title: Impact of TCF7L2 single nucleotide polymorphisms on hydrochlorothiazide-induced diabetes.
abstract: OBJECTIVE
  Thiazide diuretics have been associated with increased risk for new onset diabetes (NOD), but pharmacogenetic markers of thiazide-induced NOD are not well studied. Single nucleotide polymorphisms (SNPs) in the transcription factor 7-like 2 gene (TCF7L2) represent the strongest and most reproducible genetic associations with diabetes. We investigated the association of tag SNPs in TCF7L2 with thiazide-induced NOD.
  
  
  METHODS
  We identified cases that developed NOD and age, sex, and race/ethnicity-matched controls from the INternational VErapamil SR-Trandolapril STudy (INVEST). INVEST compared cardiovascular outcomes between two antihypertensive treatment strategies in ethnically diverse patients with hypertension and coronary artery disease. We genotyped 101 TCF7L2 tag SNPs and used logistic regression to test for pharmacogenetic (SNP×hydrochlorothiazide treatment) interactions. Permuted interaction P values were corrected with the PACT test and adjusted for diabetes-related variables.
  
  
  RESULTS
  In INVEST whites, we observed three TCF7L2 SNPs with significant SNP×treatment interactions for NOD. The strongest pharmacogenetic interaction was observed for rs7917983 [synergy index 3.37 (95% CI 1.72-6.59), P=5.0×10, PACT=0.03], which was associated with increased NOD risk in hydrochlorothiazide-treated patients [odds ratio 1.53 (1.04-2.25), P=0.03] and decreased NOD risk in non hydrochlorothiazide-treated patients [odds ratio 0.48 (0.27-0.86), P=0.02]. The TCF7L2 SNP rs4506565, previously associated with diabetes, showed a similar, significant pharmacogenetic association.
  
  
  CONCLUSIONS
  Our results suggest that hydrochlorothiazide treatment is an environmental risk factor that increases diabetes risk beyond that attributed to TCF7L2 variation in white, hypertensive patients. Further study and replication of our results is needed to confirm pharmacogenetic influences of TCF7L2 SNPs on thiazide-induced NOD.
authors.affiliation: aDepartment of Medicine, Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee bDepartment of Pharmacotherapy and Translational Research cDepartment of Pharmacotherapy and Translational Research, Center for Pharmacogenomics dDepartment of Medicine, Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida eOffice of Clinical Pharmacology, Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Karnes
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pacanowski
authors.forename: Caitrin W
authors.initials: CW
authors.lastname: McDonough
authors.forename: Meghan J
authors.initials: MJ
authors.lastname: Arwood
authors.forename: Taimour Y
authors.initials: TY
authors.lastname: Langaee
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Pepine
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Cooper-Dehoff
mesh_terms: D001741:Black or African American / Q000235:genetics; D000368:Aged; D000959:Antihypertensive Agents / Q000009:adverse effects*; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000150:complications / Q000208:ethnology; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced* / Q000208:ethnology / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D006852:Hydrochlorothiazide / Q000009:adverse effects*; D006973:Hypertension / Q000188:drug therapy* / Q000208:ethnology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D000959:Antihypertensive Agents; D005819:Genetic Markers; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D006852:Hydrochlorothiazide