TY - JOUR
T1 - Phenotypic and genetic characterization of lower LDL cholesterol and increased type 2 diabetes risk in the UK biobank
AU - Klimentidis, Yann C.
AU - Arora, Amit
AU - Newell, Michelle
AU - Zhou, Jin
AU - Ordovas, Jose M.
AU - Renquist, Benjamin J.
AU - Wood, Alexis C.
N1 - Funding Information:
The authors acknowledge the vital contributions of the GLGC and DIAGRAM as well as all organizers and participants of individual participating studies. This research was conducted using the UK Biobank resource under application number 15678. The authors thank the participants and organizers of the UK Biobank. Funding. The study received support from the National Heart, Lung, and Blood Institute (R01-HL-136528). A.C.W. was funded, in part, by U.S. Department of Agriculture/Agricultural Research Service cooperative agreement no. 58-3092-5-001. The contents of this publication do not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding Information:
Acknowledgments. The authors acknowledge the vital contributions of the GLGC and DIAGRAM as well as all organizers and participants of individual participating studies. This research was conducted using the UK Biobank resource under application number 15678. The authors thank the participants and organizers of the UK Biobank. Funding. The study received support from the National Heart, Lung, and Blood Institute (R01-HL-136528). A.C.W. was funded, in part, by U.S. Department of Agriculture/Agricultural Research Service cooperative agreement no. 58-3092-5-001.
Publisher Copyright:
© 2020 by the American Diabetes Association.
PY - 2020/10
Y1 - 2020/10
N2 - Although hyperlipidemia is traditionally considered a risk factor for type 2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations sug-gesting that lower LDL cholesterol (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 (odds ratio 0.41 [95% CI 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 Global Lipids Genetics Consortium (n = 188,577), and data on T2D from the Diabetes Genetics Replication and Meta-Analysis 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 nine have previously been implicated in nonalcoholic 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.
AB - Although hyperlipidemia is traditionally considered a risk factor for type 2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations sug-gesting that lower LDL cholesterol (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 (odds ratio 0.41 [95% CI 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 Global Lipids Genetics Consortium (n = 188,577), and data on T2D from the Diabetes Genetics Replication and Meta-Analysis 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 nine have previously been implicated in nonalcoholic 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.
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U2 - 10.2337/db19-1134
DO - 10.2337/db19-1134
M3 - Article
C2 - 32493714
AN - SCOPUS:85091470047
SN - 0012-1797
VL - 69
SP - 2194
EP - 2205
JO - Diabetes
JF - Diabetes
IS - 10
ER -