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Meta-Analysis
. 2006 Dec;3(12):e520.
doi: 10.1371/journal.pmed.0030520.

Angiotensin-converting enzyme I/D polymorphism and preeclampsia risk: evidence of small-study bias

Norma C Serrano  1 , Luis A Díaz, Maria C Páez, Clara M Mesa, Rodrigo Cifuentes, Alvaro Monterrosa, Adriana González, Liam Smeeth, Aroon D Hingorani, Juan P Casas
Affiliations
Meta-Analysis

Angiotensin-converting enzyme I/D polymorphism and preeclampsia risk: evidence of small-study bias

Norma C Serrano et al. PLoS Med. 2006 Dec.

Abstract

Background: Inappropriate activation of the renin-angiotensin system may play a part in the development of preeclampsia. An insertion/deletion polymorphism within the angiotensin-I converting enzyme gene (ACE-I/D) has shown to be reliably associated with differences in angiotensin-converting enzyme (ACE) activity. However, previous studies of the ACE-I/D variant and preeclampsia have been individually underpowered to detect plausible genotypic risks.

Methods and findings: A prospective case-control study was conducted in 1,711 unrelated young pregnant women (665 preeclamptic and 1,046 healthy pregnant controls) recruited from five Colombian cities. Maternal blood was obtained to genotype for the ACE-I/D polymorphism. Crude and adjusted odds ratio (OR) and 95% confidence interval (CI) using logistic regression models were obtained to evaluate the strength of the association between ACE-I/D variant and preeclampsia risk. A meta-analysis was then undertaken of all published studies to February 2006 evaluating the ACE-I/D variant in preeclampsia. An additive model (per-D-allele) revealed a null association between the ACE-I/D variant and preeclampsia risk (crude OR = 0.95 [95% CI, 0.81-1.10]) in the new case-control study. Similar results were obtained after adjusting for confounders (adjusted per-allele OR = 0.90 [95% CI, 0.77-1.06]) and using other genetic models of inheritance. A meta-analysis (2,596 cases and 3,828 controls from 22 studies) showed a per-allele OR of 1.26 (95% CI, 1.07-1.49). An analysis stratified by study size showed an attenuated OR toward the null as study size increased.

Conclusions: It is highly likely that the observed small nominal increase in risk of preeclampsia associated with the ACE D-allele is due to small-study bias, similar to that observed in cardiovascular disease. Reliable assessment of the origins of preeclampsia using a genetic approach may require the establishment of a collaborating consortium to generate a dataset of adequate size.

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Conflict of interest statement

Competing Interests: University College London holds patents on the measurement of asymmetric dimethylarginine in the management of preeclampsia.

Figures

Figure 1
Figure 1. Risk Association of ACE-I/D Variant with Preeclampsia in Selected Subgroups within the Current Study
Figure 2
Figure 2. Meta-Analysis of Studies of ACE-I/D Polymorphism and Risk of Preeclampsia
Figure 3
Figure 3. Studies of ACE-I/D Polymorphism and Risk of Preeclampsia Grouped by Study Characteristics
See this image and copyright information in PMC

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