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. 2019 May 25:8:100411.
doi: 10.1016/j.ssmph.2019.100411. eCollection 2019 Aug.

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

C M Schooling  1   2 , Jack C M Ng  1
Affiliations

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

C M Schooling et al. SSM Popul Health. .

Abstract

Background: According to well-established evolutionary biology theory there is a trade-off between reproduction and longevity, implying that upregulating the reproductive axis might drive major diseases. We assessed whether the central driver of reproduction gonadotropin-releasing hormone 1 (GnRH1) had a causal effect on the leading cause of global morbidity and mortality, i.e. ischemic heart disease (IHD). As a contrast we similarly examined the role of GnRH2 because it is more a driver of female sexual behavior.

Methods: We applied strong (p-value <5 × 10-6) and independent genetic predictors of GnRH1 and GnRH2 to an extensively genotyped IHD case (n = 76,014) - control (n = 264,785) study and combined the genetic variant specific Wald estimates using inverse variance weighting (IVW) with multiplicative random effects, and as a sensitivity analysis used weighted median, MR-Egger and MR-PRESSO estimates, and repeated the analysis only using genome wide significant genetic predictors.

Findings: GnRH1, predicted by 11 genetic variants, was positively associated with IHD (IVW odds ratio (OR) 1.04 per effect size, 95% confidence interval (CI) 1.01 to 1.08), but GnRH2, predicted by 15 genetic variants, was not (IVW OR 0.98, 95% CI 0.95 to 1.02). Estimates from sensitivity analysis were similar.

Interpretation: GnRH1 is a potential IHD genetic target. Apart from demonstrating a central tenet of evolutionary biology in humans, our study suggests that existing treatments and environmental factors targeting GnRH1, its drivers or consequences could be re-purposed to prevent and treat IHD. Given, the importance of reproduction to the human species, many such exposures likely exist.

Keywords: CVD, cardiovascular disease; Evolutionary biology; GWAS, genome-wide association study; GnRH; GnRH, Gonadotropin-releasing hormone; IHD; IHD, ischemic heart disease; Mendelian randomization; SNP, single nucleotide polymorphism.

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Figures

Fig. 1
Fig. 1
Overall IVW (random effects) and SNP-specific estimates for the association of (a) GnRH1 and (b) GnRH2 with IHD.
See this image and copyright information in PMC

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