Genetic variation in aldosterone synthase predicts plasma glucose levels

Abstract

The mineralocorticoid hormone, aldosterone, is known to play a role in sodium homeostasis. We serendipitously found, however, highly significant association between single-nucleotide polymorphisms in the aldosterone synthase gene and plasma glucose levels in a large population of Chinese and Japanese origin. Two polymorphisms-one in the putative promoter (T-344C) and another resulting in a lysine͞arginine substitution at amino acid 173, which are in complete linkage disequilibrium in this population-were associated with fasting plasma glucose levels (P ‫؍‬ 0.000017) and those 60 (P ‫؍‬ 0.017) and 120 (P ‫؍‬ 0.0019) min after an oral glucose challenge. A C͞T variant in intron 1, between these polymorphisms, was not associated with glucose levels. Arg-173 and -344C homozygotes were most likely to be diabetic [odds ratio 2.51; 95% confidence interval (C.I.) 1.39 -3.92; P ‫؍‬ 0.0015] and have impaired fasting glucose levels (odds ratio 3.53; 95% C.I. 2.02-5.5; P ‫؍‬ 0.0000036). These results suggest a new role for aldosterone in glucose homeostasis.H ypertension affects 15-50% of the adult population and is one of the major risk factors for stroke, myocardial infarction, and renal disease. Despite intense effort, our understanding of heritable factors in the etiology of hypertension is rather poor. Twin, adoption, and epidemiologic studies indicate that variation in blood pressure (BP) is genetically determined to some extent (1-3). Insulin resistance, defined as the sluggish uptake of glucose by peripheral tissue in the presence of normal or elevated levels of insulin, is frequently associated with hypertension (4). One of the goals of the Stanford, Asia, and Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) study is to identify predisposing genes for essential hypertension and insulin resistance.To maximize our chances of finding susceptibility genes for these diseases, we took several steps. First, in an attempt to reduce genetic heterogeneity, we focused on a relatively homogeneous population of Chinese and Japanese descent. Second, we sampled subjects from tails of the systolic or diastolic BP distributions-the affected hypertensives were recruited from the upper 20% of the distribution, whereas the unaffected ''low-normotensive'' individuals had BP readings in the lower 30% of the distribution (5). Third, because recent theoretical work suggests that association studies might be adequately powerful to detect susceptibility loci that have a modest effect on the phenotype (6), we began candidate gene studies by testing specific variants in genes that might, for biological reasons, be expected to be involved in BP regulation or glucose homeostasis for association with hypertension or insulin resistance.The mineralocorticoid hormone, aldosterone, by determining the amount of sodium and water reabsorbed by the kidney, plays a key role in regulating BP (7). Indeed, mutations in the aldosterone synthase gene or in the receptor for the hormone can cause Mendelian forms of hypertension and hypotension ...

Renin‐Angiotensin‐Aldosterone System, Glucose Metabolism and Incident Type 2 Diabetes Mellitus: MESA

“…The most studied polymorphism of CYP11B2 is T‐344C in the promoter region and the polymorphism is associated with higher aldosterone levels 23, 24. In a large population of individuals of Chinese and Japanese ancestry, CYP11B2 polymorphisms (Arg‐173 and T‐344C) were associated with higher FPG levels, higher 2‐hour post load glucose, impaired fasting glucose and type 2 diabetes mellitus,25 which is consistent with our findings of a high risk of type 2 diabetes mellitus in Chinese Americans with higher levels of aldosterone. Additionally, a prospective Japanese cohort study with 10 years of follow‐up demonstrated that plasma aldosterone levels predict the development of insulin resistance,26 suggesting our findings might extend to individuals with ancestry from the continent of Asia.…”

Aldosterone synthase alleles and cardiovascular phenotype in young adults

“…19 Indeed, it is possible that the most common polymorphisms of the renin-angiotensin-aldosterone system studied so far have very little effect (if any) on BP and its consequences, as also suggested by our results 6 and those of another recent study. 20 Studies that analysed older populations (affected sibships, cross-sectional, and case-control studies) produced widely contradictory data 2,3 even if, overall, the T(À344) allele appears to be the 'unfavourable' one. 3 Population biases (criteria used to select patients and controls or differences in age, environmental, and ethnic/genetic background), lack of statistical power, epistatic interactions, 13,14 and, finally, publication bias toward positive association have been indicated as possible causes of these contradictory results.…”

Bivariate genome-wide scan for metabolic phenotypes in non-diabetic Chinese individuals from the Stanford, Asia and Pacific Program of Hypertension and Insulin Resistance Family Study

“…The details of recruitment, exclusion criteria, phenotyping and genotyping have been described elsewhere [17,20,21]. In brief, the study was composed of concordant siblings (all siblings with hypertension) and discordant siblings (at least one hypertensive sibling).…”

“…Blood samples were taken for plasma glucose and insulin 1 and 2 h after glucose loading. The patients were not allowed to eat or drink until the end of the test [21].…”

“…Phenotyping procedures for plasma glucose and insulin were as detailed in Ranade et al [21]. Derivations from the homeostasis model assessment of insulin resistance (HOMA-IR) and beta cell function (HOMA-beta), AUC glucose and AUC insulin were identical to the previous study [9].…”