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

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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.


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