title: 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.affiliation: Division of Clinical Medicine and Biomedical Sciences, Department of Gastroenterology and Hepatology, Institute of Medical Science, Mie University Graduate School of Medicine, Mie 514-8507, Japan.
authors.forename: Naohito
authors.initials: N
authors.lastname: Urawa
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Jun
authors.initials: J
authors.lastname: Araki
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Sugimoto
authors.forename: Motoh
authors.initials: M
authors.lastname: Iwasa
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kaito
authors.forename: Yukihko
authors.initials: Y
authors.lastname: Adachi
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic
chemical_list: C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase; C107611:UDP-glucuronosyltransferase, UGT1A7