TY  - JOUR
AU  - Đorđević, Ivana
AU  - Garai, Nemanja
AU  - Perić, Stojan
AU  - Karanović, Jelena
AU  - Pešović, Jovan
AU  - Brkusanin, Milos
AU  - Lavrnic, Dragana
AU  - Apostolski, Slobodan
AU  - Savić-Pavicević, Dusanka
AU  - Basta, Ivana
PY  - 2024
UR  - https://doi.org/10.1007/s12035-024-04183-8
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2346
AB  - Genome-wide association studies (GWAS) have provided strong evidence that early- and late-onset MG have different genetic backgrounds. Recent in silico analysis based on GWAS results revealed rs231735 and rs231770 variants within CTLA-4 locus as possible MG causative genetic factors. We aimed to explore the association of rs231735 and rs231770 with MG in a representative cohort of Serbian patients. We conducted an age-, sex-, and ethnicity-matched case–control study. Using TaqMan allele discrimination assays, the frequency of rs231735 and rs231770 genetic variants was examined in 447 AChR-MG patients and 447 matched controls. There was no significant association of rs231735 and rs231770 with the entire MG cohort (P > 0.05). Nevertheless, when stratifying patients into early-onset (n = 183) and late-onset MG (n = 264), we found early-onset patients had a significantly lower frequency of the rs231735 allele T compared to controls (OR = 0.734, 95% CI = 0.575–0.938, p10e6 permutation < 0.05), and rs231735 genotype TT and rs231770 genotype TT had a protective effect on early-onset MG (OR = 0.548, 95% CI = 0.339–0.888, and OR = 0.563, 95% CI = 0.314–1.011, p10e6 permutation < 0.05). Consequently, we found that individuals with the rs231735-rs231770 haplotype GC had a higher risk for developing early-onset MG (OR = 1.360, P = 0.027, p10e6 permutation < 0.05). Our results suggest that CTLA-4 rs231735 and rs231770 may be risk factors only for patients with early-onset MG in Serbian population.
PB  - Springer
T2  - Molecular Neurobiology
T2  - Molecular NeurobiologyMol Neurobiol
T1  - Association between Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4) Locus and Early-Onset Anti-acetylcholine Receptor-Positive Myasthenia Gravis in Serbian Patients
DO  - 10.1007/s12035-024-04183-8
ER  - 

@article{
author = "Đorđević, Ivana and Garai, Nemanja and Perić, Stojan and Karanović, Jelena and Pešović, Jovan and Brkusanin, Milos and Lavrnic, Dragana and Apostolski, Slobodan and Savić-Pavicević, Dusanka and Basta, Ivana",
year = "2024",
abstract = "Genome-wide association studies (GWAS) have provided strong evidence that early- and late-onset MG have different genetic backgrounds. Recent in silico analysis based on GWAS results revealed rs231735 and rs231770 variants within CTLA-4 locus as possible MG causative genetic factors. We aimed to explore the association of rs231735 and rs231770 with MG in a representative cohort of Serbian patients. We conducted an age-, sex-, and ethnicity-matched case–control study. Using TaqMan allele discrimination assays, the frequency of rs231735 and rs231770 genetic variants was examined in 447 AChR-MG patients and 447 matched controls. There was no significant association of rs231735 and rs231770 with the entire MG cohort (P > 0.05). Nevertheless, when stratifying patients into early-onset (n = 183) and late-onset MG (n = 264), we found early-onset patients had a significantly lower frequency of the rs231735 allele T compared to controls (OR = 0.734, 95% CI = 0.575–0.938, p10e6 permutation < 0.05), and rs231735 genotype TT and rs231770 genotype TT had a protective effect on early-onset MG (OR = 0.548, 95% CI = 0.339–0.888, and OR = 0.563, 95% CI = 0.314–1.011, p10e6 permutation < 0.05). Consequently, we found that individuals with the rs231735-rs231770 haplotype GC had a higher risk for developing early-onset MG (OR = 1.360, P = 0.027, p10e6 permutation < 0.05). Our results suggest that CTLA-4 rs231735 and rs231770 may be risk factors only for patients with early-onset MG in Serbian population.",
publisher = "Springer",
journal = "Molecular Neurobiology, Molecular NeurobiologyMol Neurobiol",
title = "Association between Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4) Locus and Early-Onset Anti-acetylcholine Receptor-Positive Myasthenia Gravis in Serbian Patients",
doi = "10.1007/s12035-024-04183-8"
}

