TY  - CONF
AU  - Beletić, Anđelo
AU  - Leković, Z.
AU  - Zivković, Z.
AU  - Radlović, N.
AU  - Perisić, V.
AU  - Ljujić, Mila
AU  - Radojković, Dragica
AU  - Đorđević, Valentina
AU  - Stanković, S.
PY  - 2019
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1226
AB  - Background-aim
Alpha-1-antitrypsin deficiency (AATD) is an autosomal recessive
disorder characterized by the reduced alpha-1-antitrypsin (AAT)
level in blood. In pediatric patients, it is dominantly tested as a cause
of liver disease, while specific lung diseases might be potentially
regarded as additional indications. Measurement of AAT concentration is useful as a first-line test, although decreased level may be also
encountered in certain acquired conditions. Our aim was to
determine the interpretative cut-off for AAT concentration i.e. level
below which the presence of common AATD-associated alleles might
be suspected.
Methods
We included 37 subjects with clinical indications or familiar
history of AATD: 19 males and 18 females, aged between 2 months
and 19 years. Immunonephelometry was used for measurement of
AAT concentration in serum and PCR-reverse allele specific hybridization assay for detection of Z and S alleles, which are considered as
the common AATD-associated alleles. Kruskal-Wallis test and ROC
analysis were applied in statistical evaluation.
Results
Three cases of AATD (ZZ genotype) and 14 carriers (13
heterozygous for Z and one for S allele) were detected. AAT
concentration (median (min-max)) measured in AATD cases (0.35
(0.31–0.39) g/L), carriers (0.81 (0.56–1.41) g/L) and patients with
no Z and S allele (1.20 (0.91–2.24) g/L) were significantly different
(P b .001). Four carriers (three heterozygous for Z and one for S
allele) had AAT concentration in the reference range (0.9–2.0 g/L).
We identified the level 1.03 g/L as the most appropriate cut-off to
distinguish group comprising both cases of AATD and carriers from
patients in whom no common AATD-associated allele was present.
Corresponding AUC value (95% Confidence interval (CI)) was 0.929
(0.795–0.987) (P b .001). Sensitivity and specificity (95% CI) reached
94.1 (71.3–99.9)% and 90.0 (68.3–98.8)% respectively.
Conclusions
In pediatric patients AAT concentration below 1.03 g/L may be
regarded as a potential cut-off indicating the presence of common
AATD-associated alleles in homo-or heterozygous form. Nevertheless, this preliminary finding needs confirmation in a larger study.
PB  - Elsevier, Amsterdam
C3  - Clinica Chimica Acta
T1  - Interpretative cut-off for alpha-1-antitrypsin concentration in detection of alpha-1-antitrypsin deficiency among pediatric patients - A pilot study
EP  - S455
SP  - S455
VL  - 493
DO  - 10.1016/j.cca.2019.03.964
ER  - 

@conference{
author = "Beletić, Anđelo and Leković, Z. and Zivković, Z. and Radlović, N. and Perisić, V. and Ljujić, Mila and Radojković, Dragica and Đorđević, Valentina and Stanković, S.",
year = "2019",
abstract = "Background-aim
Alpha-1-antitrypsin deficiency (AATD) is an autosomal recessive
disorder characterized by the reduced alpha-1-antitrypsin (AAT)
level in blood. In pediatric patients, it is dominantly tested as a cause
of liver disease, while specific lung diseases might be potentially
regarded as additional indications. Measurement of AAT concentration is useful as a first-line test, although decreased level may be also
encountered in certain acquired conditions. Our aim was to
determine the interpretative cut-off for AAT concentration i.e. level
below which the presence of common AATD-associated alleles might
be suspected.
Methods
We included 37 subjects with clinical indications or familiar
history of AATD: 19 males and 18 females, aged between 2 months
and 19 years. Immunonephelometry was used for measurement of
AAT concentration in serum and PCR-reverse allele specific hybridization assay for detection of Z and S alleles, which are considered as
the common AATD-associated alleles. Kruskal-Wallis test and ROC
analysis were applied in statistical evaluation.
Results
Three cases of AATD (ZZ genotype) and 14 carriers (13
heterozygous for Z and one for S allele) were detected. AAT
concentration (median (min-max)) measured in AATD cases (0.35
(0.31–0.39) g/L), carriers (0.81 (0.56–1.41) g/L) and patients with
no Z and S allele (1.20 (0.91–2.24) g/L) were significantly different
(P b .001). Four carriers (three heterozygous for Z and one for S
allele) had AAT concentration in the reference range (0.9–2.0 g/L).
We identified the level 1.03 g/L as the most appropriate cut-off to
distinguish group comprising both cases of AATD and carriers from
patients in whom no common AATD-associated allele was present.
Corresponding AUC value (95% Confidence interval (CI)) was 0.929
(0.795–0.987) (P b .001). Sensitivity and specificity (95% CI) reached
94.1 (71.3–99.9)% and 90.0 (68.3–98.8)% respectively.
Conclusions
In pediatric patients AAT concentration below 1.03 g/L may be
regarded as a potential cut-off indicating the presence of common
AATD-associated alleles in homo-or heterozygous form. Nevertheless, this preliminary finding needs confirmation in a larger study.",
publisher = "Elsevier, Amsterdam",
journal = "Clinica Chimica Acta",
title = "Interpretative cut-off for alpha-1-antitrypsin concentration in detection of alpha-1-antitrypsin deficiency among pediatric patients - A pilot study",
pages = "S455-S455",
volume = "493",
doi = "10.1016/j.cca.2019.03.964"
}

