Abstract
Background: Obesity is a strong determinant for cardiovascular disease (CVD). It results from the complex interplay between genetic and environmental factors. Inflammation has been implicated in obesity and its related phenotypes. Leukotrienes are inflammatory mediators generated from arachidonic acid (polyunsaturated n-6 fatty acid) by the enzyme 5-lipoxygenase (5-LO). Genetic variants in genes encoding 5-LO (e.g., ALOX5) are potential contributors to obesity, probably through nutrigenetic interactions. Objectives: To examine whether genetic variants in ALOX5 are associated with obesity measures, and whether the association is modified by dietary intake of n-6 fatty acids. Methods: Thirteen tagging SNPs in ALOX5 were genotyped in 3,665 American Indians recruited by the Strong Heart Family Study from Oklahoma (OK), South/North Dakota (DK) and Arizona (AZ). Dietary intake was assessed with a food frequency questionnaire. Gene-based association and haplotype × diet interactions were investigated using generalized estimating equation, controlling for age, sex, smoking, alcohol intake, lipids, blood pressure, levels of physical activity, fibrinogen, renal function and total caloric intake. Because dietary intakes of n-3 and n-6 fatty acids are highly correlated, the nutrigenetic interactions were additionally adjusted for n-3 fatty acids. All analyses were stratified by geographic sites. Multiple testing was adjusted using the false discovery rate. Results: A 13-SNP haplotype, named HapZ, is significantly associated with obesity. Subjects carrying HapZ have significantly smaller obesity measures, including body mass index (BMI), waist circumference (WC) and body fat, compared to those not carrying this haplotype (all P<0.0001). The frequencies of HapZ among participants from OK, AZ and DK are 16.2%, 7.7% and 30.1%, respectively. Moreover, we identified a significant interaction between HapZ and dietary intake of n-6 fatty acids on obesity among participants from OK. Higher intake of n-6 fatty acids was associated with decreased level of obesity among HapZ carriers, but increased obesity level among HapZ noncarriers (Pinteraction =0.024 for BMI, Pinteraction =0.008 for WC, Pinteraction =0.003 for body fat), suggesting that the effect of n-6 fatty acids on obesity depends on the carrier status of this leukotriene haplotype. The nutrigenetic interaction was also observed in DK on BMI (Pinteraction =0.016), but not other obese parameters. Further adjustment for diabetes did not change our results. Conclusion: A novel ALOX5 haplotype is significantly and negatively associated with obesity in American Indians. Dietary intake of n-6 fatty acids modifies the apparent beneficial effect of this haplotype on obesity. If replicated, our findings could potentially lead to individualized lifestyle intervention for reducing the risk of obesity, diabetes and CVD.Funding(This research has received full or partial funding support from the American Heart Association, National Center)
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