Angiotensin-converting enzyme insertion/deletion polymorphism contributes high risk for chronic kidney disease in Asian male with hypertension--a meta-regression analysis of 98 observational studies

Abstract

Background: Associations between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphisms and chronic kidney disease (CKD) have been extensively studied, with most studies reporting that individuals with the D allele have a higher risk. Although some factors, such as ethnicity, may moderate the association between ACE I/D polymorphisms and CKD risk, gender-dependent effects on the CKD risk remain controversial.

Objectives: This study investigated the gender-dependent effects of ACE I/D polymorphisms on CKD risk.

Data sources: PubMed, the Cochrane library, and EMBASE were searched for studies published before January 2013.

Study eligibility criteria participants and interventions: Cross-sectional surveys and case-control studies analyzing ACE I/D polymorphisms and CKD were included. They were required to match the following criteria: age >18 years, absence of rare diseases, and Asian or Caucasian ethnicity.

Study appraisal and synthesis methods: The effect of carrying the D allele on CKD risk was assessed by meta-analysis and meta-regression using random-effects models.

Results: ETHNICITY [ODDS RATIO (OR): 1.24; 95% confidence interval (CI): 1.08-1.42] and hypertension (OR: 1.55; 95% CI: 1.04-2.32) had significant moderate effects on the association between ACE I/D polymorphisms and CKD risk, but they were not significant in the diabetic nephropathy subgroup. Males had higher OR for the association between ACE I/D polymorphisms and CKD risk than females in Asians but not Caucasians, regardless of adjustment for hypertension (p<0.05). In subgroup analyses, this result was significant in the nondiabetic nephropathy group. Compared with the I allele, the D allele had the highest risk (OR: 3.75; 95% CI: 1.84-7.65) for CKD in hypertensive Asian males.

Conclusions and implications of key findings: The ACE I/D polymorphisms may incur the highest risk for increasing CKD in hypertensive Asian males.

Figure 1. Flow diagram of identification process for eligible studies in this study.

n: number of studies were deleted for aforementioned reasons.

Figure 2. Forest plot of the association between ACE I/D and all-cause CKD using allele type model.

Figure 3. Gender-dependent effects of ACE I/D and all-cause CKD in each population.

Left figure was showed the OR in people without hypertension; right figure was showed the odds ratio in patient with hypertension. Red triangle and square: individual studies in Caucasian; blue triangle and square: individual studies in Asian. Solid line: unbiased estimator of odds ratio; dashed line: 95% confidence interval of odds ratios. Estimated value of log odds ratio in individual studies without hypertension used following formula: observed log odds ratio – hypertension prevalence of study population×0.437 (according to Model 2 in Table 5) Estimated value of log odds ratio in individual studies with hypertension used following formula: observed log odds ratio+(1– hypertension prevalence of study population)×0.437 (according to Model 2 in Table 5).

Figure 4. Funnel plot of three way interaction model in each subgroup.

The model in nondiabetic nephropathy subgroup was asymmetric. The triangle in that plot was study reported by Jung et, and the p value of the student residual was less 0.05. After excluding this study, the p value of Egger’s regression test was not significant (p = 0.245) and the moderate effect of interaction and hypertension were more significantly (p of interaction: 0.0304→0.0023; p of hypertension: 0.0005→<0.0001).