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

75 Citations (Scopus)

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 languageEnglish
JournalDiabetes
Volume64
Issue number9
Pages (from-to)3328-33
Number of pages6
ISSN0012-1797
DOIs
Publication statusPublished - 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

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