Abstract
Elevated plasma triglyceride (TG) levels are an established risk factor for type-2 diabetes (T2D). However, recent studies have hinted at the possibility that genetic risk for TG may paradoxically protect against T2D. In this study, we examined the association of genetic risk for TG with incident T2D, and the interaction of baseline TG with TG genetic risk on incident T2D in 13,247 European-Americans (EA) and 3,238 African-Americans (AA) from three prospective cohort studies. A TG genetic risk score (GRS) was calculated based on 31 validated single nucleotide polymorphisms (SNPs). We considered several baseline covariates, including body- mass index (BMI) and lipid traits. Among EA and AA, we find, as expected, that baseline levels of TG are strongly positively associated with incident T2D (p<2 x 10-10). However, the TG GRS is negatively associated with T2D (p=0.013), upon adjusting for only race, in the full dataset. Upon additionally adjusting for age, sex, BMI, high-density lipoprotein cholesterol and TG, the TG GRS is significantly and negatively associated with T2D incidence (p=7.0 x 10-8), with similar trends among both EA and AA. No single SNP appears to be driving this association. We also find a significant statistical interaction of the TG GRS with TG (pinteraction=3.3 x 10-4), whereby the association of TG with incident T2D is strongest among those with low genetic risk for TG. Further research is needed to understand the likely pleiotropic mechanisms underlying these findings, and to clarify the causal relationship between T2D and TG.
Highlights
Along with age, body weight, family history, and other characteristics, triglyceride (TG) level is a major risk factor for cardiovascular disease and type-2 diabetes (T2D)
We test the relationship of triglyceride-associated genetic variants, collectively and individually, with incident type-2 diabetes across three prospective cohort studies comprised of European- and African-American participants
Using a case-control analytical design in over 30,000 individuals, we previously examined the association of 17 genetic risk scores (GRS) for various traits, including lipid traits, with current T2D status, and observed an unexpected, albeit not statistically significant, pattern suggesting that being at high genetic risk for low-density lipoprotein cholesterol, total cholesterol, or TG could be protective against T2D [5]
Summary
Body weight, family history, and other characteristics, triglyceride (TG) level is a major risk factor for cardiovascular disease and type-2 diabetes (T2D). TG at baseline is positively associated with T2D incidence, independently of body mass index (BMI) and other risk factors [1], the direction of causality between TG and T2D is unclear [2], and somewhat ambiguous. As illustrated and discussed by Li et al [6], by not adjusting for TG, the negative direct path between TG genes and T2D is weakened by the positive path linking TG genes, TG, and glycemic traits
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