Variation in renin-angiotensin system and salt sensitivity genes and the risk of diabetes mellitus associated with the use of thiazide diuretics

Background: Variation in the renin-angiotensin system (RAS), and salt-sensitivity genes may influence the effect of thiazides on the risk of diabetes. Objectives: To assess whether polymorphisms in RAS and salt-sensitivity genes influence the risk of diabetes associated with thiazides. Methods: Nested-case control study 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 5) who were not (yet) diagnosed with diabetesmellitus. We genotyped ACE (G4656C), AGT (M235T), AGTR1 (A1166C), ADD1 (G460T), GNB3 (C825T). Results: Among 497 incident cases of type 2 diabetes and 2633 controls, AGTR1 CC genotype carriers had no increased risk of diabetes due to thiazides (OR 0.63 [95%CI:0.28-1.40]), whereas this risk was increased in AGTR1 1166A allele carriers (OR 1.79 [95%CI:1.43-2.23] and 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 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]). Conclusions: 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.