LDL-C_and_T2D_Supplement_clean_20200508.docx (791.39 kB)

Phenotypic and genetic characterization of lower LDL-C and increased type-2 diabetes risk in the UK Biobank

Download (791.39 kB)
figure
posted on 03.06.2020 by Ada Admin, Yann C. Klimentidis, Amit Arora, Michelle Newell, Jin Zhou, Jose M. Ordovas, Benjamin J. Renquist, Alexis C. Wood
Although hyperlipidemia is traditionally considered a risk factor for type-2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations suggesting that lower LDL-C increases T2D risk. We thus sought to more comprehensively examine the phenotypic and genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that levels of circulating LDL-C were negatively associated with T2D prevalence (OR=0.41[0.39, 0.43] per mmol/L unit of LDL-C), despite positive associations of circulating LDL-C with HbA1c and BMI. We then performed the first genome-wide exploration of variants simultaneously associated with lower circulating LDL-C and increased T2D risk, using data on LDL-C from the UK Biobank (n=431,167) and the GLGC consortium (n=188,577), and T2D from the DIAGRAM consortium (n=898,130). We identified 31 loci associated with lower circulating LDL-C and increased T2D, capturing several potential mechanisms. Seven of these loci have previously been identified for this dual phenotype, and 9 have previously been implicated in non-alcoholic fatty liver disease. These findings extend our current understanding of the higher T2D risk among individuals with low circulating LDL-C, and of the underlying mechanisms, including those responsible for the diabetogenic effect of LDL-C-lowering medications.

Funding

The authors would like to acknowledge support from the National Heart, Lung, and Blood Institutes (R01-HL136528).

History

Exports