GCKR Common Functional Polymorphisms are Associated with Metabolic Syndrome and its Components: A 10-Year Retrospective Cohort Study in Iranian Adults

Abstract

Background: Some previous studies reported that common functional variants (rs780093, rs780094, and rs1260326) in the glucokinase regulator gene (GCKR) were associated with metabolic syndrome despite the simultaneous association with the favorable and unfavorable metabolic syndrome components. We decided to examine these findings, to our knowledge for the first time, in Iranian adults. We investigated the association of the GCKR variants with incident MetS in mean follow-up times for nearly ten years.Methods: Analysis of this retrospective cohort study was performed among 5666 participants of the Tehran Cardiometabolic Genetics Study (TCGS) at 19-88 years at baseline. Linear and logistic regression analyses were used to investigate the metabolic syndrome (JIS criteria) association and its components with rs780093, rs780094, and rs1260326 in an additive genetic model. Cox regression was carried out to peruse variants' association with the incidence of metabolic syndrome in the TCGS cohort study.Results: In the current study, we have consistently replicated the association between the T-allele of GCKR SNPs and higher triglyceride levels and lower fasting blood sugar levels (p<0.05) in the Iranian population. The CT genotype of all three variants was associated with lower HDL-C levels. The proportional Cox adjusted model regression resulted that TT carriers of rs780094, rs780093, and rs1260326 were associated with 20%, 23%, and 21% excess risk metabolic syndrome incidence, respectively (p<0.05).Conclusions: Elevated triglyceride levels had the strongest association with GCKR selected variants among the metabolic syndrome components. Despite the association of these variants with decreased fasting blood sugar levels, T alleles of the variants were associated with metabolic syndrome incidence; so whether individuals are T allele carriers of the common functional variants, they have a risk factor for the future incidence of metabolic syndrome.

Title: Cohort profile update: Tehran Cardiometabolic Genetic Study, a path toward precision medicine

“…The ndings indicated the association between functional GCKR variants and higher TG and lower fasting blood sugar (FBS) levels. Moreover, the results of Cox-adjusted model regression revealed that TT carriers of rs780094, rs780093, and rs1260326 were associated with a 20, 23, and 21% higher risk of MetS incidence, respectively [41]. The following study reported that the logistic regression model showed a signi cant association of MetS with age, gender, schooling years, BMI, physical activity, rs780094, and rs780093.…”

“…To investigate the association of MetS and its components with glucokinase regulator (GCKR) polymorphisms (rs780093, rs780094, and rs1260326), linear and logistic regression analyses were used in an additive genetic model. Moreover, Cox regression analysis was carried out to show the variants' association with the incidence of MetS [41]. In a candidate gene study, to nd the optimal prediction model (s) for MetS, GCKR gene variants, along with clinical and demographic information, were used on 4756 eligible TCGS participants.…”

A haplotype-resolved genome assembly of the Nile rat facilitates exploration of the genetic basis of diabetes

“…Mammalian Gckr is composed of two sugar isomerase (SIS) domains which contain binding sites for fructose-6-phosphate (F6P) or fructose-1-phosphate (F1P) and glucokinase, where the fructose metabolites alter the affinity of Gckr for glucokinase [79]. Human GCKR has been reported as a diabetic susceptibility gene by several studies [80][81][82][83][84]. We found a full-length second copy of Gckr, LOC117716845, 1.2 Mb downstream of the canonical Gckr.…”

A haplotype-resolved genome assembly of the Nile rat facilitates exploration of the genetic basis of diabetes

“…(Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research et al 2007)(Zahedi et al 2021) …”