posted on 2020-06-03, 13:41authored byAda AdminAda 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).