Abstract
Dyslipidemia is a well-established risk factor for CVD. Studies suggest that similar fat accumulation in a given population might result in different levels of dyslipidemia risk among individuals; for example, despite similar or leaner body composition compared with Caucasians, Asians of Korean descent experience a higher prevalence of dyslipidemia. These variations imply a possible role of gene-obesity interactions on lipid profiles. Genome-wide association studies have identified more than 500 loci regulating plasma lipids, but the interaction structure between genes and obesity traits remains unclear. We hypothesized that some loci modify the effects of obesity on dyslipidemia risk and analyzed extensive gene-environment interactions (G×Es) at genome-wide levels to search for replicated gene-obesity interactive SNPs. In four Korean cohorts (n = 18,025), we identified and replicated 20 gene-obesity interactions, including novel variants (SCN1A and SLC12A8) and known lipid-associated variants (APOA5, BUD13, ZNF259, and HMGCR). When we estimated the additional heritability of dyslipidemia by considering G×Es, the gain was substantial for triglycerides (TGs) but mild for LDL cholesterol (LDL-C) and total cholesterol (Total-C); the interaction explained up to 18.7% of TG, 2.4% of LDL-C, and 1.9% of Total-C heritability associated with waist-hip ratio. Our findings suggest that some individuals are prone to develop abnormal lipid profiles, particularly with regard to TGs, even with slight increases in obesity indices; ethnic diversities in the risk alleles might partly explain the differential dyslipidemia risk between populations. Research about these interacting variables may facilitate knowledge-based approaches to personalize health guidelines according to individual genetic profiles.
Highlights
Dyslipidemia is a well-established risk factor for CVD
By conducting linkage disequilibrium (LD) clumping based on the genetic contribution to the risk of dyslipidemia, we detected 20 geneobesity interactions due to novel SNPs near SCN1A and SLC12A8 and to lipid-associated SNPs near APOA5, BUD13, ZNF259, and HMGCR that were reported in previous genome-wide association study (GWAS)
36.6% of the total heritability was due to 40 independent GWAS-identified SNPs only; the genetic contribution increased to 47.1% when we considered the interactions of APOA5 or BUD13 with waist circumference (WC)
Summary
Studies suggest that similar fat accumulation in a given population might result in different levels of dyslipidemia risk among individuals; for example, despite similar or leaner body composition compared with Caucasians, Asians of Korean descent experience a higher prevalence of dyslipidemia. These variations imply a possible role of gene-obesity interactions on lipid profiles. Our findings suggest that some individuals are prone to develop abnormal lipid profiles, with regard to TGs, even with slight increases in obesity indices; ethnic diversities in the risk alleles might partly explain the differential dyslipidemia risk between populations Research about these interacting variables may facilitate knowledge-based approaches to personalize health guidelines according to individual genetic profiles.—Kang, M., and J.
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