is the first study from Serbia that performed a GWAS of COVID-19 outcomes to identify genetic risk markers of disease severity. A group of 128 hospitalized COVID-19 patients from the Serbian population was enrolled in the study. We conducted a GWAS comparing (1) patients with pneumonia (n = 80) against patients without pneumonia (n = 48), and (2) severe (n = 34) against mild disease (n = 48) patients, using a genotyping array followed by imputation of missing genotypes. We have detected a significant signal associated with COVID-19 related pneumonia at locus 13q21.33, with a peak residing upstream of the gene KLHL1 (p = 1.91 x 10(-8)). Our study also replicated a previously reported COVID-19 risk locus at 3p21.31, identifying lead variants in SACM1L and LZTFL1 genes suggestively associated with pneumonia (p = 7.54 x 10(-6)) and severe COVID-19 (p = 6.88 x 10(-7)), respectively. Suggestive association with COVID-19 pneumonia has also been observed at chromosomes 5p15.33 (IRX, NDUFS6, MRPL36, p = 2.81 x 10(-6)), 5q11.2 (ESM1, p = 6.59 x 10(-6)), and 9p23 (TYRP1, LURAP1L, p = 8.69 x 10(-6)). The genes located in or near the risk loci are expressed in neural or lung tissues, and have been previously associated with respiratory diseases such as asthma and COVID-19 or reported as differentially expressed in COVID-19 gene expression profiling studies. Our results revealed novel risk loci for pneumonia and severe COVID-19 disease which could contribute to a better understanding of the COVID-19 host genetics in different populations.
PB  - Frontiers Media Sa, Lausanne
T2  - Frontiers in Genetics
T1  - Genome-Wide Association Study of COVID-19 Outcomes Reveals Novel Host Genetic Risk Loci in the Serbian Population
VL  - 13
DO  - 10.3389/fgene.2022.911010
ER  - 

@article{
author = "Zecević, Marko and Kotur, Nikola and Ristivojević, Bojan and Gašić, Vladimir and Skodrić-Trifunović, Vesna and Stjepanović, Mihailo and Stevanović, Goran and Lavadinović, Lidija and Zukić, Branka and Pavlović, Sonja and Stanković, Biljana",
year = "2022",
abstract = "Host genetics, an important contributor to the COVID-19 clinical susceptibility and severity, currently is the focus of multiple genome-wide association studies (GWAS) in populations affected by the pandemic. This is the first study from Serbia that performed a GWAS of COVID-19 outcomes to identify genetic risk markers of disease severity. A group of 128 hospitalized COVID-19 patients from the Serbian population was enrolled in the study. We conducted a GWAS comparing (1) patients with pneumonia (n = 80) against patients without pneumonia (n = 48), and (2) severe (n = 34) against mild disease (n = 48) patients, using a genotyping array followed by imputation of missing genotypes. We have detected a significant signal associated with COVID-19 related pneumonia at locus 13q21.33, with a peak residing upstream of the gene KLHL1 (p = 1.91 x 10(-8)). Our study also replicated a previously reported COVID-19 risk locus at 3p21.31, identifying lead variants in SACM1L and LZTFL1 genes suggestively associated with pneumonia (p = 7.54 x 10(-6)) and severe COVID-19 (p = 6.88 x 10(-7)), respectively. Suggestive association with COVID-19 pneumonia has also been observed at chromosomes 5p15.33 (IRX, NDUFS6, MRPL36, p = 2.81 x 10(-6)), 5q11.2 (ESM1, p = 6.59 x 10(-6)), and 9p23 (TYRP1, LURAP1L, p = 8.69 x 10(-6)). The genes located in or near the risk loci are expressed in neural or lung tissues, and have been previously associated with respiratory diseases such as asthma and COVID-19 or reported as differentially expressed in COVID-19 gene expression profiling studies. Our results revealed novel risk loci for pneumonia and severe COVID-19 disease which could contribute to a better understanding of the COVID-19 host genetics in different populations.",
publisher = "Frontiers Media Sa, Lausanne",
journal = "Frontiers in Genetics",
title = "Genome-Wide Association Study of COVID-19 Outcomes Reveals Novel Host Genetic Risk Loci in the Serbian Population",
volume = "13",
doi = "10.3389/fgene.2022.911010"
}

