Polymorphisms of prostaglandin-endoperoxide synthase 2 gene, and prostaglandin-E receptor 2 gene, C-reactive protein concentrations and risk of atherothrombosis: a nested case-control approach.

OBJECTIVE: Recent data have shown an association between polymorphisms of prostaglandin-endoperoxide synthase-2 gene (PTGS2; alias COX-2), and prostaglandin-E receptor-2 gene (PTGER2) and risk of atherothrombotic disorders. METHODS: We evaluated two PTGS2 (rs20417, rs689470), and three PTGER2 (rs708494/uS5, rs708495/uS7, and chr14: 50 764 013/uS10) gene polymorphisms among 600 Caucasian male participants of the Physicians' Health Study with incident myocardial infarction (MI) or ischemic stroke and 600 age- and smoking-matched controls who remained free of all reported cardiovascular disease. RESULTS: Genotype distributions were in Hardy-Weinberg equilibrium in the control groups. Genotype and allele distribution were similar between cases and controls. The polymorphisms tested were in linkage disequilibrium. Results from the adjusted haplotype-based conditional logistic regression analysis showed a modest association of the PTGER2 2-1-1 haplotype with reduced risk of MI (odds ratio = 0.50, 95% CI; CI = 0.26-0.97, P = 0.04), and the 2-2-1 haplotype with reduced risk of ischemic stroke (odds ratio = 0.68, 95% CI = 0.47-0.99, P = 0.048). In contrast to prior data, we found no evidence for an association of the PTGS2 polymorphisms/haplotypes tested with risk of incident MI nor with ischemic stroke. However, we found suggestive evidence for an association of specific PTGER2 haplotypes with reduced risk of these outcomes. CONCLUSION: Although these prospective data implicate the potential involvement of prostaglandin-E receptor-2 gene variation in atherothrombosis, external validation of our findings is needed.

C-reactive protein gene polymorphisms and the risk of venous thromboembolism: a haplotype-based analysis.

C-reactive protein (CRP) is a risk predictor for future athero-thrombotic events, and its plasma concentration has a heritable component. CRP has also been suggested to play a role in the pathophysiology of venous thromboembolism. To date, no genetic-epidemiological data are available on the relation of CRP gene variants with the risk of venous thromboembolism. The present study was carried out to investigate the possible association of two previously characterized (an exonic 1059G-->C, and an intronic T-->A) CRP gene polymorphisms in a prospective, matched case-control sample from the Physicians Health Study. Allele, genotype, and haplotype distributions were similar between 130 cases and 130 matched controls. Genotype distributions were in Hardy-Weinberg equilibrium. Further investigation using a haplotype-based matched logistic regression analysis, adjusting for age, smoking, randomized treatment group (likelihood ratio test: X(2)2df = 0.19, P = 0.91) or with further controlling for body mass index, hypertension, and diabetes (likelihood ratio test: X(2)2df = 0.66, P = 0.72) yielded similar null findings. In conclusion, we found no evidence for an association between the CRP polymorphisms/haplotypes tested and the risk of venous thromboembolism.