Beletić, A., Leković, Z., Zivković, Z., Radlović, N., Perisić, V., Ljujić, M., Radojković, D., Đorđević, V.,& Stanković, S.. (2019). Interpretative cut-off for alpha-1-antitrypsin concentration in detection of alpha-1-antitrypsin deficiency among pediatric patients - A pilot study. in Clinica Chimica Acta
Elsevier, Amsterdam., 493, S455-S455.
https://doi.org/10.1016/j.cca.2019.03.964

Beletić A, Leković Z, Zivković Z, Radlović N, Perisić V, Ljujić M, Radojković D, Đorđević V, Stanković S. Interpretative cut-off for alpha-1-antitrypsin concentration in detection of alpha-1-antitrypsin deficiency among pediatric patients - A pilot study. in Clinica Chimica Acta. 2019;493:S455-S455.
doi:10.1016/j.cca.2019.03.964 .

Beletić, Anđelo, Leković, Z., Zivković, Z., Radlović, N., Perisić, V., Ljujić, Mila, Radojković, Dragica, Đorđević, Valentina, Stanković, S., "Interpretative cut-off for alpha-1-antitrypsin concentration in detection of alpha-1-antitrypsin deficiency among pediatric patients - A pilot study" in Clinica Chimica Acta, 493 (2019):S455-S455,
https://doi.org/10.1016/j.cca.2019.03.964 . .

TY  - JOUR
AU  - Vuković, M.
AU  - Radlović, N.
AU  - Leković, Z.
AU  - Vucicević, K.
AU  - Marić, N.
AU  - Kotur, Nikola
AU  - Gašić, Vladimir
AU  - Ugrin, Milena
AU  - Stojiljković, Maja
AU  - Dokmanović, Lidija
AU  - Zukić, Branka
AU  - Pavlović, Sonja
PY  - 2018
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1153
AB  - The UGT1A1 enzyme is involved in the metabolism of bilirubin and numerous medications. Unconjugated hyper-bilirubinemia, commonly presented as Gilbert syndrome (GS), is a result of decreased activity of the UGT1A1 enzyme, variable number of TA repeats in the promoter of the UGT1A1 gene affects enzyme activity. Seven and eight TA repeats cause a decrease of UGT1A1 activity and risk GS alleles, while six TA repeats contribute to normal UGT I Al activity and non-risk GS allele. Also, the UGT1A1 (TA)(n) promoter genotype is recognized as a clinically relevant phannacogenetic marker. The aim of this study was to access diagnostic value of UGTIAI (TA) n promoter genotyping in pediatric GS patients. Correlation of the UGT1A1(TA)(n) genotypes and level of unconjugated bilirubin at diagnosis and after hypocaloric and phenobarbitone tests in these patients was analyzed. Another aim of the study was to assess phannacogenetic potential ofUGT1A1 (TA)(n) variants in Serbia. Fifty-one pediatric GS patients and 100 healthy individuals were genotyped using different methodologies, polymerise chain reaction (PCR) followed by acrylamide electrophoresis, fragment length analysis and/or DNA sequencing. Concordance of the UGT1A1 (TA)(n) promoter risk GS genotypes with GS was found in 80.0% of patients. Therefore, UGT1A1 (TA)(n) promoter genotyping is not a reliable genetic test for GS, but it is useful for differential diagnosis of diseases associated with hyperbilirubinemia. Level of bilimbin in pediatric GS patients at diagnosis wasUGT1A1 (TA)(n) promoter genotype-dependent. We found that the frequency of phannacogenetic relevant UGT1A1 (TA)(n) promoter genotypes was 63.0%, pointing out that UGT1A1 (TA)(n) promoter genoty ping could be recommended for preemptive pharmacogendic testing in Serbia.
PB  - Macedonian Acad Sciences Arts, Skopje
T2  - Balkan Journal of Medical Genetics
T1  - Ugt1a1 (ta)(n) promoter genotype: diagnostic and population pharmacogenetic marker in Serbia
EP  - 68
IS  - 1
SP  - 59
VL  - 21
DO  - 10.2478/bjmg-2018-0012
ER  - 

