Leveraging human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide signalling

Diabetologia. 2021 Dec;64(12):2773-2778. doi: 10.1007/s00125-021-05564-7. Epub 2021 Sep 9.

Abstract

Aims/hypothesis: The aim of this study was to leverage human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide (GIP) signalling.

Methods: Data were obtained from summary statistics of large-scale genome-wide association studies. We examined whether genetic associations for type 2 diabetes liability in the GIP and GIPR genes co-localised with genetic associations for 11 cardiometabolic outcomes. For those outcomes that showed evidence of co-localisation (posterior probability >0.8), we performed Mendelian randomisation analyses to estimate the association of genetically proxied GIP signalling with risk of cardiometabolic outcomes, and to test whether this exceeded the estimate observed when considering type 2 diabetes liability variants from other regions of the genome.

Results: Evidence of co-localisation with genetic associations of type 2 diabetes liability at both the GIP and GIPR genes was observed for five outcomes. Mendelian randomisation analyses provided evidence for associations of lower genetically proxied type 2 diabetes liability at the GIP and GIPR genes with lower BMI (estimate in SD units -0.16, 95% CI -0.30, -0.02), C-reactive protein (-0.13, 95% CI -0.19, -0.08) and triacylglycerol levels (-0.17, 95% CI -0.22, -0.12), and higher HDL-cholesterol levels (0.19, 95% CI 0.14, 0.25). For all of these outcomes, the estimates were greater in magnitude than those observed when considering type 2 diabetes liability variants from other regions of the genome.

Conclusions/interpretation: This study provides genetic evidence to support a beneficial role of sustained GIP signalling on cardiometabolic health greater than that expected from improved glycaemic control alone. Further clinical investigation is warranted.

Data availability: All data used in this study are publicly available. The scripts for the analysis are available at: https://github.com/vkarhune/GeneticallyProxiedGIP .

Keywords: Cardiometabolic disease; Co-localisation; Glucose-dependent insulinotropic polypeptide; Mendelian randomisation; Type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cardiovascular Diseases* / genetics
  • Diabetes Mellitus, Type 2* / genetics
  • Diabetes Mellitus, Type 2* / metabolism
  • Gastric Inhibitory Polypeptide / genetics
  • Gastric Inhibitory Polypeptide / metabolism
  • Genome-Wide Association Study
  • Glucose / metabolism
  • Human Genetics
  • Humans
  • Receptors, Gastrointestinal Hormone* / genetics
  • Receptors, Gastrointestinal Hormone* / metabolism

Substances

  • Receptors, Gastrointestinal Hormone
  • Gastric Inhibitory Polypeptide
  • Glucose