title: Common genetic polymorphisms in the 5'-flanking region of the SULT1A1 gene: haplotypes and their association with platelet enzymatic activity.
abstract: SULT1A1 is a phase II detoxification enzyme involved in the biotransformation of a wide variety of endogenous and exogenous phenolic compounds. Human platelet SULT1A1 enzymatic activity shows marked inter-individual variability and a common coding polymorphism, SULT1A1*1/*2, has been described that accounts for a proportion of this variability. We examined the 5'-flanking region of the SULT1A1 gene to determine if genetic variability in this portion of the gene influenced enzymatic activity. Direct sequencing revealed five common genetic polymorphisms (-624G>C, -396G>A, -358A>C, -341C>G and -294T>C) that were present at different allele frequencies in Caucasian, African-American and Chinese groups. Platelet SULT1A1 enzymatic activity was significantly correlated with individual promoter region polymorphisms and the associations were different between African-Americans and Caucasians. Haplotypes were constructed and platelet enzymatic activity according to haplotype was examined. The haplotypes were also significantly correlated with activity; haplotypes GAACT and GGACT (accounting for 13% and 5% of inter-individual variability in platelet activity, respectively) were important in Caucasians while haplotypes GAACC, GAACT and GGACC (accounting for 8%, 5% and 4% of variability) were significantly associated with activity in African-Americans. The coding region polymorphism, SULT1A1*1/*2 was in linkage disequilibrium with the promoter region polymorphisms and showed no effect on activity when examined in the context of the 5'-flanking region polymorphisms. These studies indicate that variation in the promoter region of the SULT1A1 gene exerts a significant influence on enzymatic activity.
authors.affiliation: Division of Pharmacogenomics and Molecular Epidemiology, National Center for Toxicological Research, Jefferson, Arizona, USA.
authors.forename: Baitang
authors.initials: B
authors.lastname: Ning
authors.forename: Susan
authors.initials: S
authors.lastname: Nowell
authors.forename: Carol
authors.initials: C
authors.lastname: Sweeney
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
authors.forename: Suzanne
authors.initials: S
authors.lastname: Williams
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Miao
authors.forename: Gang
authors.initials: G
authors.lastname: Liang
authors.forename: Dongxin
authors.initials: D
authors.lastname: Lin
authors.forename: Angie
authors.initials: A
authors.lastname: Stone
authors.forename: D Luke
authors.initials: DL
authors.lastname: Ratnasinghe
authors.forename: Mugimane
authors.initials: M
authors.lastname: Manjanatha
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Lang
authors.forename: Fred F
authors.initials: FF
authors.lastname: Kadlubar
mesh_terms: D024506:5' Flanking Region / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015239:Arylsulfotransferase / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D001792:Blood Platelets / Q000201:enzymology*; D016022:Case-Control Studies; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044465:White People / Q000235:genetics; D001741:Black or African American
chemical_list: D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human