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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., (© 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.)

Background: Epidemiologically, high-density lipoprotein (HDL) cholesterol levels associate inversely with risk of ischemic cardiovascular disease. Whether this is a causal relation is unclear., Methods: We studied 10,281 participants in the Copenhagen City Heart Study (CCHS) and 50,523 participants in the Copenhagen General Population Study (CGPS), of which 991 and 1,693 participants, respectively, had developed myocardial infarction (MI) by August 2010. Participants in the CCHS were genotyped for all six variants identified by resequencing lecithin-cholesterol acyltransferase in 380 individuals. One variant, S208T (rs4986970, allele frequency 4%), associated with HDL cholesterol levels in both the CCHS and the CGPS was used to study causality of HDL cholesterol using instrumental variable analysis., Results: Epidemiologically, in the CCHS, a 13% (0.21 mmol/liter) decrease in plasma HDL cholesterol levels was associated with an 18% increase in risk of MI. S208T associated with a 13% (0.21 mmol/liter) decrease in HDL cholesterol levels but not with increased risk of MI or other ischemic end points. The causal odds ratio for MI for a 50% reduction in plasma HDL cholesterol due to S208T genotype in both studies combined was 0.49 (0.11-2.16), whereas the hazard ratio for MI for a 50% reduction in plasma HDL cholesterol in the CCHS was 2.11 (1.70-2.62) (P(comparison) = 0.03)., Conclusion: Low plasma HDL cholesterol levels robustly associated with increased risk of MI but genetically decreased HDL cholesterol did not. This may suggest that low HDL cholesterol levels per se do not cause MI.

Rare genetic variants, identified by in-detail resequencing of loci, may contribute to complex traits. We used the apolipoprotein A-I gene (APOA1), a major high-density lipoprotein (HDL) gene, and population-based resequencing to determine the spectrum of genetic variants, the phenotypic characteristics of these variants, and how these results compared with results based on resequencing only the extremes of the apolipoprotein A-I (apoA-I) distribution. First, we resequenced APOA1 in 10,330 population-based participants in the Copenhagen City Heart Study. The spectrum and distribution of genetic variants was determined as a function of the number of individuals resequenced. Second, apoA-I and HDL cholesterol phenotypes were determined for nonsynonymous (NS) and synonymous (S) variants and were validated in the Copenhagen General Population Study (n = 45,239). Third, observed phenotypes were compared with those predicted using an extreme phenotype approach based on the apoA-I distribution. Our results are as follows: First, population-based resequencing of APOA1 identified 40 variants of which only 7 (18%) had minor allele frequencies >1%, and most were exceedingly rare. Second, 0.27% of individuals in the general population were heterozygous for NS variants which were associated with substantial reductions in apoA-I (up to 39 mg/dL) and/or HDL cholesterol (up to 0.9 mmol/L) and, surprisingly, 0.41% were heterozygous for variants predisposing to amyloidosis. NS variants associated with a hazard ratio of 1.72 (1.09-2.70) for myocardial infarction (MI), largely driven by A164S, a variant not associated with apoA-I or HDL cholesterol levels. Third, using the extreme apoA-I phenotype approach, NS variants correctly predicted the apoA-I phenotype observed in the population-based resequencing. However, using the extreme approach, between 79% (screening 0-1(st) percentile) and 21% (screening 0-20(th) percentile) of all variants were not identified; among these were variants previously associated with amyloidosis. Population-based resequencing of APOA1 identified a majority of rare NS variants associated with reduced apoA-1 and HDL cholesterol levels and/or predisposing to amyloidosis. In addition, NS variants associated with increased risk of MI., Competing Interests: The authors have declared that no competing interests exist.

Context: Epidemiologically, levels of high-density lipoprotein (HDL) cholesterol and its major protein constituent, apolipoprotein A-I (apoA-I), are inversely related to risk of ischemic heart disease (IHD)., Objective: We tested whether common genetic variation in the apolipoprotein A1 gene (APOA1) contributes to apoA-I and HDL cholesterol levels and risk of IHD in the general population., Design: We resequenced the regulatory and coding regions of APOA1 in 190 individuals from the Copenhagen City Heart Study with the lowest 1% (n=95) and highest 1% (n=95) apoA-I levels. Two single-nucleotide polymorphisms (SNPs) were subsequently genotyped in the Copenhagen City Heart Study (n=10,273) and in 2361 cases with IHD (the Copenhagen Ischemic Heart Disease Study)., Results: In total, 13 genetic variants were identified. Three SNPs, g.-560A→C, g.-151C→T, and *181A→G, determined a haplotype that differed between high and low apoA-I groups (6 vs. 1%, P=0.002). Genotype combinations of two SNPs, the g.-560A→C (tagging the g.-560A→C/g.-151C→T/*181A→G haplotype) and g.-310G→A (situated near a potential functional promoter site), were associated with increases in apoA-I and HDL cholesterol levels of up to 6.6 and 8.5%, respectively, resulting in theoretically predicted reductions in risk of 9 and 8% for IHD and 14 and 12% for myocardial infarction (MI). Despite this, these same genotype combinations were not associated with decreased risk of IHD or MI., Conclusion: Common genetic variation in APOA1 associated with increased apoA-I and HDL cholesterol levels did not associate with decreased risk of IHD or MI.