title: Comparative genomics analysis of human sequence variation in the UGT1A gene cluster.
abstract: Common polymorphisms within the human UGT1A gene locus are associated with irinotecan and tranilast toxicity. To uncover additional functional variation across this gene cluster, cross-species sequence comparisons were performed. Evolutionarily conserved segments (a total of 47.1 kb) were re-sequenced in 24 African-American, 24 European-American, and 24 Asian individuals, and 381 segregating sites (including 123 singletons) were identified. Highly conserved coding sites were less likely to be polymorphic than diverged sites (P<0.0001) but this pattern was not observed at non-coding sites (P=0.1025). Among coding variants, the distribution of those computationally predicted to affect function was skewed toward low frequencies. Some alleles occurred at similar frequencies in each population; others had wide disparities. Although strong linkage disequilibrium was detected among the hepatically expressed genes, the degree of linkage disequilibrium varied among populations. These results suggest that rare functional gene variants and inter-population variability must be considered in the interpretation of association studies between UGT1A and drug metabolism/toxicity phenotypes.
authors.affiliation: Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, IL 60637, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Maitland
authors.forename: C
authors.initials: C
authors.lastname: Grimsley
authors.forename: H
authors.initials: H
authors.lastname: Kuttab-Boulos
authors.forename: D
authors.initials: D
authors.lastname: Witonsky
authors.forename: K E
authors.initials: KE
authors.lastname: Kasza
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.forename: B A
authors.initials: BA
authors.lastname: Roe
authors.forename: A
authors.initials: A
authors.lastname: Di Rienzo
mesh_terms: D000818:Animals; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D044383:Black People / Q000235:genetics; D004285:Dogs; D005787:Gene Frequency; D014644:Genetic Variation; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D010215:Papio; D051381:Rats; D016415:Sequence Alignment; D013045:Species Specificity; D044465:White People / Q000235:genetics; D001741:Black or African American; D000099148:UGT1A1 Enzyme
chemical_list: D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme