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

Abstract

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 UGT1A1 *28 (-53 [TA]6>7) with other polymorphisms of UGT1A6 and UGT1A7. This finding suggests the occurrence of linkage disequilibrium (LD) among UGT1A1, UGT1A6 and UGT1A7 polymorphisms. UGT1A1 *6 (211G>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.

• Authors: Naohito Urawa, Yoshinao Kobayashi, Jun Araki, Ryosuke Sugimoto, Motoh Iwasa, Masahiko Kaito, Yukihko Adachi
• Journal: Oncology reports (Oncol Rep) Vol. 16 Issue 4 Pg. 801-6 (Oct 2006) ISSN: 1021-335X [Print] Greece
• PMID: 16969497 (Publication Type: Journal Article)

Chemical References

• UDP-glucuronosyltransferase, UGT1A6
• Glucuronosyltransferase
• UDP-glucuronosyltransferase, UGT1A7

Topics

• Adult
• Aged
• Alleles
• Case-Control Studies
• Female
• Glucuronosyltransferase (genetics)
• Haplotypes
• Humans
• Leukocytes (metabolism)
• Linkage Disequilibrium
• Male
• Middle Aged
• Polymorphism, Genetic