BACKGROUND - Cardiovascular disease is the leading cause of death among Americans. Inflammation is a hallmark of the development of atherosclerosis and is mediated by prostaglandins, catalyzed by cyclooxygenase (COX)-2. We sought to determine if variants in the COX-2 gene were associated with subclinical measures of cardiovascular disease in a primarily type 2 diabetic population.
METHODS - Eight polymorphisms in COX-2 were genotyped and vascular calcified plaque measured in the coronary, carotid, and aortic arterial beds in 977 Caucasian siblings (83% with T2DM) from 369 Diabetes Heart Study families. Tests for single nucleotide polymorphism (SNP) and haplotypic association were performed using SOLAR and quantitative pedigree disequilibrium test (QPDT), respectively (results adjusted for age, gender, diabetes affection status, smoking, and use of lipid altering medications).
RESULTS - All eight SNPs genotyped were found to be in strong pair-wise linkage disequilibrium (D'=1.0). Three SNPs (rs689466, rs2066826 and rs20417) are associated with either coronary or carotid calcified plaque. Subjects carrying the G allele of rs689466 (n=31) or the A allele of rs2066826 (n=16) had significantly lower coronary calcified plaque (P=0.02 and 0.04, respectively). Subjects homozygous for the C allele of rs20417 (n=22) or the A allele of rs2066826 (n=16) had increased carotid calcified plaque (P=0.011, P=0.014). In addition, multiple two-SNP and three-SNP haplotypes were associated with CorCP with P-values ranging from P=0.002 to P=0.035.
CONCLUSIONS - Polymorphisms in COX-2 were associated with significant changes in coronary and carotid calcified plaque. Diabetic individuals with these variants may be at higher risk for developing cardiovascular disease.