5‐Lipoxygenase Gene Variants Are Not Associated With Atherosclerosis or Incident Coronary Heart Disease in the Multi‐Ethnic Study of Atherosclerosis Cohort

BACKGROUND: The arachidonate 5‐lipoxygenase enzyme plays a crucial role in mediating inflammation to maintain homeostasis, yet certain allelic variants of the 5‐lipoxygenase gene, ALOX5, may increase risk of atherosclerosis and coronary heart disease (CHD). Further, relations between ALOX5 and disease outcomes may be enhanced or attenuated depending on the bioavailability of 5‐lipoxygenase enzyme substrates. By using a candidate gene approach in 6153 Multi‐Ethnic Study of Atherosclerosis (MESA) participants, associations were determined among 1348 ALOX5 single nucleotide polymorphisms (SNPs) and carotid intima‐media thickness (cIMT) as well as incident CHD, and interactions with plasma concentrations of arachidonic acid, eicosapentaenoic acid, or docosahexaenoic acid were tested. METHODS AND RESULTS: Multivariable linear regression was used to test for associations between cIMT and ALOX5 SNPs, and Cox regression was used for incident CHD. Bonferroni correction was used for multiple hypothesis testing. No significant associations between ALOX5 SNPs and cIMT or CHD events were observed. Levels of arachidonic acid, eicosapentaenoic acid, or docosahexaenoic acid concentrations did not modify the relations of ALOX5 with either outcome. CONCLUSIONS: ALOX5 gene variants do not appear to be related to clinical CHD events or subclinical atherosclerosis regardless of bioavailable enzyme substrate levels in this multiethnic cohort. Further studies that directly examine protein expression or enzyme activity may better define the arachidonate 5‐lipoxygenase pathway in disease development and progression.