Diabetologia

, Volume 59, Issue 11, pp 2369–2377

Genetic support for the causal role of insulin in coronary heart disease

  • Emmi Tikkanen
  • Matti Pirinen
  • Antti-Pekka Sarin
  • Aki S. Havulinna
  • Satu Männistö
  • Juha Saltevo
  • Marja-Liisa Lokki
  • Juha Sinisalo
  • Annamari Lundqvist
  • Antti Jula
  • Veikko Salomaa
  • Samuli Ripatti
Article

DOI: 10.1007/s00125-016-4081-6

Cite this article as:
Tikkanen, E., Pirinen, M., Sarin, AP. et al. Diabetologia (2016) 59: 2369. doi:10.1007/s00125-016-4081-6

Abstract

Aims/hypothesis

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.

Methods

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.

Results

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).

Conclusions/interpretation

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.

Keywords

Epidemiology Genetics Insulin resistance Insulin sensitivity 

Abbreviations

2SLS

Two-stage least-squares

βIns

βInsulin

βGlu

βGlucose

CVD

Cardiovascular disease

DBP

Diastolic BP

DILGOM

DIetary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome

GRS

Genetic risk score

GWAS

Genome-wide association study

ISI

Insulin sensitivity index

MAF

Minor allele frequency

MR

Mendelian randomisation

RCT

Randomised controlled trial

SBP

Systolic BP

SNP

Single-nucleotide polymorphism

Supplementary material

125_2016_4081_MOESM1_ESM.pdf (1.4 mb)
ESM(PDF 1458 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Emmi Tikkanen
    • 1
    • 2
  • Matti Pirinen
    • 2
  • Antti-Pekka Sarin
    • 2
  • Aki S. Havulinna
    • 3
  • Satu Männistö
    • 3
  • Juha Saltevo
    • 4
  • Marja-Liisa Lokki
    • 5
  • Juha Sinisalo
    • 6
  • Annamari Lundqvist
    • 3
  • Antti Jula
    • 3
  • Veikko Salomaa
    • 3
  • Samuli Ripatti
    • 1
    • 2
    • 7
  1. 1.Department of Public HealthUniversity of HelsinkiHelsinkiFinland
  2. 2.Institute for Molecular Medicine Finland FIMMUniversity of HelsinkiHelsinkiFinland
  3. 3.Department of HealthNational Institute for Health and WelfareHelsinkiFinland
  4. 4.Department of MedicineCentral Finland Central HospitalJyväskyläFinland
  5. 5.Transplantation Laboratory, Haartman InstituteUniversity of HelsinkiHelsinkiFinland
  6. 6.Heart and Lung CenterHelsinki University Central HospitalHelsinkiFinland
  7. 7.Wellcome Trust Sanger InstituteHinxtonUK

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