Meta-analysis of blood pressure and the CYP11B2 polymorphism highlights the need for better designed studies

摘要

The distribution of blood pressure in populations is almost certainly dependent on a mosaic of many genetic loci each with a minute contribution and is under the influence of multiple gene–gene [1] and gene–environment [2] interactions. Unravelling the genetic determinants of hypertension mainly rests on three approaches. First, whole-genome scans search for linkage peaks with traits of interest, and in the case of positive linkage, lead to further experimental and clinical studies to characterize potential loci of interest. Second, high-throughput genotyping using modern chip technology is like casting a net in a pond containing plenty of fish with the hope that subsequent sorting will identify the goldfish (i.e. the rare polymorphic markers carrying the breakthrough information). Finally, the candidate gene approach builds on existing pathophysiological knowledge and common polymorphisms in genes known to be involved in some aspects of blood pressure regulation. Usually, a few seminal studies raise the interest in a particular, preferably functional, polymorphism in a candidate gene. Next, large-scale case–control designs or association studies in patient cohorts or in the population at large attempt to reproduce the initial observations, but rarely generate consistent findings [3]. This is not surprising because, as outlined elsewhere [4,5], methodological issues limit the interpretation of many published studies. Key obstacles are the lack of standardization, the arbitrary dichotomization of continuous phenotypes, the inappropriate selection of cases and controls, population admixture and stratification, an insufficient sample size, and a failure to account for confounders or environmental factors. Quantitative systematic reviews, commonly known as meta-analyses, offer the possibility to provide pooled estimates across a large number of studies on a given cardiovascular trait in relation to a genetic polymorphism and to identify sources of heterogeneity in the published results. The –344C/T polymorphism in the aldosterone synthase gene (CYP11B2) ranks high among the genetic variants most frequently studied in relation to cardiovascular and renal phenotypes. In the present issue of the journal, Sookoian et al. [6] reviewed 42 studies, of which 24 were population-based and 18 hospital-based. The number of pooled reports was 19 for hypertension as dichotomous endpoint (11 225 subjects), 13 for systolic and diastolic blood pressures as continuous variables (n = 1775), 14 for the plasma aldosterone concentration (n = 2872), and eight for the plasma renin activity (n = 1428). The authors excluded heterozygotes from analysis. The bold conclusion, that –344CC homozygotes had a 17% lower risk of hypertension than their –344TT counterparts, hinged on the pooled odds ratio computed from a fixed-effect model [0.83; 95% confidence interval (CI) = 0.76–0.91; P < 0.001] across widely heterogeneous studies [6]. The odds ratio calculated from a random-effects model did not reach statistical significance (0.89; CI = 0.76–1.04; P = 0.13). In the review by Sookoian et al. [6], hypertension was a blood pressure higher than 140 mmHg systolic or 90 mmHg diastolic or treatment with antihypertensive drugs. Unlike recommendations in recent guidelines [7], untreated subjects with a systolic blood pressure of 140 mmHg or diastolic blood pressure of 90 mmHg were therefore classified as normotensive. The continuous analyses across 13 studies and 15 groups of subjects did not confirm the main conclusion because neither fixed-effects nor random-effects models demonstrated a significant difference between CC and TT homozygotes in systolic (P = 0.41 and 0.54, respectively) or diastolic (P = 0.61 and 0.85, respectively) blood pressures. Treated patients were excluded from the meta-analysis of blood pressure as continuous phenotype. In most quantitative overviews, heterogeneity is a major issue. Ioannidis et al. [3] noted between-study heterogeneity in 26 of