rs780094

This association study examined 43 diabetes-related SNPs in relation to diastolic dysfunction and cardiovascular disease across two Swedish cohorts. HNF1B rs757210 (T-allele) was the main finding, associated with prevalent diastolic dysfunction in both the discovery cohort (MPP-RES; OR 1.21, P=0.024) and replication cohort (VARA; OR 1.38, P=0.042), and with increased risk of incident CVD (HR 1.05, P=0.042) but not CHF over 30+ years of follow-up.

Transethnic fine-mapping study of glycaemic traits in 26,760 participants (Hispanic/Latino, African, Asian, and Native American) using the Metabochip. Replicated 31/39 fasting glucose and 14/17 fasting insulin loci from European GWAS. Identified two novel secondary signals at G6PC2-rs477224 and GCK-rs2908290, a population-specific signal at G6PC2-rs77719485 in African ancestry, and one novel locus at SLC17A2-rs75862513 for fasting insulin.

This comprehensive review synthesizes literature on gestational diabetes mellitus (GDM), demonstrating its complex multifactorial etiology involving genetic factors (SNPs in GCKR, KCNQ1, MTNR1B, TCF7L2), epigenetic modifications (DNA methylation and microRNA expression), and alterations in microbial composition across multiple body sites. While certain SNP variants are associated with GDM phenotypes globally, genetic predisposition alone does not explain disease development; lifestyle factors can modify epigenetic signatures and microbiota composition to modulate risk. Evidence indicates genes, epigenetic alterations, and microbiota can transfer from mother to offspring with long-term health consequences.

The GCKR rs780092 T-allele variant shows opposite effects on metabolic traits in a Chinese cohort: associated with 17% lower risk of incident type 2 diabetes (HR 0.83 [95% CI 0.73-0.95]) but 36% higher risk of hypertriacylglycerolaemia (OR 1.36 [95% CI 1.08-1.72]). Both baseline and longitudinal changes in triglyceride levels mediate the association between this variant and diabetes risk.

A genome-wide association study of 83 plasma proteins relevant to cardiovascular disease in 3,394 European subjects identified 79 genome-wide significant loci (p<5e-8), with 55 replicating in independent cohorts (n=2,639). Using eQTL analysis and network methods, the authors proposed plausible causal mechanisms for 25 trans-acting loci including post-translational regulation of KITLG by MMP9 and several receptor-ligand pairs. Multiple loci showed evidence of causal association with coronary artery disease risk.

This doctoral thesis comprises three studies on metabolic syndrome-related traits. Study III is a GWAS identifying seven novel loci associating with circulating inflammatory markers (cytokines and adhesion molecules) in 5,284 Finnish individuals from NFBC1966, with meta-analysis including three additional Finnish populations totaling 13,577 participants. Studies I and II use Mendelian randomization and association analysis to examine metabolic effects of lipid-lowering therapies and NAFLD risk alleles (PNPLA3 rs738409-G, TM6SF2 rs58542926-T, GCKR rs780094-T/rs1260326-T, LYPLAL1 rs12137855-C, and NCAN rs2228603-T).

A two-part genetic association study in Korean populations examining SNP associations with serum uric acid (SUA) concentration. Study 1 compared minor allele frequencies of 40 SNPs associated with SUA across Korean, Japanese, and European descent populations in 1,957 subjects. Study 2 analyzed associations in 402 RA patients, finding rs12734001 (PPP1R12B) most significantly associated with SUA levels (P_trend = 2.29 × 10^-9) and rs3741414 (INHBC) with P_trend = 0.01. Results showed Korean SNP frequencies were more similar to Japanese than European populations.

Of 40 SNPs previously associated with type 2 diabetes, 19 (48%) introduce or remove CpG sites. In 84 human pancreatic islet donors, all 16 analyzed CpG-SNPs showed statistically significant differential DNA methylation (p≤2.3×10⁻⁵). Several CpG-SNPs including rs391300 (SRR), rs5945326 (DUSP9), rs11708067 (ADCY5), rs5015480 (HHEX), rs13266634 (SLC30A8), rs1801214 (WFS1), rs564398 (CDKN2A), and rs2237895 (KCNQ1) were associated with differential gene expression, alternative splicing, or hormone secretion, suggesting DNA methylation-mediated mechanisms linking genetic variants to type 2 diabetes pathogenesis.

