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Variation in the renin-angiotensin system (RAS) and salt-sensitivity genes may influence the effect of thiazides on the risk of diabetes. We assessed whether polymorphisms in RAS and salt-sensitivity genes influenced the risk of diabetes associated with thiazides.Nested case-control study was conducted among antihypertensive drug users. Pharmacy records and questionnaires were used to assess new onset diabetes (cases), to ascertain antihypertensive use and risk factors for diabetes. Cases were matched to controls (up to five) who were not (yet) diagnosed with diabetes mellitus. We genotyped angiotensin-converting enzyme (ACE) (G4656C), angiotensinogen (AGT) (M235T), angiotensin II type 1 receptor, (AGTR1) (A1166C), adducin 1 (alpha) (ADD1) (G460T), guanine nucleotide binding protein (G protein), β-polypeptide 3 (GNB3) (C825T).Among 497 incident cases of type 2 diabetes and 2,633 controls, AGTR1 CC genotype carriers had no increased risk of diabetes due to thiazides (odds ratio (OR) 0.63 (95% confidence interval (CI): 0.28-1.40)) compared to AGTR1 1166A allele carriers (OR 1.79 (95% CI: 1.43-2.23)) receiving thiazides (synergy index (SI) for interaction 0.32 (95% CI: 0.15-0.68)). Although homozygous ACE GG subjects and ACE C allele carriers both had an increased risk of diabetes associated with thiazide use, this risk was more increased for ACE GG subjects (SI 1.70 (95% CI: 1.08-2.66)), particularly at doses ≥1 daily defined dose (DDD) (=25 mg hydrochlorothiazide)/day (SI 2.0 (95% CI: 1.20-3.32)). Among GNB3 T allele carriers, the risk of diabetes due to thiazide use was less increased than among homozygous GNB3 CC subjects (SI 0.62 (95% CI: 0.41-0.93)).The risk of diabetes due to thiazide use was not increased among AGTR1 1166 CC homozygous subjects and less increased among GNB3 T allele carriers. The ACE 4656 GG genotype enhanced the risk of diabetes due to thiazides.