Abstract
Background: Atherosclerosis is an inflammatory disease involving the joint contribution of multiple genetic polymorphisms. Leukotrienes are inflammatory mediators and genetic polymorphisms in key leukotriene genes have been associated with atherosclerotic cardiovascular disease (CVD). While each genetic variant may have only a minor effect on disease risk, their joint contribution to the occurrence of disease may be larger. Objective: To examine the joint impact of 32 SNPs in key leukotriene genes on subclinical CVD assessed by carotid plaque score using a pathway-based approach. Methods: We genotyped 32 tagSNPs in three genes (ALOX5, ALOX5AP and LTA4H) encoding key enzymes for leukotriene production in 3,665 American Indians recruited by the Strong Heart Family Study from Oklahoma (OK), South/North Dakota (DK) and Arizona (AZ). Subclinical atherosclerosis was assessed by carotid plaque score using ultrasound. We conducted a pathway-based analysis to evaluate the joint impact of these 32 SNPs on atherosclerotic plaque score, adjusting for classical cardiovascular risk factors, including age, sex, body mass index (BMI), cigarette smoking status (current, former vs. never), alcohol intake (current, former vs. never), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), blood pressure, diabetes, levels of physical activity, fibrinogen, and renal function (assessed by estimated glomerular filtration rate, eGFR). To avoid population substructure, all statistical analyses were stratified by study center (OK, AZ, and DK). Multiple testing was adjusted using the Bonferroni correction. Results: Multiple SNPs showed individual marginal association with carotid plaque score, but only one (rs2660880 in LTA4H gene in OK, P=0.001) passed adjustment for multiple testing. However, a genetic pathway analysis demonstrated that the leukotriene pathway as a whole in consideration of the joint contribution of all 32 SNPs was significantly associated with carotid plaque score in participants from OK (P=0.002) and DK (P=0.012), but not those from AZ. Conclusion: Genetic variants in the leukotriene pathway jointly contribute to subclinical atherosclerosis in American Indians. Our results could potentially lead to novel molecular strategies for the prevention and treatment of cardiovascular disease.
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