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

Authors: KLIMENTIDIS, YANN - University Of Arizona; ARORA, AMIT - University Of Arizona; NEWELL, MICHELLE - University Of Arizona; ZHOU, JIN - University Of Arizona; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; RENQUIST, BENJAMIN - University Of Arizona; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC)

Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/28/2020
Publication Date: 6/3/2020
Citation: Klimentidis, Y.C., Arora, A., Newell, M., Zhou, J., Ordovas, J.M., Renquist, B.J., Wood, A.C. 2020. Phenotypic and genetic characterization of lower LDL cholesterol and increased type 2 diabetes risk in the UK Biobank. Diabetes. 69(10):2194-2205. https://doi.org/10.2337/db19-1134.
DOI: https://doi.org/10.2337/db19-1134

Interpretive Summary: Having high levels of fats in the blood such as triglycerides and cholesterol is more likely to occur in people with obesity. This is called "hyperlipidemia" and has long been thought to be one of the factors that makes people with obesity more likely to develop type 2 diabetes (T2D). However, statins which are used to lower fats in the blood slightly increase the risk of T2D. This outcome of statin use is well known, but has yet to inform clinical practice and feature prominently in prescription guidelines and patent information around statins. It is a seemly paradoxical finding that hyperlipidemia predisposes individuals to T2D, but lowering them via medication can increase T2D risk. Yet, it is important to understand why this happens so that we can try to figure out how to lower fats in the blood without increasing diabetes risk, and/or identify those most at risk from T2D if they take statins. Genetic studies are one method by which we can better understand pathways to disease. While several studies have identified genetic variants that increase both fats lipids and T2D risk, a small number of newer studies have identified a smaller number of genetic variants which seem to raise one but lower the other. In the hope that a more complete list of such variants will help our understanding on this issue, we conducted the only study to date which did not examine a small number of genetic variants, but rather surveyed the whole genome for loci which had differing effects on lipidemia and T2D risk. Our study confirmed that higher levels of LDL cholesterol associated with a reduced risk of T2D, even though this type of fat (LDL cholesterol) was associated with other T2D risk factors such higher HbA1c and a higher body mass index (BMI). Our genetic analysis identified 31 loci associated with lower LDL-C and increased T2D. These loci had several known biological functions and collectively captured several potential biological mechanisms worthy of future investigation. Statins are widely used, with more than 35 million people in the US taking them, including children as young as 11 years of age. The notion that statins may increase T2D is not well accepted clinically, and this study therefore provides important information for clinicians and patients (or their parents) to better assess the risk-benefit balance of taking stain use. This study may also support efforts for the better monitoring of patients on statins for signs of T2D. Finally, this study may inform future research efforts that seek to understand what pathways in the body lead to lower cholesterol but an increased risk of T2D. Such research may eventually lead to the development of therapeutic options which lower cholesterol without raising T2D risk.

Technical Abstract: 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.