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Title: Triglyceride-increasing alleles associated with protection against type-2 diabetes

Author
item KLIMENTIDIS, YANN - University Of Arizona
item CHOUGULE, AKSHAY - University Of Arizona
item ARORA, AMIT - University Of Arizona
item FRAZIER-WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC)
item HSU, CHIU-HSIEH - Children'S Nutrition Research Center (CNRC)

Submitted to: PLoS Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/9/2015
Publication Date: 5/28/2015
Citation: Klimentidis, Y.C., Chougule, A., Arora, A., Frazier-Wood, A.C., Hsu, C. 2015. Triglyceride-increasing alleles associated with protection against type-2 diabetes. PLoS Genetics. 11(5):e1005204.

Interpretive Summary: Elevated plasma triglyceride (TG) levels is an established risk factor for type-2 diabetes (T2D). However, the genes that are associated with high TG levels have been recently shown to be associated with reduced T2D. Therefore, we examined the association of genetic risk for TG with T2D, in 13,247 European-Americans (EA) and 3,238 African-Americans (AA) from three prospective studies. Among EA, we confirmed that baseline levels of TG are strongly associated with T2D. However, the genes associated with higher TG were negatively associated with T2D. We find similar, trends among AA. This finding has important implications as it is useful to distinguish between risk emanating from genetic factors and risk emanating from other factors.

Technical 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.