This comprehensive review examines the genetic background of nonalcoholic fatty liver disease (NAFLD), focusing on variants identified by genome-wide association studies (GWAS) and candidate gene studies. The most significant GWAS-identified variants are PNPLA3 rs738409 (I148M), which strongly associates with increased liver steatosis, fibrosis severity, and HCC risk (12-fold increased risk for homozygous carriers), and TM6SF2 rs58542926 (E167K), which increases NASH progression but reduces cardiovascular risk. The review also discusses numerous candidate genes involved in lipid and glucose metabolism and liver injury mechanisms.

This study analyzed 9 uric acid-regulating SNPs and 5 progranulin-regulating SNPs in 1,061 Parkinson's disease patients and 754 controls. A cumulative genetic risk score from 8 SNPs (SLC2A9 rs734553, ABCG2 rs2231142, SLC17A1 rs1183201, SLC22A12 rs505802, GCKR rs780094, PDZK1 rs12129861, LRRC16A/SCGN rs742132, SLC16A9 rs12356193) was significantly associated with increased PD risk (OR=1.55, p=0.012). The TMEM106b rs1020004 variant showed association with PD risk (p=0.003), and SORT1 rs646776 was associated with serum progranulin levels and PD-dementia risk.

This study tested seven SNPs from European lipid-associated loci in 3,503 Chinese school-age children and found that six SNPs (rs2144300, rs1260333, rs1260326, rs10105606, rs1748195, rs964184) showed significant associations with triglyceride levels (p < 0.05 FDR-corrected), while three SNPs were associated with total cholesterol and four with LDL-cholesterol. Three SNPs (rs1260333 OR=0.82, rs1260326 OR=0.82, rs964184 OR=1.36) showed strong associations with dyslipidemia risk, demonstrating that lipid-susceptibility variants identified in European populations have similar effects in Chinese children.

Case-control study of 673 preterm birth (PTB) cases vs 1,119 controls across four maternal cohorts testing 35 SNPs in cardiovascular, inflammatory, and metabolic disease genes. Found 13 statistically significant associations with PTB (P<0.05), more than expected by chance (binomial P=0.02). Most significant was HLA-DQA1 rs9272346 G allele protective effect in US White mothers (P=0.02, OR=0.65, 95% CI 0.46-0.94), which nominally replicated in Danish cohort (P=0.02, OR=0.85, 95% CI 0.75-0.97) but lost significance after correction for multiple testing.

This study investigated gene-environment interactions between 23 GWAS-identified lipid-associated SNPs and serum vitamins A and E in the National Health and Nutrition Examination Surveys (NHANES), including 5,576 participants across three racial/ethnic groups. Nine significant interactions were identified, with the most significant being APOB rs693×vitamin E associated with LDL-C in Mexican Americans (p=8.94×10⁻⁷). These nine interactions explained only 0.35-1.28% of variation in lipid traits, suggesting that gene-environment interactions account for modest proportions of the missing heritability in lipid metabolism.

This case-control study investigated 25 T2DM-associated SNPs in a multi-ethnic Hawaiian cohort (291 GDM cases, 734 controls) and found ethnicity-specific associations with gestational diabetes. Key findings in Filipinos included rs1113132 (EXT2, OR=1.52, p=0.028), rs1111875 (HHEX, OR=1.5, p=0.047), rs2237892 (KCNQ1, OR=0.49, p<0.001), rs10830963 (MTNR1B, OR=0.63, p=0.025), and rs13266634 (SLC30A8, OR=0.58, p=0.011). In Japanese women, rs4402960 (IGFBP2, OR=0.5, p=0.031) and rs2237892 (KCNQ1, OR=0.5, p=0.03) were significant. Pacific Islanders showed associations with rs10830963 (MTNR1B, OR=0.52, p=0.037) and rs13266634 (SLC30A8, OR=2.43, p=0.03). No SNPs showed consistent associations across all three ethnic groups.

