HDL Cholesterol and Risk of Type 2 Diabetes: A Mendelian Randomization Study

TY - JOUR

T1 - HDL Cholesterol and Risk of Type 2 Diabetes

T2 - A Mendelian Randomization Study

AU - Haase, Christiane L

AU - Tybjærg-Hansen, Anne

AU - Nordestgaard, Børge G

AU - Frikke-Schmidt, Ruth

N1 - © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

PY - 2015/9

Y1 - 2015/9

N2 - Observationally, low levels of HDL cholesterol are consistently associated with increased risk of type 2 diabetes. Therefore, plasma HDL cholesterol increasing has been suggested as a novel therapeutic option to reduce the risk of type 2 diabetes. Whether levels of HDL cholesterol are causally associated with type 2 diabetes is unknown. In a prospective study of the general population (n = 47,627), we tested whether HDL cholesterol-related genetic variants were associated with low HDL cholesterol levels and, in turn, with an increased risk of type 2 diabetes. HDL cholesterol-decreasing gene scores and allele numbers associated with up to 213 and 220% reductions in HDL cholesterol levels. The corresponding theoretically predicted hazard ratios for type 2 diabetes were 1.44 (95% CI 1.38-1.52) and 1.77 (1.61-1.95), whereas the genetic estimates were nonsignificant. Genetic risk ratios for type 2 diabetes for a 0.2 mmol/L reduction in HDL cholesterol were 0.91 (0.75-1.09) and 0.93 (0.78-1.11) for HDL cholesterol-decreasing gene scores and allele numbers, respectively, compared with the corresponding observational hazard ratio of 1.37 (1.32-1.42). In conclusion, genetically reduced HDL cholesterol does not associate with increased risk of type 2 diabetes, suggesting that the corresponding observational association is due to confounding and/or reverse causation.

AB - Observationally, low levels of HDL cholesterol are consistently associated with increased risk of type 2 diabetes. Therefore, plasma HDL cholesterol increasing has been suggested as a novel therapeutic option to reduce the risk of type 2 diabetes. Whether levels of HDL cholesterol are causally associated with type 2 diabetes is unknown. In a prospective study of the general population (n = 47,627), we tested whether HDL cholesterol-related genetic variants were associated with low HDL cholesterol levels and, in turn, with an increased risk of type 2 diabetes. HDL cholesterol-decreasing gene scores and allele numbers associated with up to 213 and 220% reductions in HDL cholesterol levels. The corresponding theoretically predicted hazard ratios for type 2 diabetes were 1.44 (95% CI 1.38-1.52) and 1.77 (1.61-1.95), whereas the genetic estimates were nonsignificant. Genetic risk ratios for type 2 diabetes for a 0.2 mmol/L reduction in HDL cholesterol were 0.91 (0.75-1.09) and 0.93 (0.78-1.11) for HDL cholesterol-decreasing gene scores and allele numbers, respectively, compared with the corresponding observational hazard ratio of 1.37 (1.32-1.42). In conclusion, genetically reduced HDL cholesterol does not associate with increased risk of type 2 diabetes, suggesting that the corresponding observational association is due to confounding and/or reverse causation.

KW - ATP Binding Cassette Transporter 1

KW - Apolipoprotein A-I

KW - Cholesterol Ester Transfer Proteins

KW - Cholesterol, HDL

KW - Cohort Studies

KW - Diabetes Mellitus, Type 2

KW - Dyslipidemias

KW - Female

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Humans

KW - Lipase

KW - Male

KW - Mendelian Randomization Analysis

KW - Middle Aged

KW - Phosphatidylcholine-Sterol O-Acyltransferase

KW - Proportional Hazards Models

KW - Prospective Studies

KW - Taq Polymerase

U2 - 10.2337/db14-1603

DO - 10.2337/db14-1603

M3 - Journal article

C2 - 25972569

SN - 0012-1797

VL - 64

SP - 3328

EP - 3333

JO - Diabetes

JF - Diabetes

IS - 9

ER -