Human Lipoxygenase Pathway Gene Variation and Association with Markers of Subclinical Atherosclerosis in the Diabetes Heart Study

Abstract

Aims. Genes of the 5-lipoxygenase pathway are compelling candidates for atherosclerosis. We hypothesize that polymorphisms inALOX12, ALOX15, ALOX5, andALOX5APgenes are associated with subclinical atherosclerosis in multiple vascular beds.Methods. Families with two or more siblings with type 2 diabetes and their nondiabetic siblings were studied as part of the Diabetes Heart Study (DHS). European American diabetic (n=828) and nondiabetic (n=170) siblings were genotyped for SNPs in theALOX12, ALOX15, ALOX5, andALOX5APgenes. Subclinical measures of atherosclerosis (IMT, coronary (CorCP), carotid (CarCP) and aortic (AorCP) calcified plaque) were obtained.Results. Associations were observed betweenALOX12with CorCP,ALOX5with CorCP, AorCP, and IMT, andALOX5APwith CorCP and CarCP, independent of known epidemiologic risk factors. Further, lipoxygenase pathway SNPs that were associated with measures of atherosclerosis were associated with markers of inflammation (CRP, ICAM-1) and calcification (MGP).Conclusions. Polymorphisms withinALOX12, ALOX5, andALOX5APare genetically associated with subclinical atherosclerosis and with biomarkers of disease in families with type 2 diabetes. These results suggest that variants in lipoxygenase pathway genes may have pleiotropic effects on multiple components that determine risk of cardiovascular disease.