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

Abstract

BackgroundSmall-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.MethodsThe 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).ResultsIn 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).ConclusionThis 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.

The endothelial function biomarker soluble E‐selectin is associated with nonalcoholic fatty liver disease

“…To further examine the relationship between NAFLD and plasma sE‐selectin levels, independent of potential confounders, we studied the association of two NAFLD susceptibility genes, that is, PNPLA3 (rs738409) and GCKR (rs1260326), with plasma sE‐selectin levels in the combined CODAM and Hoorn studies (n = 1265, see Table for characteristics). Previous studies have shown that both gene variants predispose to NAFLD (including NASH) and elevated liver enzymes, but have opposing effects on factors that are associated with systemic endothelial activation, that is, plasma lipids, T2DM and coronary artery disease risk (Table ). Indeed, positive trends were observed for the relationships of the rs1260326 T‐allele ( GCKR ) and rs738409 G‐allele ( PNPLA3 ) with plasma ALT levels (β = 0.011 [95% CI: −0.004 to 0.26], P = .15; and β = 0.023 [95% CI: 0.005‐0.041], P = .01, respectively, Table ), whereas opposing effects were found for plasma triglycerides levels (β = 0.017 [95% CI: 0.006‐0.027], P = .002; and β = −0.016 [95% CI: −0.029 to − 0.004], P = .009, respectively, Table ).…”

“…Since individuals are ‘randomized’ at conception to receive an allele that either predisposes to or protects from NAFLD, these gene variants can serve as instruments to make causal inferences about the relationship between NAFLD and sE‐selectin levels. Although pleiotropic effects have been reported for both PNPLA3 and GCKR – which may violate this ‘Mendelian randomization’ assumption; it should be noted that these variants have opposing pleiotropic effects on plasma lipids, and risk of type 2 diabetes and coronary artery disease, as summarized in Table . As a combination, they therefore serve as a model to disentangle NAFLD from factors that affect systemic endothelial function, despite the presence of pleiotropy.…”

Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality

“…By using the common variant in GCKR as a model of life-long exposure to a modest increase in hepatic glucokinase activity (Fig. 3a), it can be predicted that it will indeed result in increased de novo lipogenesis and NAFLD, as well as dyslipidaemia and CVD [51,52]. Of interest, we and others have shown that the effects of this common GCKR variant on hepatic fat accumulation and plasma triacylglycerols are more pronounced in conditions of obesity and hyperglycaemia [62,63].…”

“…It cannot, however, be ruled out that the common variants in GCKR also have horizontal pleiotropic effects. Previous studies have shown that these variants also protect against chronic kidney disease and type 2 diabetes [50,52].…”

“…3a) [51], one of the principal pathways in the development of NAFLD [2]. In a recent meta-analysis, we showed that common variants in this gene (rs1260326, rs780094 and rs780093, which are all in strong linkage disequilibrium) are modestly associated with CAD (OR per risk allele 1.02 [95% CI 1.00, 1.04]) [52]. Of interest, these genetic variants have also been associated with higher serum triacylglycerols, lower serum HDLcholesterol and the presence of small-dense LDL particles [51], the lipid phenotype that characterises NAFLD [13].…”