Impact of TCF7L2 single nucleotide polymorphisms on hydrochlorothiazide- induced diabetes

Jason H. Karnes, Yan Gong, Michael A. Pacanowski, Caitrin W. McDonough, Meghan J. Arwood, Taimour Y. Langaee, Carl J. Pepine, Julie A. Johnson, Rhonda M. Cooper-DeHoff

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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 × 10-4, PACT =0.03], which was associated with increased NOD risk in hydrochlorothiazidetreated patients [odds ratio 1.53 (1.04-2.25), P= 0.03] and decreased NOD risk in non hydrochlorothiazidetreated 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. Conclusion 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. Pharmacogenetics and Genomics 23:697-705

Original languageEnglish (US)
Pages (from-to)697-705
Number of pages9
JournalPharmacogenetics and Genomics
Issue number12
StatePublished - Dec 2013


  • Diabetes mellitus
  • Hydrochlorothiazide
  • Pharmacogenetics
  • TCF7L2

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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