P4.2 CORONARY RISK IN RELATION TO GENETIC VARIATION IN MEOX2 AND TCF15 IN A FLEMISH POPULATION

Abstract

Aims: In mice, MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. We investigated whether coronary heart disease (CHD) in humans is associated with variation in these genes. Methods and results: In 2027 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes (51.0% women; mean age 43.6 years), we genotyped SNPs in MEOX2 and TCF15, measured baseline cardiovascular risk factors, and recorded CHD incidence. Over 15.2 years (median), CHD occurred in 106 participants. For SNPs, we contrasted minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers vs. non-carriers. Sex- and age-standardised CHD rates were higher in MEOX2 rs10777, rs12056299, rs7787043, rs4532497, rs1050290 variants, in MEOX2 GTCCGC haplotype carriers (prevalence, 16.5%), but lower in MEOX2 rs6959056 variants (P ≤ 0.04, adjusted for multiple testing). In multivariable-adjusted analyses, the corresponding hazard ratios were ≥1.50 (P ≤ 0.049), 1.77 (P = 0.0054) and 0.62 (P = 0.025), respectively. None of four TCF15 SNPs was associated with coronary risk (P ≥ 0.29). However, CHD risk associated with MEOX2 rs4532497 was confined to TCF15 rs12624577 variant allele carriers (P for interaction = 0.011). The MEOX2 GTCCGC hap-lotype significantly improved the prediction of CHD over and beyond traditional risk factors and was associated with similar population-attributable risk as smoking (18.7% vs. 16.2%). Conclusions: In randomly recruited Flemish, genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms.