GCKR Rs780094 Research Articles

Glucokinase receptor genetic polymorphism in Indian population and its association with Non Alcoholic Fatty Liver Disease

Background and Aim: Non Alcoholic Fatty Liver Disease (NAFLD) is now the most important cause of Chronic Liver Disease (CLD) in both Western and Asian population. While some avenues are yet to be explored, underlying cause appears to be the explosive epidemic of metabolic syndrome and obesity in particular. However, the relation between the two is still not completely elucidated. Understanding the genetic background may have relevance to surveillance, therapeutic strategies and in developing preventive measures. There are limited studies on genetic background of NAFLD in Asian population. We attempted to study one such genetic variation, Glucokinase regulator gene (GCKR) in NAFLD patients in Indian population. We aimed to find the association of GCKR gene variants (rs780094, rs1260326) in patients with NAFLD in Indian population and to assess the relation of GCKR variants with clinical profile. Methods: A cross sectional analytical study was conducted in the Department of Gastroenterology at a tertiary care centre in western India. Total 100 subjects between the age group of 18-65 were included in the study. Out of which, 50 were patients with NAFLD including fatty liver, Non Alcoholic Steatohepatitis (NASH) and NASH related cirrhosis and 50 were healthy subjects (No NAFLD). Results: GCKR rs780094 minor allele A was more common in NAFLD patients as compared to healthy subjects. (p= 0.00001). Within the spectrum of NAFLD, A allele was present more commonly among cirrhotics and in NAFLD patients as compared to Non-alcoholic steatohepatitis (NASH) and fatty liver. (p=0.00001). Morbidly obese individuals showed significant association with homozygous A allele (p=0.028). These results were not seen with GCKR rs1260326 across all alleles. Conclusions: GCKR genetic variant rs780094 appears to be significantly associated with NAFLD in Indian population.

Contribution of Rs780094 and Rs1260326 Polymorphisms in GCKR Gene to Non-alcoholic Fatty Liver Disease: A Meta-Analysis Involving 26,552 Participants

Many published studies attempted to elucidate the implication of glucokinase regulator gene (GCKR) polymorphisms in the susceptibility to non-alcoholic fatty liver disease (NAFLD), but the results among them were still controversial. This meta-analysis aims to precisely assess the relationship between the GCKR polymorphisms and the risk of NAFLD. Systematic computerized searches in six databases were performed and updated on April 6, 2020. Meta-analyses were conducted by calling the R programs based on accumulated epidemiological data. Odds ratio (OR) and 95% confidential interval (CI) were calculated to summarize the effect estimates. In total, 25 studies including 6,598 cases and 19,954 controls were included. The pooled estimates indicated that the T allele carrier of the GCKR rs780094 polymorphism has predisposition to NAFLD (allele model: OR: 1.20, 95% CI: 1.11~1.29; homozygote model: OR: 1.38, 95% CI: 1.15~1.67; heterozygote model: OR: 1.25, 95% CI: 1.12~1.39; dominant model: OR: 1.29, 95% CI: 1.13~1.47; recessive model: OR: 1.18, 95% CI: 1.06~1.31), and the same as the rs1260326 polymorphism (allele model: OR: 1.32, 95% CI: 1.22~1.42; homozygote model: OR: 1.65, 95% CI: 1.40~1.94; heterozygote model: OR: 1.24, 95% CI: 1.07~1.43; dominant model: OR: 1.39, 95% CI: 1.21~1.59; recessive model: OR: 1.44, 95% CI: 1.28~1.62). Further stratified analyses according to age and ethnicity confirmed the statistical existence in most subgroups. This meta-analysis suggested that both of the GCKR rs780094 and rs1260326 polymorphisms are significantly associated with the increased risk of NAFLD.

Lifestyle Factors and Genetic Variants on 2 Biological Age Measures: Evidence From 94 443 Taiwan Biobank Participants.

Biological age (BA) can be estimated by phenotypes and is useful for predicting life span and health span. Levine et al. proposed a PhenoAge and a BioAge to measure BA. Although there have been studies investigating the genetic predisposition to BA acceleration in Europeans, little has been known regarding this topic in Asians. I have estimated PhenoAgeAccel (age-adjusted PhenoAge) and BioAgeAccel (age-adjusted BioAge) of 94 443 Taiwan Biobank (TWB) participants, wherein 25 460 TWB1 participants formed a discovery cohort and 68 983 TWB2 individuals constructed a replication cohort. Lifestyle factors and genetic variants associated with PhenoAgeAccel and BioAgeAccel were investigated through regression analysis and a genome-wide association study. A unit (kg/m2) increase of body mass index was associated with a 0.177-year PhenoAgeAccel (95% confidence interval [CI] = 0.163-0.191, p = 6.0 × 10-129) and 0.171-year BioAgeAccel (95% CI = 0.165-0.177, p = 0). Smokers on average had a 1.134-year PhenoAgeAccel (95% CI = 0.966-1.303, p = 1.3 × 10-39) compared with nonsmokers. Drinkers on average had a 0.640-year PhenoAgeAccel (95% CI = 0.433-0.847, p = 1.3 × 10-9) and 0.193-year BioAgeAccel (95% CI = 0.107-0.279, p = 1.1 × 10-5) relative to nondrinkers. A total of 11 and 4 single-nucleotide polymorphisms (SNPs) were associated with PhenoAgeAccel and BioAgeAccel (p < 5 × 10-8 in both TWB1 and TWB2), respectively. A PhenoAgeAccel-associated SNP (rs1260326 in GCKR) and 2 BioAgeAccel-associated SNPs (rs7412 in APOE; rs16998073 near FGF5) were consistent with the finding from the UK Biobank. The lifestyle analysis shows that prevention from obesity, cigarette smoking, and alcohol consumption is associated with a slower rate of biological aging.

The Epidemiology and Genetics of Hyperuricemia and Gout across Major Racial Groups: A Literature Review and Population Genetics Secondary Database Analysis.

Gout is an inflammatory condition caused by elevated serum urate (SU), a condition known as hyperuricemia (HU). Genetic variations, including single nucleotide polymorphisms (SNPs), can alter the function of urate transporters, leading to differential HU and gout prevalence across different populations. In the United States (U.S.), gout prevalence differentially affects certain racial groups. The objective of this proposed analysis is to compare the frequency of urate-related genetic risk alleles between Europeans (EUR) and the following major racial groups: Africans in Southwest U.S. (ASW), Han-Chinese (CHS), Japanese (JPT), and Mexican (MXL) from the 1000 Genomes Project. The Ensembl genome browser of the 1000 Genomes Project was used to conduct cross-population allele frequency comparisons of 11 SNPs across 11 genes, physiologically involved and significantly associated with SU levels and gout risk. Gene/SNP pairs included: ABCG2 (rs2231142), SLC2A9 (rs734553), SLC17A1 (rs1183201), SLC16A9 (rs1171614), GCKR (rs1260326), SLC22A11 (rs2078267), SLC22A12 (rs505802), INHBC (rs3741414), RREB1 (rs675209), PDZK1 (rs12129861), and NRXN2 (rs478607). Allele frequencies were compared to EUR using Chi-Square or Fisher’s Exact test, when appropriate. Bonferroni correction for multiple comparisons was used, with p < 0.0045 for statistical significance. Risk alleles were defined as the allele that is associated with baseline or higher HU and gout risks. The cumulative HU or gout risk allele index of the 11 SNPs was estimated for each population. The prevalence of HU and gout in U.S. and non-US populations was evaluated using published epidemiological data and literature review. Compared with EUR, the SNP frequencies of 7/11 in ASW, 9/11 in MXL, 9/11 JPT, and 11/11 CHS were significantly different. HU or gout risk allele indices were 5, 6, 9, and 11 in ASW, MXL, CHS, and JPT, respectively. Out of the 11 SNPs, the percentage of risk alleles in CHS and JPT was 100%. Compared to non-US populations, the prevalence of HU and gout appear to be higher in western world countries. Compared with EUR, CHS and JPT populations had the highest HU or gout risk allele frequencies, followed by MXL and ASW. These results suggest that individuals of Asian descent are at higher HU and gout risk, which may partly explain the nearly three-fold higher gout prevalence among Asians versus Caucasians in ambulatory care settings. Furthermore, gout remains a disease of developed countries with a marked global rising.

Genetic Variations Influencing Glucose Homeostasis and Insulin Secretion and their Associations with Autism Spectrum Disorder in Kazakhstan

