title: Angiotensin-converting enzyme I/D polymorphism and preeclampsia risk: evidence of small-study bias.
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.
  
  
  RESULTS
  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.
authors.affiliation: Universidad Autónoma de Bucaramanga, Bucaramanga, Colombia. nserrano@unab.edu.co
authors.forename: Norma C
authors.initials: NC
authors.lastname: Serrano
authors.forename: Luis A
authors.initials: LA
authors.lastname: Díaz
authors.forename: Maria C
authors.initials: MC
authors.lastname: Páez
authors.forename: Clara M
authors.initials: CM
authors.lastname: Mesa
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Cifuentes
authors.forename: Alvaro
authors.initials: A
authors.lastname: Monterrosa
authors.forename: Adriana
authors.initials: A
authors.lastname: González
authors.forename: Liam
authors.initials: L
authors.lastname: Smeeth
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: Juan P
authors.initials: JP
authors.lastname: Casas
mesh_terms: D015982:Bias; D016022:Case-Control Studies; D003105:Colombia; D005260:Female; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D011110:Polymorphism, Genetic; D011225:Pre-Eclampsia / Q000235:genetics*; D011247:Pregnancy; D011446:Prospective Studies; D012084:Renin-Angiotensin System / Q000235:genetics
chemical_list: D007703:Peptidyl-Dipeptidase A