Association of common gene variants in glucokinase regulatory protein with cardiorenal disease: A systematic review and meta-analysis

Pomme I. H. G. Simons, Nynke Simons, Coen D. A. Stehouwer, Casper G. Schalkwijk, Nicolaas C. Schaper, Martijn C. G. J. Brouwers*

*Corresponding author for this work

Research output: Contribution to journal(Systematic) Review article peer-review

14 Citations (Web of Science)

Abstract

Background

Small-molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP) in the liver represent a potential new class of glucose-lowering drugs. It will, however, take years before their effects on clinically relevant cardiovascular endpoints are known. The purpose of this study was to estimate the effects of these drugs on cardiorenal outcomes by studying variants in the GKRP gene (GCKR) that mimic glucokinase-GKRP disruptors.

Methods

The MEDLINE and EMBASE databases were searched for studies reporting on the association between GCKR variants (rs1260326, rs780094, and rs780093) and coronary artery disease (CAD), estimated glomerular filtration rate (eGFR), and chronic kidney disease (CKD).

Results

In total 5 CAD studies (n = 274,625 individuals), 7 eGFR studies (n = 195,195 individuals), and 4 CKD studies (n = 31,642 cases and n = 408,432 controls) were included. Meta-analysis revealed a significant association between GCKR variants and CAD (OR: 1.02 per risk allele, 95% CI: 1.00-1.04, p = 0.01). Sensitivity analyses showed that replacement of one large, influential CAD study by two other, partly overlapping studies resulted in similar point estimates, albeit less precise (OR: 1.02; 95% CI: 0.98-1.06 and OR: 1.02; 95% CI: 0.99-1.04). GCKR was associated with an improved eGFR (+0.49 ml/min, 95% CI: 0.10-0.89, p = 0.01) and a trend towards protection from CKD (OR: 0.98, 95% CI: 0.95-1.01, p = 0.13).

Conclusion

This study suggests that increased glucokinase-GKRP disruption has beneficial effects on eGFR, but these may be offset by a disadvantageous effect on coronary artery disease risk. Further studies are warranted to elucidate the mechanistic link between hepatic glucose metabolism and eGFR.

Original languageEnglish
Article number0206174
Number of pages14
JournalPLOS ONE
Volume13
Issue number10
DOIs
Publication statusPublished - 23 Oct 2018

Keywords

  • CHRONIC KIDNEY-DISEASE
  • CORONARY-ARTERY-DISEASE
  • GENOME-WIDE ASSOCIATION
  • TYPE-2 DIABETES-MELLITUS
  • SUSCEPTIBILITY LOCI
  • JAPANESE INDIVIDUALS
  • TRIGLYCERIDE LEVELS
  • GCKR POLYMORPHISMS
  • P446L VARIANT
  • RISK

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