Introduction: There is a complex interaction between glucose and insulin homeostasis pathways, diabetes and autism spectrum disorder (ASD). It is known that neuronal migration pathways may be interrupted by intrauterine hyperinsulinemia and hyperglycemia. Moreover, neonatal hypoglycemia which is related to mitochondrial dysfunction has a potential role that influences ASD pathogenesis [6,7]. We present here a preliminary case-control study on children and adolescents (8 – 15 years old) with and without autism spectrum disorder examining the association between genetic polymorphisms impacting glucose and insulin homeostasis and autism spectrum disorder in Kazakhstan. Methods: In this case-control study looking at 211 samples, associations of glucose and insulin homeostasis gene polymorphisms of 10 genes and demographic variables with autism spectrum disorder were examined. Fisher’s exact test and multivariate logistic regression models were used to find associations between polymorphisms and other predictors. Results: Preliminary results suggest that there is a complex relation between autism spectrum disorder and genetic variations that are associated with impaired glucose and insulin homeostasis susceptibility. There is a significant association of the T allele of ADIPOQ (rs1501299) (OR=1.75, 95% CI:1.04-2.93, p-value=0.035); the T allele of GCKR (rs1260326) (OR=0.6, 95% CI:0.39-0.93, p-value=0.023); the T allele of SLC30A8 (rs13266634) (OR=1.77, 95% CI:1.12-2.78, p-value=0.014); and the recessive GG genotype of rs10757278 (CDKN2B) (OR=2.58, 95% CI: 1.24-5.36, p-value=0.011) with autism spectrum disorder in the Kazakhstan population. Conclusion: Overall, this preliminary study revealed that there is evidence of significant associations between glucose and insulin homeostasis gene polymorphisms and autism spectrum disorder susceptibility in Kazakhstan and further study in this area to further verify this, is needed.

Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort

BackgroundElevated triglycerides (TG) are associated with, and may be causal for, cardiovascular disease (CVD), and co-morbidities such as type II diabetes and metabolic syndrome. Pathogenic variants in APOA5 and APOC3 as well as risk SNVs in other genes [APOE (rs429358, rs7412), APOA1/C3/A4/A5 gene cluster (rs964184), INSR (rs7248104), CETP (rs7205804), GCKR (rs1260326)] have been shown to affect TG levels. Knowledge of genetic causes for elevated TG may lead to early intervention and targeted treatment for CVD. We previously identified linkage and association of a rare, highly conserved missense variant in SLC25A40, rs762174003, with hypertriglyceridemia (HTG) in a single large family, and replicated this association with rare, highly conserved missense variants in a European American and African American sample.MethodsHere, we analyzed a longitudinal mixed-ancestry cohort (European, African and Asian ancestry, N = 8966) from the Electronic Medical Record and Genomics (eMERGE) Network. We tested associations between median TG and the genes of interest, using linear regression, adjusting for sex, median age, median BMI, and the first two principal components of ancestry.ResultsWe replicated the association between TG and APOC3, APOA5, and risk variation at APOE, APOA1/C3/A4/A5 gene cluster, and GCKR. We failed to replicate the association between rare, highly conserved variation at SLC25A40 and TG, as well as for risk variation at INSR and CETP.ConclusionsAnalysis using data from electronic health records presents challenges that need to be overcome. Although large amounts of genotype data is becoming increasingly accessible, usable phenotype data can be challenging to obtain. We were able to replicate known, strong associations, but were unable to replicate moderate associations due to the limited sample size and missing drug information.

Association of GCKR Gene Polymorphisms with Metabolic Syndrome in a Han Population from Northeast China.

As a serious public universal health issue, metabolic syndrome (MetS) has a high prevalence world-wide. Some studies illustrated that GCKR modulated insulin action and serum lipids are critical diagnostic criteria of MetS. The goal of this study is to investigate the association between GCKR polymorphisms with metabolic syndrome (MetS) in a Han population from northeast China. Four single nucleotide polymorphisms (SNPs, rs1260326, rs8179206, rs780094, and rs2293571) were genotyped in 3,754 participants. MetS was defined according to International Diabetes Federation criteria (2009). Genotype and allele frequency distributions were compared between two groups by chi-squared test. The associations of the four SNPs under different genetic models with MetS were tested by multivariate logistic regression analysis adjusted for age, gender, location, education, occupation alcohol consumption, and smoking. p-values of no more than 0.003125 [0.05/(4 SNPs*4 different genetic models)] after Bonferroni correction were considered statistically significant. Linkage disequilibrium (LD) and haplotype analysis were evaluated by the Haploview software (version 4.2) and SNPStats program. Logistic regression analysis revealed that after Bonferroni correction, rs780094 was associated with MetS under the recessive model (p = 0.002). Weak LD was found for the four SNPs, and the CAGC haplotype appeared to be significantly decreased the risk of MetS (p = 0.026, OR = 0.88, 95% CI = 0.79 - 0.98). GCKR rs780094 was associated with MetS in northeast Han population, and haplotype CAGC generated by rs1260326, rs8179206, rs780094, and rs2293571 may decrease the risk of the disease.

The Health Impact of MAFLD, a Novel Disease Cluster of NAFLD, Is Amplified by the Integrated Effect of Fatty Liver Disease–Related Genetic Variants

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a newly proposed disease category that derived from non-alcoholic fatty liver disease. The impact of MAFLD on health events has not been investigated. UK Biobank participants were diagnosed for whether MAFLD presented at baseline. Five genetic variants (PNPLA3 rs738409 C/G, TM6SF2 rs58542926 C/T, GCKR rs1260326 T/C, MBOAT7 rs641738 C/T, and HSD17B13 rs72613567 T/TA) were integrated into a genetic risk score (GRS). Cox proportional hazard model was used to examine the association of MAFLD with incident diseases. A total of 160 979 (38.0%, 95% confidence interval [CI] 37.9%, 38.2%) participants out of 423 252 were diagnosed as MAFLD. Compared with participants without MAFLD, MAFLD cases had multivariate adjusted hazard ratio (HR) for liver cancer of 1.59 (95% CI, 1.28, 1.98), cirrhosis of 2.77 (2.29, 3.36), other liver diseases of 2.09 (1.95, 2.24), cardiovascular diseases of 1.39 (1.34, 1.44), renal diseases of 1.56 (1.48, 1.65), and cancers of 1.07 (1.05, 1.10). The impact of MAFLD, especially on hepatic events, was amplified by high GRS, of which the genetic variations in PNPLA3, TM6SF2, and MBOAT7 play the principal roles. MAFLD case with normal body weight is also associated with an increased risk of hepatic outcomes, but the genetic factor seems do not influence the risk in this subpopulation. MAFLD is independently associated with an increased risk of both intrahepatic and extrahepatic events. Fatty liver disease related genetic variants amplify the effect of MAFLD on disease outcomes.

Genetic Susceptibility to Chronic Liver Disease in Individuals from Pakistan.

Chronic liver disease, with viral or non-viral etiology, is endemic in many countries and is a growing burden in Asia. Among the Asian countries, Pakistan has the highest prevalence of chronic liver disease. Despite this, the genetic susceptibility to chronic liver disease in this country has not been investigated. We performed a comprehensive analysis of the most robustly associated common genetic variants influencing chronic liver disease in a cohort of individuals from Pakistan. A total of 587 subjects with chronic liver disease and 68 healthy control individuals were genotyped for the HSD17B13 rs7261356, MBOAT7 rs641738, GCKR rs1260326, PNPLA3 rs738409, TM6SF2 rs58542926 and PPP1R3B rs4841132 variants. The variants distribution between case and control group and their association with chronic liver disease were tested by chi-square and binary logistic analysis, respectively. We report for the first time that HSD17B13 variant results in a 50% reduced risk for chronic liver disease; while MBOAT7; GCKR and PNPLA3 variants increase this risk by more than 35% in Pakistani individuals. Our genetic analysis extends the protective role of the HSD17B13 variant against chronic liver disease and disease risk conferred by the MBOAT7; GCKR and PNPLA3 variants in the Pakistani population.

PNPLA3 and GCKR Gene Polymorphisms influence genetic Susceptibility to NAFLD in Obese Egyptians

Environmental and genetic factors have a crucial role in the development and progression of non-alcoholic fatty liver disease (NAFLD). The aim of the present study is to investigate the association between single nucleotide polymorphism (SNP) rs738409 in PNPLA3 gene and rs1260326 in GCKR gene and the development of NAFLD in obese Egyptian population. Forty obese subjects (20 with NAFLD and 20 without NAFLD) and 20 control subjects were enrolled in this study. All subjects were genotyped for (rs738409) PNPLA3 and (rs1260326) GCKR gene polymorphisms using the TaqMan assay. Results revealed that the homozygous mutant GG genotype of the PNPLA3 was the most frequent among patients with NAFLD (15%) as compared to controls (0%) (p=0.036). Regarding the GCKR rs1260326; the homozygous mutant TT genotype was most frequent among patients with NAFLD (40%) as compared to controls (20%) with trend significance (p=0.083) and as compared to obese non-FL group (10%) (p=0.014). The frequency of the T allele was found to be significantly higher in NAFLD patients (62.5%) compared to obese non-FL group (42.5%) (p=0.037). In conclusion our study confirmed the association between PNPLA3 (rs738409) and GCKR (rs1260326) polymorphisms and susceptibility to NAFLD.

GCKR rs780094 Polymorphism as A Genetic Variant Involved in Physical Exercise.

Exercise performance is influenced by genetics. However, there is a lack of knowledge about the role played by genetic variability in the frequency of physical exercise practice. The objective was to identify genetic variants that modulate the commitment of people to perform physical exercise and to detect those subjects with a lower frequency practice. A total of 451 subjects were genotyped for 64 genetic variants related to inflammation, circadian rhythms, vascular function as well as energy, lipid and carbohydrate metabolism. Physical exercise frequency question and a Minnesota Leisure Time Physical Activity Questionnaire (MLTPAQ) were used to qualitatively and quantitatively measure the average amount of physical exercise. Dietary intake and energy expenditure due to physical activity were also studied. Differences between genotypes were analyzed using linear and logistic models adjusted for Bonferroni. A significant association between GCKR rs780094 and the times the individuals performed physical exercise was observed (p = 0.004). The carriers of the minor allele showed a greater frequency of physical exercise in comparison to the major homozygous genotype carriers (OR: 1.86, 95% CI: 1.36–2.56). The analysis of the GCKR rs780094 variant suggests a possible association with the subjects that present lower frequency of physical exercise. Nevertheless, future studies are needed to confirm these findings.

An intronic variant in the GCKR gene is associated with multiple lipids

Previous studies have shown that an intronic variant rs780094 of the GCKR gene (glucokinase regulatory protein) is significantly associated with several metabolites, but the associations of this genetic variant with different lipids is largely unknown. Therefore, we applied metabolomics approach to measure metabolites in a large Finnish population sample (METSIM study) to investigate their associations with rs780094 of GCKR. We measured metabolites by mass spectrometry from 5,181 participants. P < 5.8 × 10−5 was considered as statistically significant given 857 metabolites included in statistical analyses. We found novel negative associations of the T allele of GCKR rs780094 with serine and threonine, and positive associations with two metabolites of tryptophan, indolelactate and N-acetyltryptophan. Additionally, we found novel significant positive associations of this genetic variant with 12 glycerolipids and 19 glycerophospholipids. Significant negative associations were found for three glycerophospholipids (all plasmalogen-cholines), and two sphingolipids. Significant novel associations were also found with gamma-glutamylthreonine, taurocholenate sulfate, and retinol. Our study adds new information about the pleiotropy of the GCKR gene, and shows the associations of the T allele of GCKR rs780094 with lipids.

The relationship among GNB3 rs5443, PNPLA3 rs738409, GCKR rs780094 gene polymorphisms, type of maternal gestational weight gain and neonatal outcomes (STROBE-compliant article).

The gestational weight gain is determined by food habits, environmental and genetic factors.The aims of this paper were to establish relationships between maternal gene polymorphisms (patatin-like phospholipase domain-containing protein 3 rs738409 [PNPLA3 rs738409], glucokinase regulatory protein rs780094 [GCKR rs780094], and guanine nucleotide-binding protein rs5443 [GNB3 rs5443]) and mothers’ gestational weight gain, but also neonatal outcomes (birth weight, length, and ponderal index [PI]).We performed a cross-sectional study in a sample of 158 mothers and their product of conception’ in an Obstetrics-Gynecology Clinic from Romania. We divided the pregnant women according to the Institute of Medicine recommendations into 3 subgroups: (1) insufficient gestational weight gain; (2) normal gestational weight gain; and (3) excessive gestational weight gain.The gestational weight gain among pregnant women included in this study was classified as insufficient (10.1%), normal (31%), and excessive (58.9%). We found a tendency towards statistical significance for mothers that were overweight or obese before pregnancy to present an excessive gestational weight gain as compared to the normal weight ones. Similarly, we identified a tendency for statistical significance regarding the association between the variant genotype of GNB3 rs5443 and excessive gestational weight gain. We noticed differences that tended to be statistical significant concerning aspartate aminotransferase values between the 3 subgroups, mothers with excessive gestational weight gain having higher values than mothers with normal gestational weight gain (median, IQR: 22.89[17.53; 31.59] for mothers with excessive gestational weight gain versus 22.71[18.58; 27.37] for mothers with normal gestational weight gain). In mothers with excessive gestational weight gain, we found a significant association between the variant genotype of PNPLA3 rs738409 polymorphism and neonatal PI noticing a decrease of this index in case of newborns from mothers carrying the variant genotype.Excessive gestational weight gain was noticed in pregnant women that were obese and overweight before pregnancy. We found a positive association between the variant genotype of GNB3 rs5443 polymorphism and excessive gestational weight gain. Similarly, the presence of variant genotype of PNPLA3 rs738409 in mothers was associated with a lower PI in their newborns. Our study pointed out the most important factors that influence gestational weight gain and related birth outcomes.

Contribution of a genetic risk score to clinical prediction of hepatic steatosis in obese children and adolescents

BackgroundNonalcoholic fatty liver disease (NAFLD) is the commonest liver disease in children and adolescents in Western countries. Complex traits arise from the interplay between environmental and genetic factors in the pathogenesis of NAFLD. AimsWe examined the association between NAFLD and eleven single nucleotide polymorphisms (SNPs) at genetic loci potentially associated with liver damage (GCKR, MBOAT7, GPR120), oxidative stress (SOD2), lipid metabolism (PNPLA3, TM6SF2, LPIN1, ELOVL2, FADS2, MTTP) and fibrogenesis (KLF6) in a paediatric population. A genetic risk score (GRS) was performed taking into account both these SNPs and clinical risk factors. MethodsWe recruited a cohort of 514 obese children and adolescents (mean age [±SD]: 11.2 ± 2.8 years, z-BMI 3.3 ± 0.8). NAFLD was identified by ultrasonography. Genotyping was performed by TaqMan-based RT-PCR system. ResultsThe overall prevalence of NAFLD was 67.5% (347 patients). Among the eleven genotyped SNPs, the genetic variants in TM6SF2 rs58542926 (OR = 4.13, p = 0.002), GCKR rs1260326 (OR = 1.53, p = 0.003), PNPLA3 rs738409 (OR = 1.58, p = 0.004) and ELOVL2 rs2236212 (OR = 1.34, p = 0.047) were significantly associated with a higher risk of NAFLD. Addition of a 11-polymorphism GRS to established clinical risk factors significantly (albeit modestly) improved the discriminatory capability of the regression model for predicting the risk of NAFLD (with SNPs C-statistic 0.81 [95%CI 0.75–0.88] vs. 0.77 [0.70–0.84] without SNPs; p = 0.047). ConclusionsNAFLD was strongly associated with three genetic variants, TM6SF2 rs58542926, PNPLA3 rs738409 and GCKR rs1260326, and more slightly with ELOVL2 rs2236212, in obese children and adolescents. Addition of a 11-polymorphism GRS to clinical risk factors improved the predictability of NAFLD.

1845-P: Divergent Effects on T2D of Alleles Associated with Increased Liver Fat Reflect Differential Impact on Hepatic Glucose and Lipid Output: An IMI DIRECT Study

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) often coincide but the physiological relationship is unclear. Important clues are provided by human genetics: variants associated with NAFLD-risk have divergent effects on T2D. At TM6SF2 the NAFLD-risk allele (rs58542926:T) predisposes to T2D whilst at GCKR (rs1260326:T), it protects. We hypothesize that these divergent effects result from the impact of NAFLD-raising alleles on hepatic lipid output (HLO) and hepatic glucose output (HGO) respectively. To test this hypothesis, we applied structural equation modeling (SEM) to data from the IMI-DIRECT study, including 1350 European participants, 923 nondiabetic (C1) and 427 with recently-diagnosed T2D (C2). Insulin sensitivity (IS) was modeled from frequently sampled OGTT (C1) and mixed-meal tolerance tests (C2), and liver fat (LF) measured by MRI. SEM fit was assessed by comparing model χ2s with comparable null models: variables randomized to nodes in identical SEM definition giving comparable degrees of freedom and structure, 10,000 iterations. The hypothesized model provided a better fit than null models (C1: χ2=242, P=0.005; C2: χ2=63, P=0.01). Decreasing HLO (via TM6SF2) was associated with an increase in LF (C1: ß=0.28 [SE 0.09], P=0.001; C2: ß=0.28 [0.12], P=0.02) and fasting plasma glucose (FG): these were mediated by LF and IS (C1: ß=0.09 [0.03], P=0.001; C2: ß=0.07 [0.03], P=0.027). Decreasing HGO (via GCKR) was not associated with LF in either cohort but was associated with a direct (non-mediated) decrease in FG (C1 only: ß=-0.08 [0.04], P=0.04). The results support a model whereby increased genetic risk of NAFLD, arising from defects in two processes (HLO and HGO) results in opposing glycemic effects. This has important consequences for therapeutic strategies for combatting NAFLD: approaches to reduce NAFLD through targeting of HLO (as opposed to HGO) may also reduce risk of hyperglycaemia and T2D. Disclosure R.W. Koivula: None. P.W. Franks: Board Member; Self; Zoe Ltd. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Novo Nordisk Foundation, Sanofi, Servier. T.H. Hansen: None. M. Laakso: None. E. Pearson: None. F. Rutters: None. F. Karpe: None. J.W. Tomlinson: Advisory Panel; Self; Novo Nordisk Inc., Pfizer Inc., Poxel SA. A. Mahajan: None. M. McCarthy: Advisory Panel; Self; European Association for the Study of Diabetes, Pfizer Inc. Consultant; Self; Eli Lilly and Company, Merck &amp; Co., Inc. Consultant; Spouse/Partner; Merck &amp; Co., Inc. Research Support; Self; AbbVie Inc., Boehringer Ingelheim International GmbH. Research Support; Spouse/Partner; Diabetes UK. Research Support; Self; Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., National Institutes of Health. Research Support; Spouse/Partner; National Institutes of Health. Research Support; Self; Novo Nordisk A/S. Research Support; Spouse/Partner; Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation, Roche Pharma, Sanofi-Aventis, Servier, Takeda Pharmaceutical Company Limited. Funding Novo Nordisk Foundation (NNF18OC0031650); Innovative Medicines Initiative Joint Undertaking (115317)

Gout and the risk of Alzheimer's disease: A Mendelian randomization study.

This study aimed to examine whether gout is causally associated with Alzheimer's disease. I used the publicly available summary statistics datasets of three genome-wide association studies (GWASs) on gout as the exposure dataset and meta-analysis results of four GWAS datasets consisting of 17008 cases with Alzheimer's disease and 37154 controls of European descent as the outcome dataset. The data were subjected to 2-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. I selected seven independent single nucleotide polymorphisms (SNPs) from gout GWASs as instrumental variables (IVs) to improve inference. These SNPs were located at MAP3K11 (rs10791821), SLC2A9 (rs11722228, rs734553), GCKR (rs1260326), ABCG2 (rs2231142, rs2728125), and CNIH-2 (rs4073582). The IVW data did not support a causal association between gout and Alzheimer's disease (β=0.013, standard error [SE]=0.017, P=0.445). The MR-Egger regression indicated that directional pleiotropy did not bias the result (intercept=0.002, P=0.654); it also revealed no causal association between gout and Alzheimer's disease (β=-0.013, SE=0.076, P=0.870). The weighted median approach yielded similar results (β=0.004, SE=0.022, P=0.846). Cochran's Q test indicated no evidence of heterogeneity between IV estimates based on individual variants, and the results of "leave-one-out" analysis demonstrated that no single SNP drove the IVW estimate. The MR analysis results did not support a causal association between gout and Alzheimer's disease.

Genetic polymorphisms associated with nonalcoholic fatty liver disease in Uyghur population: a case-control study and meta-analysis

BackgroundPolymorphisms have been identified to predispose to NAFLD. Here, we accessed the seven polymorphisms of rs1260326, rs780094 in GCKR, rs2954021 near TRIB1, rs2228603 in NCAN, rs58542926 in TM6SF2, rs12137855 near LYPLAL1, and rs10883437 near CPN1 on NAFLD susceptibility in the Uygur population.Material and methodsWe collected 620 samples (317 NAFLD and 303 controls) for this case-control study. Meta-analysis was performed using Stata Software.ResultsOur data detected that the rs1260326 (T vs. C: OR = 1.27, 95% CI = 1.01–1.59) and rs780094 (T vs. C: OR = 1.30, 95% CI = 1.04–1.63) were significantly associated with the susceptibility to NAFLD in Uygur population. The rs1260326 and rs780094 T/T genotype are significantly associated with soda, egg, and soybean intakes in the consumption group with twice or more in a week. Furthermore, a significant haplotype effect of rs1260326/T- rs780094/T was found (OR = 1.29, 95% CI: 1.03–1.62) compared with CC haplotype. An additional meta-analysis using 4352 cases and 10,168 controls established that rs780094 (OR = 1.21, 95%CI: 1.14–1.28) is significantly associated with NAFLD. Finally, among the 4 case-control studies on rs1260326, including 712 NAFLD and 658 controls, significant associations were found in Asian, liver biopsy, adult and pediatric groups.ConclusionCollectively, both our case-control study and meta-analysis confirm a significant association between rs780094 and NAFLD. Additionally, our results suggest Asian-specific, liver biopsy-specific, adult-specific and pediatric-specific associations between the rs1260326 and NAFLD. Moreover, the rs1260326 and rs780094 T/T genotype are significantly associated with food habits, such as soda, egg, and soybean.

