title: Genetic support for the causal role of insulin in coronary heart disease.
abstract: Epidemiological studies have identified several traits associated with CHD, but few of these have been shown to be causal risk factors and thus suitable targets for treatment. Our aim was to evaluate the causal role of a large set of known CHD risk factors using single-nucleotide polymorphisms (SNPs) as instrumental variables.
  
  
  
  Based on published genome-wide association studies (GWASs), we estimated the associations between the established risk factors (blood lipids, obesity, glycaemic traits and BP) and CHD with two complementary approaches: (1) using summary statistics from GWASs to analyse the accordance of SNP effects on risk factors and on CHD; and (2) individual-level analysis where we constructed genetic risk scores (GRSs) in a large Finnish dataset (N = 26,554, CHD events n = 4016). We used a weighted regression-based method for summary-level data to evaluate the causality of risk factors. The associations between the GRSs and CHD in the Finnish dataset were evaluated with logistic and conditional logistic regression models.
  
  
  
  The summary-level data analysis revealed causal effects between glycaemic traits (insulin and glucose) and CHD. The individual-level data analysis supported the causal role of insulin, but not of glucose, on CHD. The GRS for insulin was associated with CHD in the Finnish cohort (OR 1.06 per SD in GRS, 95% CI 1.02, 1.10, p = 0.002).
  
  
  
  These results support the causal role of insulin in the pathogenesis of CHD. Efficient treatment and prevention of insulin resistance is essential to prevent future CHD events.
authors: Department of Public Health, University of Helsinki, PO Box 20, Tukholmankatu 8 B, FIN-00014, Helsinki, Finland. emmi.tikkanen@helsinki.fi.|Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland. emmi.tikkanen@helsinki.fi.
authors: Emmi
authors: E
authors: Tikkanen
authors: Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
authors: Matti
authors: M
authors: Pirinen
authors: Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
authors: Antti-Pekka
authors: AP
authors: Sarin
authors: Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
authors: Aki S
authors: AS
authors: Havulinna
authors: Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
authors: Satu
authors: S
authors: Männistö
authors: Department of Medicine, Central Finland Central Hospital, Jyväskylä, Finland.
authors: Juha
authors: J
authors: Saltevo
authors: Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors: Marja-Liisa
authors: ML
authors: Lokki
authors: Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
authors: Juha
authors: J
authors: Sinisalo
authors: Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
authors: Annamari
authors: A
authors: Lundqvist
authors: Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
authors: Antti
authors: A
authors: Jula
authors: Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
authors: Veikko
authors: V
authors: Salomaa
authors: Department of Public Health, University of Helsinki, PO Box 20, Tukholmankatu 8 B, FIN-00014, Helsinki, Finland. samuli.ripatti@fimm.fi.|Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland. samuli.ripatti@fimm.fi.|Wellcome Trust Sanger Institute, Hinxton, UK. samuli.ripatti@fimm.fi.
authors: Samuli
authors: S
authors: Ripatti
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D003327:Coronary Disease / Q000097:blood* / Q000453:epidemiology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
chemical_list: D001786:Blood Glucose; D007328:Insulin
keywords: Epidemiology; Genetics; Insulin resistance; Insulin sensitivity