Objective— C-reactive protein (CRP) concentrations are predictive of cardiovascular disease, and levels are heritable, in part. We identified novel polymorphisms in the CRP gene and assessed their influence on CRP level. Methods and Results— CRP was measured in 250 male army recruits before and after strenuous exercise and perioperatively in 193 coronary artery bypass graft (CABG) patients. Two novel polymorphisms were identified in the CRP gene, −717G>A in the promoter and +1444C>T in the 3′UTR. Among army recruits, CRP was higher in +1444TT homozygotes than +1444 C-allele carriers at baseline (1.04±0.38 versus 0.55±0.06, P =0.014) and at all time points after exercise (2.35±0.68 versus 1.07±0.12, 2.11±0.53 versus 0.88±0.09, and 1.77±0.44 versus 0.71±0.09, P =0.034, P =0.007, and P =0.013, at 2, 48, and 96 hours after exercise, respectively). In the CABG patients, mean CRP (mg/L) rose from 1.97±0.36 at baseline to 167.2±5.0 72 hours postoperatively. Genotype did not influence CRP at baseline; however, peak post-CABG CRP levels were higher in +1444TT homozygotes compared with +1444C-allele carriers (198±17 versus 164±5, P =0.03). Conclusions— The CRP gene +1444C>T variant influences basal and stimulated CRP level. These findings have implications both for the prediction and pathogenesis of coronary heart disease.

Polymorphisms in the endothelial NO synthase (eNOS) gene have been evaluated as risk factors for preeclampsia. However, data from small studies are conflicting. We assessed whether eNOS genotypes alter the risk of preeclampsia in a population in which the incidence of this disorder is high. A total of 844 young pregnant women (322 preeclamptic and 522 controls) were recruited from 5 cities. Genotyping for the Glu298Asp, intron-4 and –786T→C polymorphisms in the eNOS gene was conducted. Multivariate odds ratios (ORs) were obtained to estimate the association of individual polymorphisms and haplotypes with preeclampsia risk. No increase in the risk of preeclampsia for the intron-4 or –786T→C polymorphisms was observed under any model of inheritance. In contrast, in women homozygous for the Asp298 allele, the adjusted OR for preeclampsia was 4.60 (95% confidence interval [CI], 1.73 to 12.22) compared with carriers of the Glu298 allele. After a multivariate analysis, carriage of the “Asp298–786C-4b” haplotype was also associated with increased risk of preeclampsia (OR, 2.11 [95% CI, 1.33 to 3.34]) compared with carriers of the “Glu298–786T-4b” haplotype. The eNOS Glu298Asp polymorphism and the Asp298–786C-4b haplotype are risk factors for preeclampsia.

Background Pre-eclampsia is thought to have a polygenic basis, but the identification of susceptibility genes and the quantification of associated risks have been elusive owing to lack of replication from published genetic association studies. Objective To perform a systematic review and meta-analysis of genetic association studies to evaluate the evidence for the associations of various candidate genes with pre-eclampsia. Methods For inclusion, studies had to involve unrelated subjects and examine the associations between pre-eclampsia (excluding publications without a measurement of proteinuria) and any candidate variant. Authors were contacted to obtain unpublished data when necessary. A meta-analysis was conducted for all variants with three or more independent samples available. Summary odds ratios (ORs), 99% confidence intervals (CIs) and P-values were calculated using random effects models. Results Data from 192 genetic association studies met the selection criteria and were included in 25 independent meta-analyses. There was some evidence of association for F5 rs6025 (OR = 1.74; 99% CI 1.43–2.12), F2 rs1799963 (OR = 1.72; 99% CI 1.31–2.26), ACE rs4646994 (OR = 1.17; 99% CI 0.99–1.40), AGT rs699 (OR = 1.26; 99% CI 1.00–1.59) and AGTR1 rs5186 (OR = 1.22; 99% CI 0.96–1.56), but only the first two associations reached moderate epidemiological credibility. Possible bias resulting from small study size and poor reporting of individual studies were the most important factors affecting the reported associations. Conclusion To date, candidate gene studies in pre-eclampsia have not robustly documented any associations with strong epidemiological credibility. Large-scale replication of the most promising associations, exhibited by two genetic variants, and incorporation of agnostic high-throughput data may improve our genetic knowledge base for this complex phenotype.

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. 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. 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.