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 language | English |
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Article number | 0206174 |
Number of pages | 14 |
Journal | PLOS ONE |
Volume | 13 |
Issue number | 10 |
DOIs | |
Publication status | Published - 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