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

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 −13 and −20% 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.

[1]  B. Nordestgaard,et al.  Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. , 2014, The New England journal of medicine.

[2]  D. Sviridov,et al.  Effects of High-Density Lipoprotein Elevation With Cholesteryl Ester Transfer Protein Inhibition on Insulin Secretion , 2013, Circulation research.

[3]  M. Linton,et al.  Killing two birds with one stone, maybe: CETP inhibition increases both high-density lipoprotein levels and insulin secretion. , 2013, Circulation research.

[4]  D. Sviridov,et al.  Effects of HDL Elevation with CETP Inhibition on Insulin Secretion , 2013 .

[5]  Sonia Shah,et al.  Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study , 2013, The Lancet.

[6]  B. Nordestgaard,et al.  ABC Transporter Genes and Risk of Type 2 Diabetes , 2012, Diabetes Care.

[7]  Tanya M. Teslovich,et al.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes , 2012, Nature Genetics.

[8]  Claude Bouchard,et al.  A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance , 2012, Nature Genetics.

[9]  P. Barter,et al.  The emerging role of HDL in glucose metabolism , 2012, Nature Reviews Endocrinology.

[10]  Mark I. McCarthy,et al.  Mendelian Randomization Studies Do Not Support a Role for Raised Circulating Triglyceride Levels Influencing Type 2 Diabetes, Glucose Levels, or Insulin Resistance , 2011, Diabetes.

[11]  P. Barter,et al.  Effects of High-Density Lipoproteins on Pancreatic &bgr;-Cell Insulin Secretion , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[12]  C. Hedrick,et al.  An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic beta cells. , 2010, The Journal of clinical investigation.

[13]  Lukasz Januszkiewicz [The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus]. , 2010, Kardiologia polska.

[14]  John B Buse,et al.  Effects of combination lipid therapy in type 2 diabetes mellitus. , 2010, The New England journal of medicine.

[15]  D. Sviridov,et al.  High-Density Lipoprotein Modulates Glucose Metabolism in Patients With Type 2 Diabetes Mellitus , 2009, Circulation.

[16]  M. Hayden,et al.  Carriers of Loss-of-Function Mutations in ABCA1 Display Pancreatic β-Cell Dysfunction , 2008, Diabetes Care.

[17]  Børge G Nordestgaard,et al.  Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. , 2008, JAMA.

[18]  C. Aguilar-Salinas,et al.  Association of the ATP-Binding Cassette Transporter A1 R230C Variant With Early-Onset Type 2 Diabetes in a Mexican Population , 2008, Diabetes.

[19]  R. Lai,et al.  Apolipoprotein A-I stimulates AMP-activated protein kinase and improves glucose metabolism , 2007, Diabetologia.

[20]  Ralph B D'Agostino,et al.  Prediction of incident diabetes mellitus in middle-aged adults: the Framingham Offspring Study. , 2007, Archives of internal medicine.

[21]  James D. Johnson,et al.  β-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment , 2007, Nature Medicine.

[22]  Heejung Bang,et al.  Identifying individuals at high risk for diabetes: The Atherosclerosis Risk in Communities study. , 2005, Diabetes care.

[23]  S. Ebrahim,et al.  'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? , 2003, International journal of epidemiology.

[24]  I. Stratton,et al.  Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom prospective diabetes study (UKPDS: 23) , 1998, BMJ.

[25]  P. Toth LCAT, HDL Cholesterol and Ischemic Cardiovascular Disease: A Mendelian Randomization Study of HDL Cholesterol in 54,500 Individuals , 2012 .

[26]  George Davey Smith,et al.  Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology , 2008, Statistics in medicine.

[27]  M. Taskinen Diabetic dyslipidemia. , 2002, Atherosclerosis. Supplements.

[28]  武井泉,et al.  United Kingdom Prospective Diabetes Study (UKPDS) , 1999 .