Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

• Published in: The pharmacogenomics journal Vol. 6; no. 1; pp. 52 - 62
• Main Authors: Maitland, M L, Grimsley, C, Kuttab-Boulos, H, Witonsky, D, Kasza, K E, Yang, L, Roe, B A, Di Rienzo, A
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01-01-2006
• Subjects: Animals; Asian People - genetics; Base Sequence; Black or African American; Black People - genetics; Conserved sequence; Dogs; Drug metabolism; Gene Frequency; Genetic Variation; Glucuronosyltransferase - genetics; Humans; Irinotecan; Linkage disequilibrium; Mice; Molecular Sequence Data; Multigene Family; Papio; Phenotypes; Population genetics; Rats; Sequence Alignment; Species Specificity; Toxicity; White People - genetics
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/sj.tpj.6500351

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.