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

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.

Reproduction and longevity A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart disease

“…27 Insulin increases IHD risk. 28 Insulin raises testosterone 29 30 providing a pathway from GnRH1 to IHD. Other potential drivers of GnRH1 include neurokinins, 31 32 nitric oxide, 33 aspartate/glutamate, 34 35 gamma-aminobutyric acid 36 and dynorphin.…”

Reproduction and longevity: A Mendelian randomization study of gonadotropin-releasing hormone and ischemic heart disease

“…To ensure optimal timing of reproduction GnRH is likely regulated by many modifiable, environmental factors, which could provide new targets for IHD prevention or treatment. Some drivers of GnRH are already known to be related to IHD, specifically insulin which increases GnRH (Sliwowska et al, 2014) also increases IHD (Tikkanen et al, 2016; Zhan et al, 2017), while nitric oxide which decreases GnRH (Bellefontaine et al, 2011) is a component of one of the oldest treatments for IHD, i.e., nitroglycerin.…”

Sex-specific Mendelian randomization study of genetically predicted insulin and cardiovascular events in the UK Biobank

“…First, MR is based on three stringent assumptions, i.e., the genetic variants are strongly related to the exposure, are not related to the exposure-outcome confounders, and the genetic variants are related to the outcomes only via influencing the exposure 34,35 . To satisfy the first assumption, we used genetic variants strongly associated with insulin and insulin resistance from a large GWAS 27,29 , as previously 16,17 . To satisfy the second assumption, we checked for associations with known exposure-outcome confounders, including socioeconomic position and lifestyle in the UK Biobank, where there was no association with these potential confounders.…”

“…Unexpectedly and controversially, use of insulin has long been suspected to play a role in CVD 14 , especially in men 15 . Genetically predicted insulin and insulin resistance are consistently positively associated with higher risk of IHD 16–18 , independent of adiposity 18 . Patients switching from metformin to an insulin secretagogue, sulphonylurea, have a higher risk of myocardial infarction (MI) 19 .…”