Zecević, M., Kotur, N., Ristivojević, B., Gašić, V., Skodrić-Trifunović, V., Stjepanović, M., Stevanović, G., Lavadinović, L., Zukić, B., Pavlović, S.,& Stanković, B.. (2022). Genome-Wide Association Study of COVID-19 Outcomes Reveals Novel Host Genetic Risk Loci in the Serbian Population. in Frontiers in Genetics
Frontiers Media Sa, Lausanne., 13.
https://doi.org/10.3389/fgene.2022.911010

Zecević M, Kotur N, Ristivojević B, Gašić V, Skodrić-Trifunović V, Stjepanović M, Stevanović G, Lavadinović L, Zukić B, Pavlović S, Stanković B. Genome-Wide Association Study of COVID-19 Outcomes Reveals Novel Host Genetic Risk Loci in the Serbian Population. in Frontiers in Genetics. 2022;13.
doi:10.3389/fgene.2022.911010 .

Zecević, Marko, Kotur, Nikola, Ristivojević, Bojan, Gašić, Vladimir, Skodrić-Trifunović, Vesna, Stjepanović, Mihailo, Stevanović, Goran, Lavadinović, Lidija, Zukić, Branka, Pavlović, Sonja, Stanković, Biljana, "Genome-Wide Association Study of COVID-19 Outcomes Reveals Novel Host Genetic Risk Loci in the Serbian Population" in Frontiers in Genetics, 13 (2022),
https://doi.org/10.3389/fgene.2022.911010 . .

TY  - JOUR
AU  - Kotur, Nikola
AU  - Lazić, Jelena
AU  - Ristivojević, Bojan
AU  - Stanković, Biljana
AU  - Gašić, Vladimir
AU  - Dokmanović, Lidija
AU  - Krstovski, Nada
AU  - Milosević, Goran
AU  - Janić, Dragana
AU  - Zukić, Branka
AU  - Pavlović, Sonja
PY  - 2020
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1322
AB  - Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients.
PB  - MDPI, Basel
T2  - Genes
T1  - Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment
IS  - 4
VL  - 11
DO  - 10.3390/genes11040468
ER  - 

@article{
author = "Kotur, Nikola and Lazić, Jelena and Ristivojević, Bojan and Stanković, Biljana and Gašić, Vladimir and Dokmanović, Lidija and Krstovski, Nada and Milosević, Goran and Janić, Dragana and Zukić, Branka and Pavlović, Sonja",
year = "2020",
abstract = "Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients.",
publisher = "MDPI, Basel",
journal = "Genes",
title = "Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment",
number = "4",
volume = "11",
doi = "10.3390/genes11040468"
}

Kotur, N., Lazić, J., Ristivojević, B., Stanković, B., Gašić, V., Dokmanović, L., Krstovski, N., Milosević, G., Janić, D., Zukić, B.,& Pavlović, S.. (2020). Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment. in Genes
MDPI, Basel., 11(4).
https://doi.org/10.3390/genes11040468

Kotur N, Lazić J, Ristivojević B, Stanković B, Gašić V, Dokmanović L, Krstovski N, Milosević G, Janić D, Zukić B, Pavlović S. Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment. in Genes. 2020;11(4).
doi:10.3390/genes11040468 .

Kotur, Nikola, Lazić, Jelena, Ristivojević, Bojan, Stanković, Biljana, Gašić, Vladimir, Dokmanović, Lidija, Krstovski, Nada, Milosević, Goran, Janić, Dragana, Zukić, Branka, Pavlović, Sonja, "Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment" in Genes, 11, no. 4 (2020),
https://doi.org/10.3390/genes11040468 . .

