Staessen J A, Wang J G, Ginocchio G, Petrov V, Saavedra A P, Soubrier F, Vlietinck R, Fagard R
Department of Molecular and Cardiovascular Research, University of Leuven, Belgium.
J Hypertens. 1997 Dec;15(12 Pt 2):1579-92. doi: 10.1097/00004872-199715120-00059.
This meta-analysis attempted to derive pooled estimates for the associations between various cardiovascular-renal disorders and the deletion/insertion (D/I) polymorphism of the angiotensin converting enzyme (ACE) gene.
Case-control studies were combined, using the Mantel-Haenszel approach. Joint P values for continuous variables were calculated by Stouffer's method. Continuous measurements reported in different units were expressed on a percentage scale using the within-study mean of the II genotype as the denominator.
The computerized database used for this analysis included 145 reports with an overall sample size of 49 959 subjects. Overall, possession of the D allele was associated with an increased risk of atherosclerotic and renal microvascular complications. In comparison with the II reference group, the excess risk in DD homozygotes (P < 0.001) was 32% for coronary heart disease (CHD; 30 studies), 45% for myocardial infarction (20 studies), 94% for stroke (five studies) and 56% for diabetic nephropathy (11 studies). The corresponding risk in DI heterozygotes amounted to 11% (P= 0.02), 13% (P= 0.02), 22% (P= 0.10) and 40% (P < 0.001), respectively. Hypertension (23 studies), left ventricular hypertrophy (five studies), hypertrophic or dilated cardiomyopathy (eight studies) and diabetic retinopathy (two studies) were not related to the DI polymorphism. Publication bias was observed for CHD, myocardial infarction and microvascular nephropathy, but not hypertension. In studies with DNA amplification in the presence of insertion-specific primers, the risk associated with the DD genotype increased to 150% [95% confidence interval (CI) 76-256; four studies] for diabetic nephropathy, but decreased to 12% (95% CI -3 to 28; seven studies) for CHD and 14% (95% CI -6 to 37; four studies) for myocardial infarction. On the other hand, the pooled odds ratios did not materially change if the meta-analysis was limited to articles published in journals with an impact factor of at least 4. Furthermore, compared with the II control group, the circulating ACE levels (29 studies) were raised 58 and 31% (P < 0.001) in DD and DI subjects, respectively. In contrast, plasma renin (10 studies), systolic and diastolic blood pressure (46 studies) and body mass index (30 studies) were not associated with the D allele.
The D allele is not associated with hypertension, but behaves as a marker of atherosclerotic cardiovascular complications and diabetic nephropathy. These associations do not necessarily imply a causal relationship and may have been inflated by publication bias. Nevertheless, their possible therapeutic implications may be subject to further investigation in prospective (intervention) studies.
本荟萃分析旨在得出各种心血管-肾脏疾病与血管紧张素转换酶（ACE）基因缺失/插入（D/I）多态性之间关联的合并估计值。
采用Mantel-Haenszel方法合并病例对照研究。连续变量的联合P值通过Stouffer法计算。以II基因型的研究内均值为分母，将不同单位报告的连续测量值以百分比形式表示。
用于该分析的计算机化数据库包含145篇报告，总样本量为49959名受试者。总体而言，携带D等位基因与动脉粥样硬化和肾脏微血管并发症风险增加相关。与II参照组相比，DD纯合子中冠心病（CHD；30项研究）的额外风险为32%（P<0.001），心肌梗死（20项研究）为45%，中风（5项研究）为94%，糖尿病肾病（11项研究）为56%。DI杂合子中的相应风险分别为11%（P = 0.02）、13%（P = 0.02）、22%（P = 0.10）和40%（P<0.001）。高血压（23项研究）、左心室肥厚（5项研究）、肥厚型或扩张型心肌病（8项研究）和糖尿病视网膜病变（2项研究）与D/I多态性无关。观察到CHD、心肌梗死和微血管肾病存在发表偏倚，但高血压不存在。在使用插入特异性引物进行DNA扩增的研究中，DD基因型与糖尿病肾病相关的风险增加至150%[95%置信区间（CI）76 - 256；4项研究]，但CHD降至12%（95%CI - 3至28；7项研究），心肌梗死降至14%（95%CI - 6至37；4项研究）。另一方面，如果荟萃分析仅限于发表在影响因子至少为4的期刊上的文章，合并比值比没有实质性变化。此外，与II对照组相比，DD和DI受试者的循环ACE水平（29项研究）分别升高了58%和31%（P<0.001）。相比之下，血浆肾素（10项研究）、收缩压和舒张压（46项研究）以及体重指数（30项研究）与D等位基因无关。
D等位基因与高血压无关，但可作为动脉粥样硬化性心血管并发症和糖尿病肾病的标志物。这些关联不一定意味着因果关系，可能因发表偏倚而被夸大。然而，它们可能的治疗意义有待在前瞻性（干预）研究中进一步探讨。