@article{
author = "Vuković, M. and Radlović, N. and Leković, Z. and Vucicević, K. and Marić, N. and Kotur, Nikola and Gašić, Vladimir and Ugrin, Milena and Stojiljković, Maja and Dokmanović, Lidija and Zukić, Branka and Pavlović, Sonja",
year = "2018",
abstract = "The UGT1A1 enzyme is involved in the metabolism of bilirubin and numerous medications. Unconjugated hyper-bilirubinemia, commonly presented as Gilbert syndrome (GS), is a result of decreased activity of the UGT1A1 enzyme, variable number of TA repeats in the promoter of the UGT1A1 gene affects enzyme activity. Seven and eight TA repeats cause a decrease of UGT1A1 activity and risk GS alleles, while six TA repeats contribute to normal UGT I Al activity and non-risk GS allele. Also, the UGT1A1 (TA)(n) promoter genotype is recognized as a clinically relevant phannacogenetic marker. The aim of this study was to access diagnostic value of UGTIAI (TA) n promoter genotyping in pediatric GS patients. Correlation of the UGT1A1(TA)(n) genotypes and level of unconjugated bilirubin at diagnosis and after hypocaloric and phenobarbitone tests in these patients was analyzed. Another aim of the study was to assess phannacogenetic potential ofUGT1A1 (TA)(n) variants in Serbia. Fifty-one pediatric GS patients and 100 healthy individuals were genotyped using different methodologies, polymerise chain reaction (PCR) followed by acrylamide electrophoresis, fragment length analysis and/or DNA sequencing. Concordance of the UGT1A1 (TA)(n) promoter risk GS genotypes with GS was found in 80.0% of patients. Therefore, UGT1A1 (TA)(n) promoter genotyping is not a reliable genetic test for GS, but it is useful for differential diagnosis of diseases associated with hyperbilirubinemia. Level of bilimbin in pediatric GS patients at diagnosis wasUGT1A1 (TA)(n) promoter genotype-dependent. We found that the frequency of phannacogenetic relevant UGT1A1 (TA)(n) promoter genotypes was 63.0%, pointing out that UGT1A1 (TA)(n) promoter genoty ping could be recommended for preemptive pharmacogendic testing in Serbia.",
publisher = "Macedonian Acad Sciences Arts, Skopje",
journal = "Balkan Journal of Medical Genetics",
title = "Ugt1a1 (ta)(n) promoter genotype: diagnostic and population pharmacogenetic marker in Serbia",
pages = "68-59",
number = "1",
volume = "21",
doi = "10.2478/bjmg-2018-0012"
}

Vuković, M., Radlović, N., Leković, Z., Vucicević, K., Marić, N., Kotur, N., Gašić, V., Ugrin, M., Stojiljković, M., Dokmanović, L., Zukić, B.,& Pavlović, S.. (2018). Ugt1a1 (ta)(n) promoter genotype: diagnostic and population pharmacogenetic marker in Serbia. in Balkan Journal of Medical Genetics
Macedonian Acad Sciences Arts, Skopje., 21(1), 59-68.
https://doi.org/10.2478/bjmg-2018-0012

Vuković M, Radlović N, Leković Z, Vucicević K, Marić N, Kotur N, Gašić V, Ugrin M, Stojiljković M, Dokmanović L, Zukić B, Pavlović S. Ugt1a1 (ta)(n) promoter genotype: diagnostic and population pharmacogenetic marker in Serbia. in Balkan Journal of Medical Genetics. 2018;21(1):59-68.
doi:10.2478/bjmg-2018-0012 .

Vuković, M., Radlović, N., Leković, Z., Vucicević, K., Marić, N., Kotur, Nikola, Gašić, Vladimir, Ugrin, Milena, Stojiljković, Maja, Dokmanović, Lidija, Zukić, Branka, Pavlović, Sonja, "Ugt1a1 (ta)(n) promoter genotype: diagnostic and population pharmacogenetic marker in Serbia" in Balkan Journal of Medical Genetics, 21, no. 1 (2018):59-68,
https://doi.org/10.2478/bjmg-2018-0012 . .