Combined effects of the UGT1A1 and OATP2 gene polymorphisms as major risk factor for unconjugated hyperbilirubinemia in Indian neonates

• Published in: Gene Vol. 547; no. 1; pp. 18 - 22
• Main Authors: D'Silva, Selma, Colah, Roshan B., Ghosh, Kanjaksha, Mukherjee, Malay B.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.08.2014
• Subjects: Female; Gene polymorphisms; Genetic Predisposition to Disease; Genome-Wide Association Study; Glucuronosyltransferase - genetics; Haplotypes; Humans; Hyperbilirubinemia; Hyperbilirubinemia, Neonatal - genetics; India; Infant, Newborn; Male; Newborns; OATP2; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Risk Factors; Solute Carrier Organic Anion Transporter Family Member 1b1 - genetics; UGT1A1; G6PD; TSB; UGT1A1; μmol/L; India; Newborns; Gene polymorphisms; DPIP; MAF; Hyperbilirubinemia; SNPs; OATP2; PCR; RFLP
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2014.05.047

Genetic association studies have linked a number of single nucleotide polymorphisms (SNPs) with unconjugated hyperbilirubinemia. The present study was undertaken to validate the association of SNPs with development of hyperbilirubinemia in Indian neonates. Genotyping of five SNPs in two candidate genes was performed in 126 infants with hyperbilirubinemia and 181 controls by PCR-RFLP, Gene Scan analysis and direct DNA sequencing. Genetic polymorphisms of the UGT1A1 promoter, specifically the −3279 T➔G phenobarbital responsive enhancer module (rs4124874) and (TA)7 dinucleotide repeat (rs8175347) as well as the coding region variants (rs2306283 and rs4149056) of the OATP2 gene were significantly higher among the cases than the controls. The presence of the mutant haplotypes either in homozygous, heterozygous or compound heterozygous state had a significant effect on neonatal hyperbilirubinemia as well as on the requirement of phototherapy than those with the wild haplotype. Further, a significantly higher number of hyperbilirubinemic cases had ≥3 variants than the controls (73.80% vs 40.36%, p<0.0001) and the mean total serum bilirubin levels and requirement of phototherapy also increased according to the number of variants co-expressed. This study demonstrates that UGT1A1 and OATP2 polymorphisms were associated with altered bilirubin metabolism and could be genetic risk factors for neonatal hyperbilirubinemia. •Genetic variations in UGT1A1 and OATP2 genes were greater in cases than controls.•Mutant haplotypes had a significant effect on neonatal hyperbilirubinemia.•A significantly higher number of cases had ≥3 variants than controls.•Co-expression of variants increased neonatal hyperbilirubinemia and severity.