title: Low-density-lipoprotein cholesterol concentrations and risk of incident diabetes: epidemiological and genetic insights from the Framingham Heart Study.
abstract: OBJECTIVE
  Statins and niacin (nicotinic acid) reduce circulating LDL-cholesterol (LDL-C) levels by different mechanisms. Yet, both increase the risk of diabetes mellitus. Our objective was to relate blood LDL-C concentrations and a genetic risk score (GRS) for LDL-C to the risk of incident diabetes in individuals not treated with lipid-modifying therapy.
  
  
  METHODS
  We evaluated participants of the Framingham Heart Study who attended any of Offspring cohort examination cycles 3-8 and Third Generation cohort examination cycle 1 (N =14,120 person-observations, 6,011 unique individuals; mean age 50 ± 11 years, 56% women), who were not treated with lipid-modifying or antihypertensive medications and who were free from cardiovascular disease at baseline. Incident diabetes was assessed at the next examination.
  
  
  RESULTS
  The GRS was significantly associated with LDL-C concentrations (sex- and age-adjusted estimated influence 0.24, p < 0.0001). On follow-up (mean 4.5 ± 1.5 years), 312 individuals (2.2%) developed new-onset diabetes. In multivariable models, a higher LDL-C concentration was associated with lower risk of diabetes (OR per SD increment 0.81, 95% CI 0.70, 0.93, p = 0.004). The GRS was associated with incident diabetes in a similar direction and of comparable magnitude (OR per SD increment 0.85, 95% CI 0.76, 0.96, p = 0.009).
  
  
  CONCLUSIONS
  Among individuals not treated with lipid-modifying therapy low LDL-C concentrations were associated with increased diabetes risk. These observations may contribute to our understanding of why lipid-lowering treatment may cause diabetes in some individuals. Additional studies are warranted to elucidate the molecular mechanisms underlying our observations.
authors.affiliation: Framingham Heart Study, 73 Mt Wayte Avenue, Suite 2, Framingham, MA, 01702-5827, USA. ca@heart.dk.|Department of Cardiology, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. ca@heart.dk.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Andersson
authors.affiliation: Framingham Heart Study, 73 Mt Wayte Avenue, Suite 2, Framingham, MA, 01702-5827, USA.|Department of Mathematics and Statistics, Boston University, Boston, MA, USA.
authors.forename: Asya
authors.initials: A
authors.lastname: Lyass
authors.affiliation: Framingham Heart Study, 73 Mt Wayte Avenue, Suite 2, Framingham, MA, 01702-5827, USA.|Department of Mathematics and Statistics, Boston University, Boston, MA, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Larson
authors.affiliation: Framingham Heart Study, 73 Mt Wayte Avenue, Suite 2, Framingham, MA, 01702-5827, USA.
authors.forename: Sander J
authors.initials: SJ
authors.lastname: Robins
authors.affiliation: Framingham Heart Study, 73 Mt Wayte Avenue, Suite 2, Framingham, MA, 01702-5827, USA.|Section of Preventive Medicine and Cardiology, Boston University School of Medicine, Boston, MA, USA.|Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
mesh_terms: D000328:Adult; D008078:Cholesterol, LDL / Q000097:blood*; D015331:Cohort Studies; D003920:Diabetes Mellitus / Q000097:blood / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood
chemical_list: D008078:Cholesterol, LDL; D014280:Triglycerides
keywords: Diabetes risk; Low-density lipoprotein concentrations; Mendelian randomisation; Untreated individuals