The C825T polymorphism of the G-protein β3 subunit gene and its association with hypertension and stroke: an updated meta-analysis

Abstract

Objective: Several epidemiological studies have evaluated the association between the GNB3 C825T polymorphism and hypertension or stroke. The results of these studies were inconsistent; therefore, we performed a meta-analysis to clarify these discrepancies.

Methods: We systematically searched the PubMed, Embase, Web of Science, CNKI, and CBM databases, and manually searched reference lists of relevant papers, meeting abstracts, and relevant journals. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for dominant, recessive, and allelic models. A fixed or random effects model was separately adopted depending on study heterogeneity. Subgroup and sensitivity analyses were performed to detect study heterogeneity and examine result stability, respectively. Publication bias was tested using funnel plots, the Egger's regression test, and Begg's test.

Results: We screened 66 studies regarding hypertension and eight concerning stroke. A combined analysis showed that only the allelic model found a marginal association with hypertension (OR = 1.07, 95% CI = 1.01-1.13) and female gender (OR = 1.11, 95% CI = 0.99-1.24). However, no comparison models found an association with stroke (allelic model: OR = 1.11, 95% CI = 0.94-1.32; dominant model: OR = 1.16, 95% CI = 0.92-1.48; and recessive model: OR = 1.05, 95% CI = 0.97-1.14). Sensitivity analysis suggested that all models did not yield a relationship to hypertension or stroke among Asians. Besides, there was a lack of statistical association with hypertension in Caucasians, which maybe due to a small sample size. When we restricted the included studies to normal populations according to the Hardy-Weinberg equilibrium, no association was found.

Conclusions: There was no evidence indicating that the 825T allele or TT genotype was associated with hypertension or stroke in Asians or hypertension in Caucasians. However, further studies regarding Africans and other ethnicities are needed to identify further correlations.

Figure 1. A flow diagram of the literature search for associations between the GNB3 C825T polymorphism and hypertension (A) or stroke (B).

Figure 2. A forest plot for (A) the allelic model (T allele vs. C allele), (B) the dominant model (GG+GA vs. AA), and (C) the recessive model (TT vs. CT+CC).

Random effects models were used with I² values of 81, 76, and 71%. No evidence of association between the GNB3 C825T polymorphism and stroke were detected in the allelic model (OR = 1.11, 95% CI = 0.94–1.32), dominant model (OR = 1.16, 95% CI = 0.92–1.48), or recessive model (OR = 1.08, 95% CI = 0.84–1.38).

Figure 3. A cumulative plot by publication year for (A) the allelic model, (B) the dominant model, and (C) the recessive model.

The ORs and associated 95% CIs became more stable over time. The study by Benjafield et al. was the first report to show a significant association between the GNB3 C825T polymorphism and the risk of hypertension, and this study likely influenced the overall estimation.

Figure 4. Funnel plots for the GNB3 C825T polymorphism and its association with hypertension.

(A) the allelic model (T allele vs. C allele, p = 0.150), (B) the dominant model (TT+CT vs. CC, p = 0.565), and (C) the recessive model (TT vs. CT+CC, p = 0.043). The funnel plots should be symmetrical when no publication bias occurs; however, the funnel plot of the recessive model was asymmetrical (p = 0.043), suggesting publication bias. The other two were symmetrical (p = 0.150 and 0.565, respectively). SE, standard error; OR, odds ratio.

Figure 5. Funnel plots for the GNB3 C825T polymorphism and its association with stroke.

(A) the allelic model (T allele vs. C allele, p = 0.145), (B) the dominant model (TT+CT vs. CC, p = 0.281), and (C) the recessive model (TT vs. CT+CC, p = 0.116). The funnel plots should be symmetrical when no publication bias occurs. No evidence of publication bias was detected in the three models. SE, standard error; OR, odds ratio.