This association study examined 455 obese children and adolescents (181 Caucasians, 139 African Americans, 135 Hispanics) and found that rs1260326 in GCKR is associated with hepatic fat accumulation and elevated triglycerides/large VLDL levels across all ethnic groups (p=0.034-0.00002). The PNPLA3 rs738409 variant also associated with hepatic fat content. Jointly, these variants explained 32% of hepatic fat variance in Caucasians, 39% in African Americans, and 15% in Hispanics.

This replication study in 11,530 Japanese individuals (8,552 type 2 diabetes cases, 2,978 controls) confirmed that rs10906115 in CDC123/CAMK1D and rs1359790 near SPRY2 are significantly associated with susceptibility to type 2 diabetes, with ORs of 1.15-1.17 and 1.12-1.14 respectively. Meta-analysis with the original Chinese cohort further strengthened these associations across East Asian populations, while rs1436955 in C2CD4A/C2CD4B showed nominal association and rs10751301 in ODZ4 was not significant.

Comprehensive review of genetic background in nonalcoholic fatty liver disease (NAFLD). The PNPLA3 I148M variant (rs738409 C>G) is identified as a major genetic player strongly associated with increased liver fat content, NASH development, fibrosis severity, and HCC risk. The TM6SF2 E167K variant (rs58542926) emerges as another key contributor to NAFLD pathogenesis and disease progression. Multiple additional GWAS-identified variants and candidate genes are reviewed for their roles in NAFLD susceptibility and progression.

This is a special issue of the Italian medical journal BeAdfiles (September 2012) dedicated to genetic conditioning in HIV and hepatitis virus infections. It reviews the major genetic polymorphisms that influence disease progression, treatment response, and drug toxicity in HIV and chronic hepatitis B and C infections, with particular emphasis on IL28B polymorphisms (rs809917 and others) predicting HCV treatment response to interferon-alpha and ribavirin therapy, and ITPA gene variants protecting against ribavirin-induced anemia. The issue also covers pharmacogenetic markers (CYP2B6, ABCB1, HLA-B*5701) and their clinical applications in antiretroviral therapy.

Replication study in Japanese (n=4,813) and Sri Lankan (n=2,319) populations confirmed association of five common variants at four loci (GCK rs1799884, GCKR rs780094, G6PC2-ABCB11 rs560887, MTNR1B rs1387153 and rs10830963) with fasting plasma glucose levels (p<0.05). Fine-mapping identified a novel independent SNP rs3755157 in the G6PC2-ABCB11 region with stronger association (β=0.055-0.069 mmol/l, p=2.6×10⁻⁸ in Japanese) and confirmed allelic heterogeneity. Type 2 diabetes association was replicated in case-control studies (OR 1.09-1.28).

This association study of 4,213 Danish individuals examined 25 type 2 diabetes risk variants and their association with birthweight. The study found that type 2 diabetes risk alleles near ADCY5 (rs11708067, β = -33 g, p = 0.004), CDKAL1 (rs7756992, β = -22 g, p = 0.04), and HHEX-IDE (rs1111875, β = -16 g in meta-analysis, p = 8×10⁻⁵, n = 25,164) were associated with reduced birthweight, supporting the fetal insulin hypothesis. Meta-analyses confirmed these associations and showed no strong general effect on birthweight from the 25 common type 2 diabetes risk alleles combined.

This GWAS of fasting glucose in the ARIC study examined 5,782-8,372 individuals across four longitudinal visits and identified five genomic regions significantly associated with fasting glucose (p < 5×10⁻⁸): GCKR, G6PC2, GCK, SLC30A8, and MTNR1B. The study demonstrated that averaging fasting glucose measures across visits improved statistical power and detected additional signals (GCKR rs780094, SLC30A8 rs13266634) not visible in single-visit analyses. Analysis of candidate SNPs revealed significant interactions with diabetes status: associations with fasting glucose were stronger in non-diabetic individuals than in those with prevalent diabetes for multiple SNPs including rs10830963 (MTNR1B), rs560887 (G6PC2), rs4607517 (GCK), and rs780094 (GCKR).

