Abstract
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.
Original language | English |
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Journal | Diabetes |
Volume | 64 |
Issue number | 9 |
Pages (from-to) | 3328-33 |
Number of pages | 6 |
ISSN | 0012-1797 |
DOIs | |
Publication status | Published - Sept 2015 |
Keywords
- ATP Binding Cassette Transporter 1
- Apolipoprotein A-I
- Cholesterol Ester Transfer Proteins
- Cholesterol, HDL
- Cohort Studies
- Diabetes Mellitus, Type 2
- Dyslipidemias
- Female
- Genetic Predisposition to Disease
- Genetic Variation
- Humans
- Lipase
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Phosphatidylcholine-Sterol O-Acyltransferase
- Proportional Hazards Models
- Prospective Studies
- Taq Polymerase