Genetic variant of the renin-angiotensin system and prevalence of type 2 diabetes mellitus: a modest but significant effect of aldosterone synthase

Abstract

Recent genome-wide association studies have identified multiple variants that confer risk of type 2 diabetes mellitus (DM). However, established associations explain only a part of the heritability. Thus, even at the genome-wide association studies era, candidate gene approach should be still useful. Recent interventional studies against the renin-angiotensin system (RAS) showed reduction in new onset of DM, implying the system is involved in the onset. We substantiated the hypothesis that genetic variants of RAS have significant association with prevalence of DM. We enrolled to the study consecutive 782 subjects who had consulted our hospitals for mainly lifestyle related diseases. They consisted of 282 (36.1 %) diabetes cases. Genotypes were assayed with genomic DNA for conventional four genes of the RAS, i.e., angiotensin converting enzyme (ACE) insertion/deletion variant, angiotensinogen (AGT) M235T variant, angiotensin II type I receptor (AT1) A1166C variant, and aldosterone synthase (CYP11B2) C-344T variant. Association between the genetic variants of the RAS and prevalence of type 2 DM was tested. A significant association of DM and CYP11B2 genotype was obtained. There was no significant association between DM and ACE, AGT and AT1 variants. A multivariate logistic regression showed that age, gender, and CYP11B2 genotype were independent factors for association to diabetes, the DM risk of CC/CT to TT being 1.40 (95 % CI 1.04–1.90, p = 0.029). Thus, it is concluded that a genetic variant of the RAS should have a modest but significant impact on the onset of type 2 diabetes mellitus.

Associations of the –344T>C polymorphism of CYP11B2 gene with 24-hour blood pressure profiles in middle-aged women with essential hypertension

“…Consistently with this observation, Bellili et al found in the general French population that the -344T/C polymorphism was associated with increased risks for incident type 2 diabetes and metabolic syndrome [13]. Similar suggestions were from study of Ichikava et al in which the CT/CC carriers had increased risk of type 2 diabetes by 40% in comparison to TT carriers [30]. Additionally, recent studies have emphasized that the aldosterone synthase CYP11B2 (-344T>C) gene polymorphism may be a useful predictor of the antihypertensive response to valsartan [25,29].…”

Association of Angiotensin Converting Enzyme Insertion-Deletion Polymorphism with Hypertension in Emiratis with Type 2 Diabetes Mellitus and Its Interaction with Obesity Status

“…The rising prevalence has been attributed to sedentary lifestyle related factors; however, genetic predisposition may play a vital role in the etiology and manifestation of the disease [ 3 – 5 ]. Recently, an ample amount of studies has focused on genetic variants in Renin-Angiotensin-Aldosterone System (RAAS) in association with the components of metabolic syndrome, especially hypertension and T2DM [ 6 – 8 ]. The association between insulin resistance, hyperinsulinemia, and the RAAS independent of plasma potassium and cortisol levels has been shown [ 9 ] and has been implicated in the development of cardiovascular and renal diseases in T2DM [ 10 ].…”

A Genetic Variant in the Distal Enhancer Region of the Human Renin Gene Affects Renin Expression

“…The renin-angiotensin system (RAS) plays pivotal roles in blood pressure regulation,[ 1 ] cardiovascular, renal and metabolic conditions[ 2 – 4 ] and pharmacological status. [ 5 , 6 ] One of the major rate-limiting steps of this system is the conversion of angiotensinogen to angiotensin I, which is catalyzed by renin.…”