Research has shown that bradykinin β 2 receptor (BDKRB2) −58T/C gene polymorphism is correlated with the risk of essential hypertension (EH), but the results remain inconclusive.
The objective of this study was to explore the association between BDKRB2−58T/C gene polymorphism and EH. A meta-analysis of 11 studies with 3882 subjects was conducted. Pooled odds ratios (ORs) for the association between BDKRB2−58T/C gene polymorphism and EH and their corresponding 95% confidence intervals (CIs) were estimated using the random effects model.
The BDKRB2−58T/C gene polymorphism was significantly correlated with EH under an allelic genetic model (OR = 1.24, 95% CI = 1.05–1.46; P = 0.01), a dominant genetic model (OR = 0.65, 95% CI = 0.47–0.90; P = 0.01), a recessive genetic model (OR = 1.146, 95% CI = 1.035–1.269; P = 0.009), a homozygote genetic model (OR = 1.134, 95% CI = 1.048–1.228; P = 0.002), and a heterozygote genetic model (OR = 1.060, 95% CI = 1.009–1.112; P = 0.019).
The BDKRB2−58T/C gene polymorphism is associated with increased EH risk. The results of this study suggest that carriers of the −58C allele are susceptible to EH.
The kallikrein–kinin system (KKS) is an important hormonal system that takes part in blood pressure (BP) and renal sodium regulation. Bradykinin is one of the strongest vasodilator substances, and it has powerful diuretic effects. It exerts its vasodilatory effects mainly by expanding the vessels directly, confronting the vasoconstrictive effects of angiotensin II and noradrenaline, and promoting the synthesis of endogenous vasodilator substances, such as nitric oxide.
The function of bradykinin is mediated by two receptor subtypes, namely, β 1 (BDKRB1) and β 2 (BDKRB2). BDKRB1 expression is low in healthy individuals; however, under such pathological states as inflammation and tissue injury, it could be upregulated. The physical effects of bradykinin are mostly mediated by BDKRB2. The BDKRB2 gene, located in 14q32.1–32.2, spans approximately 4 kb and consists of three exons. In 1996, Braun et al. detected −58T/C variations in the BDKRB2 promoter region and found that these could lead to a reduction in BDKRB2 transcription, which might be associated with the pathogenesis of essential hypertension (EH).
The relationship between BDKRB2−58T/C gene polymorphism and EH has been widely studied, but the results remain inconclusive. In 2000, Gainer et al. found that BDKRB2−58C might represent a susceptibility marker for EH in African Americans. In 2006, Dong et al. found an association between BDKRB2−58T/C gene polymorphism and EH and concluded that the −58CC genotype is associated with increased EH risk in a Chinese population. However, in 2012, Bhupatiraju et al. did not identify any such association in an Indian population. We thus performed a meta-analysis of 11 studies, including 1947 patients with EH and 1935 control subjects, to deduce a reasonable conclusion on the relationship between BDKRB2−58T/C gene polymorphism and EH (Supplement S5).
PubMed, EMBASE, Web of Science, China Biological Medicine Database, and China National Knowledge Infrastructure were searched for relevant articles with the terms “essential hypertension”, “bradykinin β 2 receptor”, and “polymorphism”. Studies published before 2012 were obtained (last research updated on July 7, 2012).
Studies that met the following major criteria were included: (a) the association between BDKRB2−58T/C gene polymorphism and EH was assessed; (b) the diagnosis of EH was in line with the 1999 diagnostic criteria of the World Health Organization in which systolic BP≥140 mmHg, diastolic BP≥90 mmHg, and treatment with antihypertensive medication defined EH, excluding patients with secondary hypertension, cardiomyopathy, valvular heart disease, congenital heart diseases, and renal failure; (c) the Hardy–Weinberg equilibrium (HWE) was followed; and (d) the results of the same data used in different studies were adopted only once. If articles with similar data were published by the same work group, the study with the larger sample size was selected.
The data were collected according to a standard protocol. Repeated publications, studies against the selection criteria, and work providing insufficient data were excluded from the meta-analysis. Data were recorded as follows: first author’s name, publication year, study region, number of genotypes, genotyping, study design, matching criteria, total number of case patients, and total number of control subjects.
Five genetic models (allelic, dominant, recessive, homozygote, and heterozygote) were used. The association between BDKRB2−58T/C gene polymorphism and EH reported under these models was analyzed using odds ratios (ORs) with 95% confidence intervals (CIs). Between-study heterogeneity was calculated by χ 2-based Q analysis, and significance was set at P<0.05. The variation caused by heterogeneity was estimated by calculating the inconsistency index I 2. If heterogeneity among studies was detected, the DerSimonian–Laird random effects pooling method was used; otherwise, the Mantel–Haenszel method fixed effects model was applied. The Z test was used to determine the pooled OR, and significance was set at P<0.05.
Fisher’s exact test was used to assess the HWE, and P<0.05 was considered statistically significant. Potential publication bias was estimated by funnel plot analysis. The funnel plot asymmetry was assessed by Egger’s linear regression test on the natural logarithm scale of the OR (P<0.05). Statistical analysis was performed using STATA 11.0 (StataCorp, College Station, TX).
Our literature search yielded 20 relevant articles, 11 of which met the inclusion criteria. Of the 9 excluded studies, 2 were double publications, 2 were reviews, and 5 were not associated with the BDKRB2−58T/C gene polymorphism. No study was excluded for deviating from the HWE. Data were collected from 1947 patients with EH and 1935 control subjects (Supplement S1 and S6). The six surveyed regions representing Asia, North America, and Europe included China, Japan, India, the United States, Canada, and Italy.
A significant association between BDKRB2−58T/C gene polymorphism and EH was found under the allelic (OR = 1.24, 95% CI = 1.05–1.46; P = 0.01), dominant (OR = 0.65, 95% CI = 0.47–0.90; P = 0.01), recessive (OR = 1.146, 95% CI = 1.035–1.269; P = 0.009), homozygote (OR = 1.134, 95% CI = 1.048–1.228; P = 0.002), and heterozygote (OR = 1.060, 95% CI = 1.009–1.112; P = 0.019) genetic models. Subgroup analysis stratified by continent also revealed a significant association between BDKRB2−58T/C gene polymorphism and EH in the Asian subgroup under the allelic (OR = 1.24, 95% CI = 1.01–1.52; P = 0.04), dominant (OR = 0.63, 95% CI = 0.43–0.92; P = 0.02), recessive (OR = 1.152, 95% CI = 1.010–1.315; P = 0.036), homozygote (OR = 1.166, 95% CI = 1.047–1.298; P = 0.005), and heterozygote (OR = 1.070, 95% CI = 1.011–1.132; P = 0.019) genetic models. No significant association was found in the American and European subgroups under any of the genetic models (P>0.05) (Supplement S2; Figures 1 and 2).
Figure 5. Funnel plot for studies of the association of essential hypertension associated with BDKRB2 -58T/C gene polymorphism under an allelic genetic model (distribution of C allelic frequency of BDKRB2 gene). The horizontal and vertical axis correspond to the OR and confidence limits. OR: odds ratio; SE: standard error.
In consideration of the significant heterogeneity we observed, a meta-regression was performed to explore the source of heterogeneity. Under the allelic genetic model, the heterogeneity could be explained by the
