rs1260326

A literature review of 70 studies examining single nucleotide polymorphisms (SNPs) associated with obesity in Mexican populations published 2011-2021. The authors identified SNPs with differential behavior in Mexican compared to Caucasian populations, including rs17782313 (MC4R), rs6548238 (TMEM18), rs6265 (BDNF), rs7498665 (SH2B1), and notably rs6232 (PCSK1) associated with early-onset obesity in Mexican youth. The review emphasizes ethnicity-dependent genetic effects on BMI heritability (40-70%) and highlights genes involved in cholesterol metabolism and adipokine signaling pathways.

Meta-analysis of 34,748 European ancestry adults from 11 CHARGE Consortium cohorts examining sugar-sweetened beverage (SSB) intake associations with glycemic traits. SSB intake was associated with higher fasting glucose (β=0.014 mmol/l, p=1.5×10⁻³) and fasting insulin (β=0.030 log pmol/l, p=2.0×10⁻¹⁰). Although a suggestive interaction between SSB and KLB-rs1542423 was observed in discovery cohorts for fasting insulin (p=0.006), this was not confirmed in replication analysis.

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.

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.

This replication study analyzed 2255 variants in LD with GWAS-identified gout/serum urate susceptibility loci in 1255 Han Chinese gout patients and 1848 controls. Twenty-three variants (41%) showed nominal association (p<0.05), with the strongest signal at ABCG2 rs1481012 (p=8.96×10⁻¹¹, OR=1.890). Previous gout-associated loci including ABCG2, SLC2A9, GCKR, ALDH2, and CNIH2 were replicated, while cumulative genetic risk scores showed that individuals with ≥8 risk alleles had significantly increased gout risk (OR=16.361 for ≥12 alleles).

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 genome-wide association study (GWAS) of platelet count (PLT) and mean platelet volume (MPV) in 13,582 and 6,291 participants respectively from the eMERGE network identified 5 chromosomal regions associated with PLT and 8 with MPV at genome-wide significance (P<5E-8). Key findings include variants in ARHGEF3 (rs1354034, P=6E-24 for PLT; P=9E-34 for MPV), SH2B3 (rs3184504, P=5E-12), and multiple other loci. The study replicated 20 SNPs for PLT and 22 for MPV from prior meta-analyses and demonstrated pleiotropic effects with myocardial infarction, autoimmune, and hematologic disorders through phenome-wide association study (PheWAS).

Genome-wide association study of plasma protein C levels in 2,701 African Americans from the ARIC study identified 79 genome-wide significant SNPs in two regions (2q14 and 20q11). The top signal was rs867186 (missense, S219G in PROCR; p=9.84×10⁻⁶⁵, β=0.49 µg/ml, 10% variance explained). Additional significant hits were rs7580658 and rs1799808 near the PROC gene, and novel associations with CYP27C1 and MYO7B were discovered.

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.

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.

A comprehensive review of the pathogenesis of non-alcoholic fatty liver disease (NAFLD) in children and adolescents, examining the evolution from the 'two-hit theory' to the 'multiple-hit model'. The paper discusses genetic factors including PNPLA3 rs738409 and GCKR rs1260326 polymorphisms, which together account for up to one-third of variability in liver fat content in obese children, along with contributions from MBOAT7, SAMM50, PARVB, TM6SF2, and other genes involved in lipid metabolism.

This replication study examined 2,255 variants in linkage disequilibrium with GWAS-identified gout/urate susceptibility loci in 1,255 Han Chinese gout patients and 1,848 controls. Twenty-three variants (41% of 56 LD-pruned variants) showed nominal association with gout (p < 0.05), with the strongest signals at ABCG2 (rs1481012, OR=1.890, p=8.96×10⁻¹¹) and SLC2A9 (rs11722228, OR=1.619, p=2.40×10⁻⁶). Cumulative genetic risk score analysis demonstrated increasing gout risk with growing numbers of risk alleles (OR=16.361 for ≥12 alleles vs ≤5 reference).

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.

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 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 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.