Linkage disequilibrium of UGT1A1*6 and UGT1A1*28 in relation to UGT1A6 and UGT1A7 polymorphisms

UDP-glucuronosyltransferase (UGT) enzymes are responsible for the glucuronidation and detoxification of many endogenous or exogenous xenobiotics. Gilbert's syndrome (GS) and Crigler Najjar syndrome type 2 (CNS-II) are characterized by unconjugated hyperbilirubinemia due to reduced enzymatic activity of UGT1A1. Recent studies have demonstrated the frequent co-existence of UGTIA1*28 (-53 [TA](6 > 7)) with other polymorphisms of UGT1A6 and UGT1A7. This finding suggests the occurrence of linkage disequilibrium (LD) among UGT1A4, UGT1A6 and UGT1A7 polymorphisms. UGT1A1*6 (21 IG > A, G71R) and UGT1A1*28 are common in Asian populations. In the present study, we investigated the LD of UGT1A1*6 and UGT1A1*28 in relation to UGT1A6 and UGT1A7 polymorphisms. Exon 1 of UGT1A1, UGT1A6 and UGT1A7 was sequenced using genomic DNA isolated from peripheral leukocytes of 390 Japanese subjects. LD and haplotypes were analyzed using SNPAlyze ver. 5.0 software. UGT1A1*6 had a strong LD in relation to UGT1A6 variants including 541A > G and 552A > C (D'=0.846-0.848, r(2)=0.413-0.438) and UGT1A7 variants including 387T > G, 391C > A, 392G > A and 622T > C (D'=0.667-0.858, r(2)=0.207-0.413). UGT1A1*28 had a lower degree of LD than UGT1A1*6 in relation to these variants (D'=0.245-0.401, r(2)=0.025-0.063). All the haplotypes with G71R lacked -53[TA](6 > 7). The present study showed for the first time that the LD of UGT1A1*6 in relation to UGT1A6 and 1A7 polymorphisms is far stronger than UGT1A1*28. The UGT1A1*6 allele appears to be independent of the UGT1A1*28 allele. Although patients with GS and CNS-II are believed to have good prognosis, a subgroup of GS or CNS-II patients with the UGT1A1*6 polymorphism might be at risk of abnormal drug metabolism and of developing malignant disease.