Relationship between N,N-dimethylformamide exposure, PNPLA3, GCKR, COL13A1 and TM6SF2 genes, and liver injury

BackgroundCurrent researches show that N,N-dimethylformamide (DMF) exposure is associated with liver injury, but it is debatable whether PNPLA3, GCKR, COL13A1 and TM6SF2 gene polymorphisms are associated with liver injury. Our objective was to examine the relationship among DMF exposure, PNPLA3 rs738409, GCKR rs780094, COL13A1 rs1227756, TM6SF2 rs58542926 and liver injury. MethodsThe cohort consisted of 461 workers exposed above the DMF threshold limit value (TLV) and 211 exposed below the DMF TLV in China, who were followed for 5 years. The relationship between the measured dose of DMF and the relative risk (RR) of liver injury was also investigated by Poisson analysis. Logistic regression models were used to examine the association between measured dose of DMF, gene locus, and RR for liver injury. All workers had a annual physical examinations were conducted at certified physical examination centers in Taicang CDC, including liver serum transaminase assessment and abdominal ultrasound. Genomic DNA was extracted from peripheral blood leukocytes using a genomic DNA extraction kit. ResultsThe incidence of liver injury in the above DMF TLV group was significantly higher than in the below DMF TLV group. GCKR rs780094 was associated with liver injury. The interaction among the GCKR rs780094, DMF exposure and liver injury showed no significant association. ConclusionsOur data indicated that in DMF exposure, GCKR rs780094 may contribute to the risk of liver injury. Our results suggest that GCKR rs780094 is a useful genetic marker to help identify liver injury.

No clinical utility of common polymorphisms in IGF1, IRS1, GCKR, PPARG, GCK1 and KCTD1 genes previously associated with insulin resistance in overweight children from Romania and Moldova.

Background Previous genome-wide association studies (GWAS) identified IGF1, IRS1, GCKR, PPARG, GCK1 and KCTD1 as candidate genes for insulin resistance and type 2 diabetes (T2D). We investigated the associations of these previously reported common variants in these genes with insulin resistance in overweight children from Romania and Moldova. Methods Six single nucleotide polymorphisms (SNPs), IGF1 (rs35767), IRS1 (rs2943634), GCKR (rs780094), PPARG (rs1801282), GCK1 (rs1799884) and KCTD15 (rs29941), were genotyped in 100 overweight children along with clinical and metabolic parameters. Homeostatic model assessment of insulin resistance (HOMA-IR) above 3.4 (defining insulin resistance) was used as the outcome. Results Children differed in insulin resistance status despite having similar body mass index (BMI) standard deviation scores (SDS) (World Health Organization, [WHO] reference). The identified predictors for altered insulin metabolism were higher cholesterol levels, higher diastolic blood pressure and higher waist-to-hip-ratio (as a marker for increased abdominal fat). None of the SNPs showed significant association with increase in the risk for insulin resistance in children (p range=0.478-0.724; odds ratio [OR] range=1.924-4.842); however, the risk allele in GCKR (rs780094, p=0.06, OR=6.871) demonstrated near statistical significance. Conclusions The interrogated risk alleles did not show any significant association with insulin resistance in children in our cohort; however, the GCKR (rs780094) might be a viable candidate in larger cohorts. The lack of replication of the proposed association may point to differences in linkage disequilibrium or effect modifiers across studies.

Association of type 2 diabetes susceptible genes GCKR, SLC30A8, and FTO polymorphisms with gestational diabetes mellitus risk: a meta-analysis.

Current studies have detected the correlation of polymorphisms in type 2 diabetes susceptible genes GCKR, SLC30A8 and FTO with gestational diabetes mellitus (GDM) risk. However, findings of these studies were incongruous. Hence, we performed an integrated review and meta-analysis for the researches regarding the association of single nucleotide polymorphisms (SNPs) in GCKR, SLC30A8 and FTO genes and GDM risk. Eligible publications were selected on the basis of several inclusion and exclusion criteria. Correlation between each SNP and GDM risk was estimated by computing odds ratios (ORs) with 95% confidence intervals (95%CIs). Consequently, 19 case-control studies (from 16 citations) including 3636 GDM cases and 7229 GDM-free controls were participated in a meta-analysis of seven prevalent SNPs (GCKR rs1260326 and rs780094; SLC30A8 rs13266634 and rs11558471; FTO rs8050136, rs1421085 and rs9939609). Our results demonstrated that the rs780094, rs13266634 and rs9939609 SNPs were significantly associated with GDM risk. In stratified analysis, correlations of rs780094 and rs13266634 SNPs could be observed in Asian and Caucasian subgroups. Moreover, association between rs9939609 SNP and GDM risk was detected in Caucasian subgroup. The GCKR rs780094, SLC30A8 rs13266634 and FTO rs9939609 SNPs were demonstrated to be the potential biomarkers for GDM risk prediction.