Đorđević, I., Garai, N., Perić, S., Karanović, J., Pešović, J., Brkusanin, M., Lavrnic, D., Apostolski, S., Savić-Pavicević, D.,& Basta, I.. (2024). Association between Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4) Locus and Early-Onset Anti-acetylcholine Receptor-Positive Myasthenia Gravis in Serbian Patients. in Molecular Neurobiology
Springer..
https://doi.org/10.1007/s12035-024-04183-8

Đorđević I, Garai N, Perić S, Karanović J, Pešović J, Brkusanin M, Lavrnic D, Apostolski S, Savić-Pavicević D, Basta I. Association between Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4) Locus and Early-Onset Anti-acetylcholine Receptor-Positive Myasthenia Gravis in Serbian Patients. in Molecular Neurobiology. 2024;.
doi:10.1007/s12035-024-04183-8 .

Đorđević, Ivana, Garai, Nemanja, Perić, Stojan, Karanović, Jelena, Pešović, Jovan, Brkusanin, Milos, Lavrnic, Dragana, Apostolski, Slobodan, Savić-Pavicević, Dusanka, Basta, Ivana, "Association between Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4) Locus and Early-Onset Anti-acetylcholine Receptor-Positive Myasthenia Gravis in Serbian Patients" in Molecular Neurobiology (2024),
https://doi.org/10.1007/s12035-024-04183-8 . .

TY  - CONF
AU  - Garai, Nemanja
AU  - Dejanović, Ivana
AU  - Perić, Stojan
AU  - Karanović, Jelena
AU  - Pešović, Jovan
AU  - Miloš, Brkušanin
AU  - Slobodan, Apostolski
AU  - Lavrnić, Dragana
AU  - Basta, Ivana
AU  - Savić- Pavićević, Dušanka
PY  - 2023
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2217
AB  - Myasthenia gravis (MG) is a rare autoimmune disease mediated by antibodies against
components of the neuromuscular junction, particularly the acetylcholine receptor
(AChR). The prevalence of MG in Belgrade has been estimated at 189 cases per
1,000,000 inhabitants, which is among the highest prevalence reported to date.
Genetic studies have mainly pointed to specific HLA alleles associated with MG.
However, CTLA-4 and TNFRSF11A, playing a role in the immune response, have
recently been associated with MG in genome-wide association studies. Since CTLA-4
and TNFRSF11A promote other autoimmune diseases, the main objective of this casecontrol
study was to determine the association between these candidate genes and the
risk for developing MG in Serbian population.
Genotyping of rs231735 and rs231770 within the CTLA-4 gene and rs4263037 within
TNFRSF11A in 447 AChR-MG patients and 447 individually sex- and age-matched
controls revealed no association with MG (p=0.344, p=0.923 and p=0.557,
respectively). However, when stratifying patients into those with early-onset (n=183)
and late-onset MG (n=264), we found an association of minor rs231735 allele T with
early-onset MG under the recessive genetic model (OR=0.548, 95% CI=0.339-0.888,
p=0.014, p10e6 permutation=0.014). Haplotype analysis revealed that individuals
with the GC haplotype rs231735-rs231770 had a higher risk for developing earlyonset
MG (OR =1.360, p=0.027, p10e6 permutation =0.027). Considering the
sufficient statistical power of the study (>90%) and the selection criteria for controls,
our results suggest that the CTLA-4 may be associated with early-onset MG in Serbian
population. Analysis of additional variants is needed to understand the association of
CTLA-4 with MG
PB  - Belgrade : Serbian Neuroscience Society
C3  - 8th Congress of the Serbian Neuroscience Society
T1  - Genetic risk factors in patients with Myasthenia gravis
EP  - 87
SP  - 87
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2217
ER  - 