This population-based association study of 3,210 Han Chinese individuals examined GCKR rs780094 and GCK rs1799884 variants and their associations with type 2 diabetes. The GCKR rs780094 A allele was significantly associated with reduced risk of type 2 diabetes and IFG combined (OR 0.86, 95% CI 0.77-0.96, p=0.0032), as well as decreased fasting glucose and increased beta cell function (HOMA-B). The effect on type 2 diabetes was mediated through beta cell function rather than obesity. The GCK rs1799884 A allele was significantly associated with decreased HOMA-B but not diabetes risk.

This study examined the combined effects of SNPs in four genes (GCK, GCKR, G6PC2, and MTNR1B) on fasting plasma glucose (FPG) levels and type 2 diabetes risk in 4,669 Dutch participants. A risk allele score combining GCK, G6PC2, and MTNR1B variants showed a significant association with FPG (0.05 mmol/l per additional risk allele, p=2×10⁻¹³) and type 2 diabetes, where carriers with >5 risk alleles had OR 2.05 (p=4×10⁻⁶) compared to the reference group with 4 risk alleles.

This study found that rs560887 G allele in the G6PC2/ABCB11 locus is associated with increased fasting plasma glucose (OR 1.26, 95% CI 1.08-1.47 for impaired fasting glucose risk, p=0.002) and increased basal hepatic glucose production in elderly twins (p=0.04). The variant also associates with increased insulin release after oral and intravenous glucose loads, but shows no association with type 2 diabetes (OR 0.93, p=0.2) or metabolic syndrome.

This study evaluated whether the rs1260326 (P446L) polymorphism in the glucokinase regulatory protein (GCKR) gene affects postprandial lipid response in 770 Amish participants from the HAPI Heart Study. The T allele at rs1260326 was significantly associated with higher fasting triglycerides (Pa=0.06 additive, Pr=0.0003 recessive) and higher postprandial triglyceride levels, including greater maximum TG (Pa=0.006), TG area under curve (Pa=0.02), and atherogenic VLDL particles after a high-fat challenge.

This review examines 15 years of ischemic stroke susceptibility gene research, organized into three periods: early candidate gene studies (1985-1995) testing variants in hemostasis and homocysteine metabolism genes; expansion period with functional variants discovered from other diseases tested on larger stroke cohorts; and current GWAS-driven large-scale genotyping studies. Key findings include identification of susceptibility loci in CELSR1 (rs6007897, rs4044210 in Japanese populations), PITX2 (rs2200733, rs10033464), and other genes involved in lipid metabolism (APOA5, APOCIII, MLXIPL) and signal transduction (PDE4D, ALOX5AP), with evidence that alleles are often shared across diseases and that careful clinical stratification is critical.

This prospective study of 16,143 individuals from the Malmö Preventive Project (mean follow-up 23 years) investigated whether genetic variants in 26 genes previously associated with type 2 diabetes or metabolic syndrome components could predict future development of metabolic syndrome. Polymorphisms in TCF7L2 (rs7903146, OR 1.10, p=0.00097), FTO (rs9939609, OR 1.08, p=0.0065), WFS1 (rs10010131, OR 1.07, p=0.0078), and IGF2BP2 (rs4402960, OR 1.07, p=0.021) predicted metabolic syndrome development, with TCF7L2, WFS1, and IGF2BP2 acting through hyperglycemia and FTO through obesity. A composite genotype score of 17 polymorphisms predicted metabolic syndrome risk (OR 1.04, p<0.00001), with carriers of ≥19 risk alleles having 51% increased risk compared to carriers of ≤12 alleles.

This study of 16,853 Danes validates the association between GCKR rs780094 A-allele and elevated fasting triacylglycerol (p=6×10⁻¹⁴) while showing reduced fasting (p=0.001) and OGTT-related insulin (p=3×10⁻⁶), improved insulin sensitivity (HOMA-IR p=0.0004), increased dyslipidemia risk (p=6×10⁻⁹), and modestly decreased type 2 diabetes risk (OR=0.92, p=0.01). An additive interaction with GCK -30G>A was demonstrated for fasting insulin (p=0.0002).