Genetic variation in the renin-angiotensin system modifies the beneficial effects of ACE inhibitors on the risk of diabetes mellitus among hypertensives

Abstract

The aim of this study was to assess whether the association between angiotensin-converting enzyme (ACE) inhibitor use and the incidence of treated diabetes mellitus is modified by genetic polymorphisms in the renin-angiotensin system (RAS).In a nested case-control study, treated hypertensive patients were genotyped for ACE (insertion (I)/deletion (D)), angiotensinogen (AGT; M235T) and angiotensin II type 1 receptor (AGTR1; A1166C). Cases of newly treated diabetes were identified based on pharmacy records and controls were not yet drug treated for diabetes (case:control ratio 1:10). Self-administered questionnaires and physical examinations were used to assess risk factors for diabetes mellitus. Logistic regression was used to calculate the relative risk of diabetes associated with ACE inhibitor use relative to other antihypertensive treatment, stratified by the RAS genotypes. Among 205 cases and 2050 controls, homozygous 1166A carriers of the AGTR1 gene had a significantly decreased incidence of diabetes associated with current use of ACE inhibitors (odds ratio, OR: 0.47; 95% CI: 0.26-0.84), whereas this incidence was increased among 1166C allele carriers (OR: 1.32; 95% CI: 0.81-2.14). The interaction OR was 3.21 (95% CI: 1.53-6.75). ACE I allele carriers had a significantly reduced incidence of diabetes associated with ACE inhibitors use (OR: 0.63; 95% CI: 0.41-0.98), whereas DD homozygotes had no reduced risk (OR: 0.95; 95% CI: 0.46-1.96). The risk of diabetes associated with ACE inhibitor use was not significantly modified by the AGT-M235T polymorphism. Treatment with ACE inhibitors in hypertensive subjects significantly reduces the occurrence of diabetes in homozygous 1166A carriers of the AGTR1 gene and carriers of the ACE I allele, but not in 1166C allele carriers of the AGTR1 gene and in homozygous ACE D allele carriers.

Genotypic interactions of renin–angiotensin system genes with diabetes type 2 in a Tunisian population

“…However, Wu et al (2000) suggested that the DD genotype might be an independent risk factor of diabetic nephropathy in Chinese patients with T2DM. Treatment with ACE inhibitors in hypertensive subjects significantly reduces the occurrence of diabetes in homozygous carriers of the I allele, but not in homozygous D allele carriers (Bozkurt and Verschuren 2008). The DD genotype is associated with twice the normal level of serum ACE activity (Rigat et al 1990;Mehri et al 2010).…”

“…But some researchers reported no obvious association between a specific AGT genotype and diabetic nephropathy (Eroglu et al 2008;Buraczyńska et al 2002). The risk of diabetes associated with ACE inhibitor use was not significantly modified by the AGT-M235T polymorphism (Bozkurt and Verschuren 2008). The AGT T allele has been functionally related to increased AGT plasma levels (Winkelmann et al 1999).…”

Renin-angiotensin system polymorphisms and the association between use of angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors and the risk of diabetes

“…Based on our previous findings, we assumed a recessive model for the interaction with the AT 1 -receptor and ACE gene and a dominant model for the AGT gene. 12 The interaction odds ratio (OR) was calculated by adding an interaction term (ARB (or ACE inhibitor) × GENOTYPE) to the logistic regression model. The interaction OR can be interpreted as the ratio of the OR in subjects with a susceptible genotype and the OR in subjects without this genotype.…”

“…11 Previously, we found in a small study among treated hypertensives that the AT 1 -receptor C allele and the ACE I/D polymorphism modified the risk of diabetes associated with ACE inhibitors. 12 Whether the risk of diabetes associated with ARB use is influenced by genetic polymorphisms in RAS genes is unknown. The aim of this study was 1) to assess whether the association between the use of ARBs and the incidence of new onset diabetes is modified by genetic polymorphisms in RAS genes such as angiotensinogen (AGT), ACE, and AT 1 -receptor and 2) to confirm our initial findings with regard to ACE inhibitors.…”

SNP Analysis, Genome Wide Association Studies and Pharmacogenetic implications of Acute Myocardial Infarction

“…[19] This SNP was associated with two other variants, rs4341, and rs4344 that influence drug therapy for Fluvastatin, Thiazides, Furosemide, Spironolactone, Pravastatin, and Ramipril respectively. [20][21] [22] These drugs, especially Fluvastatin, are prescribed for hypercholesterolemia and for prevention of cardiovascular diseases. [23] For the gene MIA3, with the sole SNP variant association of variants rs10495197 and rs17163303, it was found that each of the SNPs individually has the potential to influence the drug therapy for Vancomycin.…”