@conference{
author = "Garai, Nemanja and Dejanović, Ivana and Perić, Stojan and Karanović, Jelena and Pešović, Jovan and Miloš, Brkušanin and Slobodan, Apostolski and Lavrnić, Dragana and Basta, Ivana and Savić- Pavićević, Dušanka",
year = "2023",
abstract = "Myasthenia gravis (MG) is a rare autoimmune disease mediated by antibodies against
components of the neuromuscular junction, particularly the acetylcholine receptor
(AChR). The prevalence of MG in Belgrade has been estimated at 189 cases per
1,000,000 inhabitants, which is among the highest prevalence reported to date.
Genetic studies have mainly pointed to specific HLA alleles associated with MG.
However, CTLA-4 and TNFRSF11A, playing a role in the immune response, have
recently been associated with MG in genome-wide association studies. Since CTLA-4
and TNFRSF11A promote other autoimmune diseases, the main objective of this casecontrol
study was to determine the association between these candidate genes and the
risk for developing MG in Serbian population.
Genotyping of rs231735 and rs231770 within the CTLA-4 gene and rs4263037 within
TNFRSF11A in 447 AChR-MG patients and 447 individually sex- and age-matched
controls revealed no association with MG (p=0.344, p=0.923 and p=0.557,
respectively). However, when stratifying patients into those with early-onset (n=183)
and late-onset MG (n=264), we found an association of minor rs231735 allele T with
early-onset MG under the recessive genetic model (OR=0.548, 95% CI=0.339-0.888,
p=0.014, p10e6 permutation=0.014). Haplotype analysis revealed that individuals
with the GC haplotype rs231735-rs231770 had a higher risk for developing earlyonset
MG (OR =1.360, p=0.027, p10e6 permutation =0.027). Considering the
sufficient statistical power of the study (>90%) and the selection criteria for controls,
our results suggest that the CTLA-4 may be associated with early-onset MG in Serbian
population. Analysis of additional variants is needed to understand the association of
CTLA-4 with MG",
publisher = "Belgrade : Serbian Neuroscience Society",
journal = "8th Congress of the Serbian Neuroscience Society",
title = "Genetic risk factors in patients with Myasthenia gravis",
pages = "87-87",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2217"
}

Garai, N., Dejanović, I., Perić, S., Karanović, J., Pešović, J., Miloš, B., Slobodan, A., Lavrnić, D., Basta, I.,& Savić- Pavićević, D.. (2023). Genetic risk factors in patients with Myasthenia gravis. in 8th Congress of the Serbian Neuroscience Society
Belgrade : Serbian Neuroscience Society., 87-87.
https://hdl.handle.net/21.15107/rcub_imagine_2217

Garai N, Dejanović I, Perić S, Karanović J, Pešović J, Miloš B, Slobodan A, Lavrnić D, Basta I, Savić- Pavićević D. Genetic risk factors in patients with Myasthenia gravis. in 8th Congress of the Serbian Neuroscience Society. 2023;:87-87.
https://hdl.handle.net/21.15107/rcub_imagine_2217 .

Garai, Nemanja, Dejanović, Ivana, Perić, Stojan, Karanović, Jelena, Pešović, Jovan, Miloš, Brkušanin, Slobodan, Apostolski, Lavrnić, Dragana, Basta, Ivana, Savić- Pavićević, Dušanka, "Genetic risk factors in patients with Myasthenia gravis" in 8th Congress of the Serbian Neuroscience Society (2023):87-87,
https://hdl.handle.net/21.15107/rcub_imagine_2217 .

TY  - CONF
AU  - Garai, Nemanja
AU  - Petrović, Kristina
AU  - Karanović, Jelena
AU  - Dejanović, Ivana
AU  - Perić, Stojan
AU  - Basta, Ivana
AU  - Jovanović, Vladimir
AU  - Savić-Pavićević, Dušanka
PY  - 2023
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2196
AB  - Introduction: Genome-wide association studies (GWAS) identify genomic loci that contain genetic determinants
of complex diseases. Subsequent functional genomic approaches, such as bioinformatic finemapping
and transcriptome-wide association studies (TWAS), can reveal potentially causal single
nucleotide variants (SNVs) that can be tested on patient samples. We applied this approach to study
causal SNVs for acetylcholine receptor (AChR) seropositive myasthenia gravis (MG). We focused on
CHRNA1 and CHRNB1 loci, coding AChR subunits, and CTLA-4 locus, coding protein transmitting an inhibitory
signal to T cells.
Methods: CHRNA1 was fine-mapped by PAINTOR using data from GWAS summary statistics, 1000
genome and RegulomeDB. Alongside, rs4151121 identified by TWAS in CHRNB1, and rs231735 and
rs231770 identified by fine-mapping in CTLA-4 were studied. SNVs were genotyped using allele discrimination
assays in 447 Serbian AChR-MG patients (183 early-onset and 264 late-onset) and 447 sex- and
age-matched controls.
Results: CHRNA1 rs35274388 was fine-mapped as a potentially causal variant (PIP2=92%) exhibiting
transcription factor binding and chromatin accessibility peaks. CHRNA1 rs35274388 minor allele A and
CHRNAB1 rs4151121 minor allele G increased the risk for late-onset MG (OR=1.669, 95% CI=1.05-2.638,
p=0.027, p10e6 permutation=0.031 and OR=1.322, 95% CI=1.063-1.644, p10e6 permutation=0.014, respectively).
On the other hand, CTLA-4 rs231735 recessive genotype TT decreased, while rs231735-
rs231770 haplotype GC increased the susceptibility to early-onset MG (OR=0.548, 95% CI=0.339-0.888,
p=0.014, p10e6 permutation=0.014 and OR=1.360, p=0.027, p10e6 permutation=0.027, respectively).
Conclusion: CHRNA1 rs35274388 and CHRNAB1 rs4151121 loci could be causal genetic factors for lateonset
MG while CTLA-4 rs231735 and rs231770 could be causal genetic factors for early-onset MG in Serbian
population.
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  - Identification of potentally causal variants for myasthenia gravis: a bioinformatics-driven fine-mapping approach combined with genetic association study
EP  - 39
SP  - 39
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2196
ER  - 

