ORIGINAL ARTICLESCommon genetic polymorphisms in the 5′-flanking Region of the SULT1A1 gene: haplotypes and their association with platelet enzymatic activityNing, Baitanga *; Nowell, Susana c *; Sweeney, Carold; Ambrosone, Christine B.c; Williams, Suzannee; Miao, Xiaopingf; Liang, Gangf; Lin, Dongxinf; Stone, Angiea; Luke Ratnasinghe, D.a; Manjanatha, Mugimaneb; Lang, Nicholas P.e g; Kadlubar, Fred F.aAuthor Information Divisions of aPharmacogenomics and Molecular Epidemiology bGenetic Toxicology, National Center for Toxicological Research, Jefferson, Arizona, USA cRoswell Park Cancer Institute, Buffalo, New York, USA dUniversity of Utah, Salt Lake City, Utah, USA eCentral Arkansas Veteran's Health Care System, 11-LR, Little Rock, Arkansas, USA fDepartment of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China gDepartment of Surgery, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA Sponsorship: This work was supported in part by Department of Defense DAMD17-02-1-0274. Correspondence and requests for reprints to Susan Nowell, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA Tel: +1 716 845 3103; fax: +1 716 845 1356; e-mail: [email protected] Received 19 November 2004 Accepted 5 April 2005 *These authors contributed equally to this work. Pharmacogenetics and Genomics: July 2005 - Volume 15 - Issue 7 - p 465-473 doi: 10.1097/01.fpc.0000166823.74378.79 Buy Metrics 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. © 2005 Lippincott Williams & Wilkins, Inc.