Abstract
A retrospective case control study of breast-fed full-term infants was carried out to determine whether variants in Uridine Diphosphate Glucuronosyl Transferase 1A1 (UGT1A1) and Heme Oxygenase-1 (HMOX1) were associated with neonatal hyperbilirubinemia. Eight genetic variants of UGT1A1 and 3 genetic variants of HMOX1 were genotyped in 170 hyperbilirubinemic newborns and 779 controls. Five significant associations with breast-fed hyperbilirubinemia were detected after adjusting for gender, birth season, birth weight, delivery mode, gestational age and False Discovery Rate (FDR) correction: the dominant effect of rs887829 (c-364t) (Odds Ratio (OR): 0.55; 95% Confidence Interval (CI): 0.34–0.89; p = 0.014), the additive effect of (TA)n repeat (OR: 0.59; 95%CI: 0.38–0.91; p = 0.017), the dominant effect of rs4148323 (Gly71Arg, G211A) (OR: 2.02; 95%CI: 1.44–2.85; p = 5.0×10−5), the recessive effect of rs6717546 (g+914a) (OR: 0.30; 95%CI: 0.11–0.83; p = 0.021) and rs6719561 (t+2558c) (OR: 0.38; 95%CI: 0.20–0.75; p = 0.005). Neonates carrying the minor allele of rs887829 (TA)n repeat had significantly lower peak bilirubin than wild types, while the minor allele carriers of rs4148323 had significantly higher peak bilirubin than wild types. No association was found in HMOX1. Our findings added to the understanding of the significance of UGT1A1 in association with neonatal hyperbilirubinemia in East Asian population. Additional studies were required to investigate the mechanisms of the protective effects.
Highlights
Neonatal jaundice is a physiological and generally benign phenomenon
Birth season, birth weight, delivery mode and gestational age, the minor allele of rs4148323 was found to be a risk factor of hyperbilirubinemia (Odds Ratio (OR): 1.75; 95% Confidence Interval (CI): 1.32–2.31; p = 8.061025); whereas, the minor alleles of the remaining variants were shown to be protective factors: rs887829 (OR: 0.61; 95%CI: 0.39–0.94; p = 0.027) and (TA)n repeat (OR: 0.58; 95%CI: 0.37–0.90; p = 0.015) are two variants at the promoter region and are 310 nucleotides apart from each other; rs6717546 (OR: 0.70; 95%CI: 0.53–0.93; p = 0.015) and Gender,n(%) Male
All of the five variants were associated with hyperbilirubinemia in its best-fitting inheritance model, and remained significantly after controlling gender, birth season, birth weight, delivery mode and gestational age and the False Discovery Rate (FDR) correction: the dominant effect of rs887829 (OR: 0.55; 95%CI: 0.34–0.89; p = 0.014), the additive effect of (TA)n repeat (OR: 0.59; 95%CI: 0.38–0.91; p = 0.017), the dominant effect of rs4148323 (OR: 2.02; 95%CI: 1.44–2.85; p = 5.061025), the recessive effect of rs6717546 (OR: 0.30; 95%CI: 0.11–0.83; p = 0.021) and rs6719561 (OR: 0.38; 95%CI: 0.20–0.75; p = 0.005) on neonatal jaundice
Summary
Neonatal jaundice is a physiological and generally benign phenomenon. excessively high bilirubin concentration may cause permanent neural damage in newborns, i.e., ‘‘chronic bilirubin encephalopathy’’ or kernicterus [1]. Variants in the rate limiting enzymes in the bilirubin metabolism pathway may be associated with hyperbilirubinemia. Uridine Diphosphate Glucuronosyl Transferase 1A1 (UGT1A1) is the key enzyme for bilirubin conjugation while unconjugated bilirubin is the main cause of hyperbilirubinemia [3]. In Caucasian newborns, the minor allele homozygote of this variant significantly increases bilirubin concentration during the first 2 days of life [5]. When the minor allele homozygote or heterozygote combined with Glucose-6-Posphate Dehydrogenase (G6PD) deficiency, the incidence of hyperbilirubinemia is increased [6]. In East Asian populations, such as Japanese and Chinese, the minor allele of rs4148323 (Gly71Arg, G211A) in exon 1, but not (TA)n repeat, is found to be associated with neonatal hyperbilirubinemia [7,8,9]
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