TY  - JOUR
AU  - Stanković, Biljana
AU  - Kotur, Nikola
AU  - Gašić, Vladimir
AU  - Klaassen, Kristel
AU  - Ristivojević, Bojan
AU  - Stojiljković, Maja
AU  - Pavlović, Sonja
AU  - Zukić, Branka
PY  - 2020
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1362
AB  - Uvod: Kako ne postoje odobreni terapeutici za lečenje pacijenata sa COVID-19, mogućnost upotrebe postojećih lekova je postala važna. U nedostatku vremena za testiranje farmakogenomskih markera kod pojedinaca, populaciona farmakogenomika bi mogla biti od koristi u predviđanju povećanog rizika za pojavu neželjenih reakcija i neuspeha lečenja kod pacijenata sa COVID-19. Cilj naše studije bio je identifikovanje farmakogena i farmakogenomskih markera povezanih sa lekovima koji se preporučuju za lečenje COVID-19, hlorokin/hidroksihlorokin, azitromicin, lopinavir i ritonavir, u populaciji Srbije i drugim svetskim populacijama. Metode: Podaci o genotipu 143 osobe srpskog porekla dobijeni su iz baze podataka prethodno formirane analizama genoma korišćenjem TruSight One Gene Panel (Illumina). Podaci o genotipu pojedinaca iz različitih svetskih populacija dobijeni su iz Projekta 1000 genoma. Fišerov egzaktni test korišćen je za poređenje učestalosti alela. Rezultati: Identifikovali smo 11 potencijalnih farmakogenomskih markera u 7 farmakogena značajnih za lečenje COVID-19. Na osnovu visoke alterativne učestalosti alela u populaciji Srbije i funkcionalnog efekta varijanti, ABCB1 rs1045642 i rs2032582 mogu biti značajne za smanjeni klirens lekova azitromicina, lopinavira i ritonavira, a varijanta UGT1A7 rs17868323 za hiperbilirubinemiju kod bolesnika sa COVID-19 koji se leče ritonavirom. SLCO1B1 rs4149056 je potencijalni marker odgovora na lopinavir, posebno u populaciji Italije. Naši rezultati potvrdili su da se farmakogenomski profil afričke populacije razlikuje od ostatka sveta. Zaključak: Uzimajući u obzir farmakogenomski profil specifičan za populaciju, preventivno testiranje farmakogena značajnih za lekove koji se koriste u lečenju COVID-19 moglo bi doprineti boljem razumevanju interindividualnih razlika u odgovorima na terapiju i poboljšanju ishoda lečenja pacijenata sa COVID-19.
AB  - Background: Since there are no certified therapeutics to treat COVID-19 patients, drug repurposing became important. With lack of time to test individual pharmacogenomics markers, population pharmacogenomics could be helpful in predicting a higher risk of developing adverse reactions and treatment failure in COVID-19 patients. Aim of our study was to identify pharmacogenes and pharmacogenomics markers associated with drugs recommended for COVID-19 treatment, chloroquine/hydroxychloroquine, azithromycin, lopinavir and ritonavir, in population of Serbia and other world populations. Methods: Genotype information of 143 individuals of Serbian origin was extracted from database previously obtained using TruSight One Gene Panel (Illumina). Genotype data of individuals from different world populations were extracted from the 1000 Genome Project. Fisher's exact test was used for comparison of allele frequencies. Results: We have identified 11 potential pharmacogenomics markers in 7 pharmacogenes relevant for COVID-19 treatment. Based on high alternative allele frequencies in population and the functional effect of the variants, ABCB1 rs1045642 and rs2032582 could be relevant for reduced clearance of azithromycin, lopinavir and ritonavir drugs and UGT1A7 rs17868323 for hyperbilirubinemia in ritonavir treated COVID-19 patients in Serbian population. SLCO1B1 rs4149056 is a potential marker of lopinavir response, especially in Italian population. Our results confirmed that pharmacogenomics profile of African population is different from the rest of the world. Conclusions: Considering population specific pharmacogenomics landscape, preemptive testing for pharmacogenes relevant for drugs used in COVID-19 treatment could contribute to better understanding of the inconsistency in therapy response and could be applied to improve the outcome of the COVID-19 patients.
PB  - Društvo medicinskih biohemičara Srbije, Beograd i Versita
T2  - Journal of Medical Biochemistry
T1  - Farmakogenomski profil odgovora na terapiju za COVID-19 u populaciji Srbije i poređenje sa populacijama širom sveta
T1  - Pharmacogenomics landscape of COVID-19 therapy response in Serbian population and comparison with worldwide populations
EP  - 499
IS  - 4
SP  - 488
VL  - 39
DO  - 10.5937/jomb0-26725
ER  - 

