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

Abstract

Insulin drives growth and reproduction which trade-off against longevity. Genetically predicted insulin, i.e., insulin proxied by genetic variants, is positively associated with ischemic heart disease, but sex differences are unclear, despite different disease rates and reproductive strategies by sex. We used Mendelian randomization in 392,010 white British from the UK Biobank to assess the sex-specific role of genetically predicted insulin in myocardial infarction (MI) (14,442 cases, 77% men), angina (21,939 cases, 65% men) and heart failure (5537 cases, 71% men). Genetically predicted insulin was associated with MI (odds ratio (OR) 4.27 per pmol/L higher insulin, 95% confidence interval (CI) 1.60 to 11.3) and angina (OR 2.93, 1.27 to 6.73) in men, but not women (MI OR 0.80, 95% CI 0.23 to 2.84, angina OR 1.10, 95% CI 0.38 to 3.18). Patterns were similar for insulin resistance and heart failure. Mitigating the effects of insulin might address sexual disparities in health.

Insulin: too much of a good thing is bad

“…with masking the type of intervention, long-term compliance, and because of ethical concerns. Alternatively, Mendelian randomization studies are suitable tools to test for causality in humans, and such studies have found hyperinsulinemia to increase the risk of obesity [27,28] and cardiovascular disease [127,128]. A straightforward approach for lowering circulating insulin levels is restricting the exposure of islet ß cells to insulin secretagogues.…”

“…Final proof of a causal relationship between hyperinsulinemia and disease risk cannot be obtained by randomized controlled trials, due to problems with masking the type of intervention, long-term compliance, and because of ethical concerns. Alternatively, Mendelian randomization studies are suitable tools to test for causality in humans, and such studies have found hyperinsulinemia to increase the risk of obesity [ 27 , 28 ] and cardiovascular disease [ 127 , 128 ].…”

“…When comparing individuals carrying ≥ 17 alleles that raise fasting insulin levels with those exhibiting genetically determined low fasting insulin levels, an increased risk of elevated blood pressure, cardiovascular disease, and type 2 diabetes was observed [127]. In two large recent Mendelian randomization studies, a genetic profile predicting high insulin levels in the blood, after adjustment for BMI, was also associated with increased systolic blood pressure and risk of myocardial infarction [128].…”

Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian randomisation

“…In addition, our findings are consistent with well-established evolutionary biology theory, that is reproductive success may be at the expense of longevity, possibly in a sex-specific manner, impling that central drivers of the reproductive axis, as well as androgen production and catabolism, and their environmental cues may be relevant to IHD ( Schooling, 2016 ; Schooling and Ng, 2019 ; Figure 2 ) encompassing the relations tested here ( Figure 1 ). Notably, upregulation of indicators of plentiful living conditions, such as insulin, appear to cause IHD, particularly in men ( Zhao et al, 2019 ), likely via gonadotropin releasing hormone (GnRH) ( Schooling and Ng, 2019 ). Similarly, fatty acids may affect GnRH ( Tran et al, 2016 ; Matsuyama and Kimura, 2015 ).…”

Association of genetically predicted blood sucrose with coronary heart disease and its risk factors in Mendelian randomization

“…Unregulated fructose metabolism can also raise uric acid concentration, which has been linked to endothelial dysfunction, hypertension, and increased risk of CVD 33 . It is also possible that sugar intake might affect glucagon or insulin which may cause CHD 37,38 . However, we did not find any evidence of these pathways, which need validation using stronger instruments predicting sugar.…”