*3.5. ABCA1 Gene Variation and Coronary Heart Disease*

Because low HDL-C levels are a well-established independent risk factor for CHD, genetic variants known to increase HDL-C levels would be expected to decrease CHD risk, and variants associated with lower HDL-C levels would increase CHD risk. However, high HDL-C levels are not always protective of CHD, and Mendelian randomization studies suggest that the inverse relationship between HDL-C levels and CHD risk is not causal [95,96]. Possible explanations are differences in the functionality of HDL-C particles, and pleiotropic effects of ABCA1 [97]. Interestingly the R230C variant was found to be associated with both lower HDL-C levels and lower risk of premature coronary artery disease in the Mexican population [98]. While the possible effects of this and other variants on HDL-C functionality require further study, it is possible that the paradoxical effect of this variant could be due to a pleiotropic effect on platelet, endothelial and leukocyte-derived microparticle formation, all involved in atherosclerosis and CHD pathogenesis. This is the matter of ongoing research by our group.