@article{
author = "Stanković, Biljana and Kotur, Nikola and Gašić, Vladimir and Klaassen, Kristel and Ristivojević, Bojan and Stojiljković, Maja and Pavlović, Sonja and Zukić, Branka",
year = "2020",
abstract = "Uvod: Kako ne postoje odobreni terapeutici za lečenje pacijenata sa COVID-19, mogućnost upotrebe postojećih lekova je postala važna. U nedostatku vremena za testiranje farmakogenomskih markera kod pojedinaca, populaciona farmakogenomika bi mogla biti od koristi u predviđanju povećanog rizika za pojavu neželjenih reakcija i neuspeha lečenja kod pacijenata sa COVID-19. Cilj naše studije bio je identifikovanje farmakogena i farmakogenomskih markera povezanih sa lekovima koji se preporučuju za lečenje COVID-19, hlorokin/hidroksihlorokin, azitromicin, lopinavir i ritonavir, u populaciji Srbije i drugim svetskim populacijama. Metode: Podaci o genotipu 143 osobe srpskog porekla dobijeni su iz baze podataka prethodno formirane analizama genoma korišćenjem TruSight One Gene Panel (Illumina). Podaci o genotipu pojedinaca iz različitih svetskih populacija dobijeni su iz Projekta 1000 genoma. Fišerov egzaktni test korišćen je za poređenje učestalosti alela. Rezultati: Identifikovali smo 11 potencijalnih farmakogenomskih markera u 7 farmakogena značajnih za lečenje COVID-19. Na osnovu visoke alterativne učestalosti alela u populaciji Srbije i funkcionalnog efekta varijanti, ABCB1 rs1045642 i rs2032582 mogu biti značajne za smanjeni klirens lekova azitromicina, lopinavira i ritonavira, a varijanta UGT1A7 rs17868323 za hiperbilirubinemiju kod bolesnika sa COVID-19 koji se leče ritonavirom. SLCO1B1 rs4149056 je potencijalni marker odgovora na lopinavir, posebno u populaciji Italije. Naši rezultati potvrdili su da se farmakogenomski profil afričke populacije razlikuje od ostatka sveta. Zaključak: Uzimajući u obzir farmakogenomski profil specifičan za populaciju, preventivno testiranje farmakogena značajnih za lekove koji se koriste u lečenju COVID-19 moglo bi doprineti boljem razumevanju interindividualnih razlika u odgovorima na terapiju i poboljšanju ishoda lečenja pacijenata sa COVID-19., Background: Since there are no certified therapeutics to treat COVID-19 patients, drug repurposing became important. With lack of time to test individual pharmacogenomics markers, population pharmacogenomics could be helpful in predicting a higher risk of developing adverse reactions and treatment failure in COVID-19 patients. Aim of our study was to identify pharmacogenes and pharmacogenomics markers associated with drugs recommended for COVID-19 treatment, chloroquine/hydroxychloroquine, azithromycin, lopinavir and ritonavir, in population of Serbia and other world populations. Methods: Genotype information of 143 individuals of Serbian origin was extracted from database previously obtained using TruSight One Gene Panel (Illumina). Genotype data of individuals from different world populations were extracted from the 1000 Genome Project. Fisher's exact test was used for comparison of allele frequencies. Results: We have identified 11 potential pharmacogenomics markers in 7 pharmacogenes relevant for COVID-19 treatment. Based on high alternative allele frequencies in population and the functional effect of the variants, ABCB1 rs1045642 and rs2032582 could be relevant for reduced clearance of azithromycin, lopinavir and ritonavir drugs and UGT1A7 rs17868323 for hyperbilirubinemia in ritonavir treated COVID-19 patients in Serbian population. SLCO1B1 rs4149056 is a potential marker of lopinavir response, especially in Italian population. Our results confirmed that pharmacogenomics profile of African population is different from the rest of the world. Conclusions: Considering population specific pharmacogenomics landscape, preemptive testing for pharmacogenes relevant for drugs used in COVID-19 treatment could contribute to better understanding of the inconsistency in therapy response and could be applied to improve the outcome of the COVID-19 patients.",
publisher = "Društvo medicinskih biohemičara Srbije, Beograd i Versita",
journal = "Journal of Medical Biochemistry",
title = "Farmakogenomski profil odgovora na terapiju za COVID-19 u populaciji Srbije i poređenje sa populacijama širom sveta, Pharmacogenomics landscape of COVID-19 therapy response in Serbian population and comparison with worldwide populations",
pages = "499-488",
number = "4",
volume = "39",
doi = "10.5937/jomb0-26725"
}

Stanković, B., Kotur, N., Gašić, V., Klaassen, K., Ristivojević, B., Stojiljković, M., Pavlović, S.,& Zukić, B.. (2020). Farmakogenomski profil odgovora na terapiju za COVID-19 u populaciji Srbije i poređenje sa populacijama širom sveta. in Journal of Medical Biochemistry
Društvo medicinskih biohemičara Srbije, Beograd i Versita., 39(4), 488-499.
https://doi.org/10.5937/jomb0-26725

Stanković B, Kotur N, Gašić V, Klaassen K, Ristivojević B, Stojiljković M, Pavlović S, Zukić B. Farmakogenomski profil odgovora na terapiju za COVID-19 u populaciji Srbije i poređenje sa populacijama širom sveta. in Journal of Medical Biochemistry. 2020;39(4):488-499.
doi:10.5937/jomb0-26725 .

Stanković, Biljana, Kotur, Nikola, Gašić, Vladimir, Klaassen, Kristel, Ristivojević, Bojan, Stojiljković, Maja, Pavlović, Sonja, Zukić, Branka, "Farmakogenomski profil odgovora na terapiju za COVID-19 u populaciji Srbije i poređenje sa populacijama širom sveta" in Journal of Medical Biochemistry, 39, no. 4 (2020):488-499,
https://doi.org/10.5937/jomb0-26725 . .

TY  - JOUR
AU  - Komazec, Jovana
AU  - Ristivojević, Bojan
AU  - Zukić, Branka
AU  - Zdravković, Vera
AU  - Karan-Đurašević, Teodora
AU  - Pavlović, Sonja
AU  - Ugrin, Milena
PY  - 2020
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1359
AB  - Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes caused by the variants in MODY-related genes. In addition to coding variants, variants in the promoter region of MODY-related genes can cause the disease as well. In this study, we screened the promoter regions of the most common MODY-related genesGCK,HNF1A,HNF4AandHNF1Bin our cohort of 29 MODY patients. We identified one genetic variant in theHNF1Agene, a 7 bp insertion c.-154-160insTGGGGGT, and three variants in theGCKgene, -282C gt T; -194A gt G; 402C gt G appearing as set. Chloramphenicol acetyltransferase (CAT) assay was performed to test the effect of the 7 bp insertion and the variant set on the activity of the reporter gene in HepG2 and RIN-5F cell, respectively, where a decreasing trend was observed for both variants. In silico analysis and electrophoretic mobility shift assay showed that the 7 bp insertion did not create the binding site for new transcriptional factors, but gave rise to additional binding sites for the existing ones. Results from our study indicated that the 7 bp insertion in theHNF1Agene could be associated with the patient's diabetes. As for theGCKvariant set, it is probably not associated with diabetes in patients, but it may modify the fasting glucose level by causing small elevation in variant set carriers. We have presented two promoter variants in MODY-related genes. Variant in theHNF1Agene is presumed to be disease-causing and theGCKpromoter variant set could be a phenotype modifier.
PB  - Springer, Dordrecht
T2  - Molecular Biology Reports
T1  - Analysis of the promoter regions of disease-causing genes in maturity-onset diabetes of the young patients
EP  - 6768
IS  - 9
SP  - 6759
VL  - 47
DO  - 10.1007/s11033-020-05734-7
ER  - 