@conference{
author = "Garai, Nemanja and Petrović, Kristina and Karanović, Jelena and Dejanović, Ivana and Perić, Stojan and Basta, Ivana and Jovanović, Vladimir and Savić-Pavićević, Dušanka",
year = "2023",
abstract = "Introduction: Genome-wide association studies (GWAS) identify genomic loci that contain genetic determinants
of complex diseases. Subsequent functional genomic approaches, such as bioinformatic finemapping
and transcriptome-wide association studies (TWAS), can reveal potentially causal single
nucleotide variants (SNVs) that can be tested on patient samples. We applied this approach to study
causal SNVs for acetylcholine receptor (AChR) seropositive myasthenia gravis (MG). We focused on
CHRNA1 and CHRNB1 loci, coding AChR subunits, and CTLA-4 locus, coding protein transmitting an inhibitory
signal to T cells.
Methods: CHRNA1 was fine-mapped by PAINTOR using data from GWAS summary statistics, 1000
genome and RegulomeDB. Alongside, rs4151121 identified by TWAS in CHRNB1, and rs231735 and
rs231770 identified by fine-mapping in CTLA-4 were studied. SNVs were genotyped using allele discrimination
assays in 447 Serbian AChR-MG patients (183 early-onset and 264 late-onset) and 447 sex- and
age-matched controls.
Results: CHRNA1 rs35274388 was fine-mapped as a potentially causal variant (PIP2=92%) exhibiting
transcription factor binding and chromatin accessibility peaks. CHRNA1 rs35274388 minor allele A and
CHRNAB1 rs4151121 minor allele G increased the risk for late-onset MG (OR=1.669, 95% CI=1.05-2.638,
p=0.027, p10e6 permutation=0.031 and OR=1.322, 95% CI=1.063-1.644, p10e6 permutation=0.014, respectively).
On the other hand, CTLA-4 rs231735 recessive genotype TT decreased, while rs231735-
rs231770 haplotype GC increased the susceptibility to early-onset MG (OR=0.548, 95% CI=0.339-0.888,
p=0.014, p10e6 permutation=0.014 and OR=1.360, p=0.027, p10e6 permutation=0.027, respectively).
Conclusion: CHRNA1 rs35274388 and CHRNAB1 rs4151121 loci could be causal genetic factors for lateonset
MG while CTLA-4 rs231735 and rs231770 could be causal genetic factors for early-onset MG in Serbian
population.",
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 = "Identification of potentally causal variants for myasthenia gravis: a bioinformatics-driven fine-mapping approach combined with genetic association study",
pages = "39-39",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2196"
}

Garai, N., Petrović, K., Karanović, J., Dejanović, I., Perić, S., Basta, I., Jovanović, V.,& Savić-Pavićević, D.. (2023). Identification of potentally causal variants for myasthenia gravis: a bioinformatics-driven fine-mapping approach combined with genetic association study. 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., 39-39.
https://hdl.handle.net/21.15107/rcub_imagine_2196

Garai N, Petrović K, Karanović J, Dejanović I, Perić S, Basta I, Jovanović V, Savić-Pavićević D. Identification of potentally causal variants for myasthenia gravis: a bioinformatics-driven fine-mapping approach combined with genetic association study. 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;:39-39.
https://hdl.handle.net/21.15107/rcub_imagine_2196 .

Garai, Nemanja, Petrović, Kristina, Karanović, Jelena, Dejanović, Ivana, Perić, Stojan, Basta, Ivana, Jovanović, Vladimir, Savić-Pavićević, Dušanka, "Identification of potentally causal variants for myasthenia gravis: a bioinformatics-driven fine-mapping approach combined with genetic association study" 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):39-39,
https://hdl.handle.net/21.15107/rcub_imagine_2196 .