title: Combined effects of the UGT1A1 and OATP2 gene polymorphisms as major risk factor for unconjugated hyperbilirubinemia in Indian neonates.
abstract: 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.
authors.affiliation: National Institute of Immunohaematology (ICMR), 13th floor, NMS Building, KEM Hospital Campus, Parel, Mumbai 400 012, India.
authors.forename: Selma
authors.initials: S
authors.lastname: D'Silva
authors.affiliation: National Institute of Immunohaematology (ICMR), 13th floor, NMS Building, KEM Hospital Campus, Parel, Mumbai 400 012, India.
authors.forename: Roshan B
authors.initials: RB
authors.lastname: Colah
authors.affiliation: National Institute of Immunohaematology (ICMR), 13th floor, NMS Building, KEM Hospital Campus, Parel, Mumbai 400 012, India.
authors.forename: Kanjaksha
authors.initials: K
authors.lastname: Ghosh
authors.affiliation: National Institute of Immunohaematology (ICMR), 13th floor, NMS Building, KEM Hospital Campus, Parel, Mumbai 400 012, India. Electronic address: malaybmukherjee@gmail.com.
authors.forename: Malay B
authors.initials: MB
authors.lastname: Mukherjee
mesh_terms: D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D051556:Hyperbilirubinemia, Neonatal / Q000235:genetics*; D007194:India; D007231:Infant, Newborn; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics*; D008297:Male; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D000099148:UGT1A1 Enzyme
chemical_list: D014453:Glucuronosyltransferase; D027381:Liver-Specific Organic Anion Transporter 1; D000099148:UGT1A1 Enzyme
keywords: Gene polymorphisms; Hyperbilirubinemia; India; Newborns; OATP2; UGT1A1