@article{
author = "Komazec, Jovana and Ristivojević, Bojan and Zukić, Branka and Zdravković, Vera and Karan-Đurašević, Teodora and Pavlović, Sonja and Ugrin, Milena",
year = "2020",
abstract = "Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes caused by the variants in MODY-related genes. In addition to coding variants, variants in the promoter region of MODY-related genes can cause the disease as well. In this study, we screened the promoter regions of the most common MODY-related genesGCK,HNF1A,HNF4AandHNF1Bin our cohort of 29 MODY patients. We identified one genetic variant in theHNF1Agene, a 7 bp insertion c.-154-160insTGGGGGT, and three variants in theGCKgene, -282C gt T; -194A gt G; 402C gt G appearing as set. Chloramphenicol acetyltransferase (CAT) assay was performed to test the effect of the 7 bp insertion and the variant set on the activity of the reporter gene in HepG2 and RIN-5F cell, respectively, where a decreasing trend was observed for both variants. In silico analysis and electrophoretic mobility shift assay showed that the 7 bp insertion did not create the binding site for new transcriptional factors, but gave rise to additional binding sites for the existing ones. Results from our study indicated that the 7 bp insertion in theHNF1Agene could be associated with the patient's diabetes. As for theGCKvariant set, it is probably not associated with diabetes in patients, but it may modify the fasting glucose level by causing small elevation in variant set carriers. We have presented two promoter variants in MODY-related genes. Variant in theHNF1Agene is presumed to be disease-causing and theGCKpromoter variant set could be a phenotype modifier.",
publisher = "Springer, Dordrecht",
journal = "Molecular Biology Reports",
title = "Analysis of the promoter regions of disease-causing genes in maturity-onset diabetes of the young patients",
pages = "6768-6759",
number = "9",
volume = "47",
doi = "10.1007/s11033-020-05734-7"
}

Komazec, J., Ristivojević, B., Zukić, B., Zdravković, V., Karan-Đurašević, T., Pavlović, S.,& Ugrin, M.. (2020). Analysis of the promoter regions of disease-causing genes in maturity-onset diabetes of the young patients. in Molecular Biology Reports
Springer, Dordrecht., 47(9), 6759-6768.
https://doi.org/10.1007/s11033-020-05734-7

Komazec J, Ristivojević B, Zukić B, Zdravković V, Karan-Đurašević T, Pavlović S, Ugrin M. Analysis of the promoter regions of disease-causing genes in maturity-onset diabetes of the young patients. in Molecular Biology Reports. 2020;47(9):6759-6768.
doi:10.1007/s11033-020-05734-7 .

Komazec, Jovana, Ristivojević, Bojan, Zukić, Branka, Zdravković, Vera, Karan-Đurašević, Teodora, Pavlović, Sonja, Ugrin, Milena, "Analysis of the promoter regions of disease-causing genes in maturity-onset diabetes of the young patients" in Molecular Biology Reports, 47, no. 9 (2020):6759-6768,
https://doi.org/10.1007/s11033-020-05734-7 . .