Additive genetic effect of GCKR, G6PC2, and SLC30A8 variants on fasting glucose levels and risk of type 2 diabetes

Abstract

Impaired glucose tolerance is a major risk factor for type 2 diabetes (T2D) and several cardiometabolic disorders. To identify genetic loci underlying fasting glucose levels, we conducted an analysis of 9,232 individuals of European ancestry who at enrollment were either nondiabetic or had untreated type 2 diabetes. Multivariable linear mixed models were used to test for associations between fasting glucose and 7.9 million SNPs, with adjustment for age, body mass index (BMI), sex, significant principal components of the genotypes, and cryptic relatedness. Three previously discovered loci were genome-wide significant, with the lead SNPs being rs1260326, a missense variant in GCKR (p = 1.06×10−8); rs560887, an intronic variant in G6PC2 (p = 3.39×10−11); and rs13266634, a missense variant in SLC30A8 (p = 4.28×10−10). Fine mapping, genome-wide conditional analysis, and functional annotation indicated that the three loci were independently associated with fasting glucose. Each copy of an alternate allele at any of these three SNPs was associated with a reduction of 0.012 mmol/L in fasting glucose levels (p = 8.0×10−28), and this association was replicated in trans-ethnic analysis of 14,303 individuals (p = 2.2×10−16). The three SNPs were jointly associated with significantly reduced T2D risk, with an odds ratio (95% CI) of 0.93 (0.88, 0.98) per protective allele. Our findings implicate additive effects across pathophysiological pathways involved in type 2 diabetes, including glycolysis, gluconeogenesis, and insulin secretion. Since none of the individuals homozygous for the alternate alleles at all three loci has T2D, it might be possible to use a genetic predictor of fasting glucose levels to identify individuals at low vs. high risk of developing type 2 diabetes.

Prevalence of GCKR rs1260326 Variant in Subjects with Obesity Associated NAFLD and T2DM: A Case-Control Study in South Punjab, Pakistan

“…Visceral obesity and high BMI were high risk factors, especially in both metabolic disorders. Previous studies indicated that the prevalence of obesity usually surpassed 90% of the subjects in NAFLD [ 8 ]. The development of obesity was also significantly linked with the GCKR rs1260326 mutant allele (C) especially in NAFLD subjects, while the frequency of mutant allele (C) was considerably higher in T2DM obese subjects but did not show a statistical significance in comparison to normal weight subjects.…”

“…The GCKR rs1260326 genetic variant is functionally relevant comprising of an amino acid substitution as C to T coding for a proline-to-leucine at position 446 (P446L) (Supplementary Figure 1 ) [ 7 ]. A missense variant in the GCKR rs1260326 is associated with abnormal fasting glucose levels and a higher risk of T2DM development [ 8 ]. Similarly, genome-wide association studies (GWASs) also reported that functional variants of the GCKR including rs1260326 are associated with low plasma insulin and fasting plasma glucose, as well as higher fasting and postprandial serum triglyceride levels [ 9 , 10 ].…”

A Missense Variant in COMT Associated with Hearing Loss among Young Adults: The National Longitudinal Study of Adolescent to Adult Health (Add Health)

“…From a paradigm of protein sequence-to-structure-to-function, we uploaded translated sequences (amino acid sequences) to the I-TASSER online server ( , accessed on 19 October 2022) [ 26 , 27 , 28 ] to predict the three-dimensional (3D) protein structure. We used the protein 3D structure to find matches in a protein function database in order to predict protein functions [ 29 ]. PyMol [ 30 ] was used to view and analyze the protein structure.…”