rs841853 is a single nucleotide variant found in the SLC2A1 gene and is located on Chromosome 1 at position 43401438. Glucose transporter 1 (or GLUT1), also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the SLC2A1 gene. GLUT1 facilitates the transport of glucose across the plasma membranes of mammalian cells. Variants in SLC2A1 have been studied and associated with type 2 diabetes mellitus (T2DM), diabetic nephropathy (DN), diabetic retinopathy, renal cell carcinoma, and more recently in breast cancer and age-related macular degeneration (AMD) (discussed in [PMID 16337858], [PMID 22707195], [PMID 18613291], [PMID 23480298], [PMID 18065784], [PMID 23631762], [PMID 22509097]). Variant rs841853 (also termed SLC2A1 XbaI G>T polymorphism) influences the glucose transport capabilities of GLUT1, in conjunction with other neighboring SNPs, forming haplotype blocks. Several studies have indicated that significant association exists between rs841853 polymorphism and increased risk in T2DM and DN, but this association is population-specific and varied generating some controversies.
Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, which may be combined with relatively reduced insulin secretion. Classic symptoms are weight loss, polyuria, polydipsia, and polyphagia. Late stage symptoms include blurry vision, headache, fatigue, slow healing of cuts, vision changes and skin rashes. Diabetic nephropathy (DN) develops in a large number of DM patients after a variable latency period. It is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse glomerulosclerosis. Late stage symptoms of DN include increased blood pressure, eye swelling and general body swelling (edema), weight gain, fatigue, headache, anorexia, nausea, hiccups, malaise and arteriosclerosis of the renal artery. Age-related macular degeneration (AMD) occurs when the small central portion of the retina, known as the macula, deteriorates. The "dry" form of AMD is characterized by the presence of yellow deposits in the macula. The "wet" form of AMD is characterized by the growth of abnormal blood vessels from the choroid underneath the macula, which leak blood and fluid into the retina. Symptoms include loss of color vision, shape distortion, and gradual blindness.
[PMID 23480298] Association between glucose transporter 1 rs841853 polymorphism and type 2 diabetes mellitus risk may be population specific
A comprehensive literature search of electronic databases was conducted to obtain 14 articles and 19 individual studies, focused on the relationship between the GLUT1 rs841853 polymorphism and T2DM, followed by a systemic meta-analysis. The meta-analysis examined the overall association with T2DM between mutant T allele and wild-type G allele. This relationship was also tested in a recessive model (TT vs TG + GG) and a dominant model (TT + TG vs GG). Studies include information on 3431 controls and 2263 cases. In the control group, the T allele prevalence, TT genotype, TG genotype and GG genotype distribution of the rs841853 SNP was 30.9%, 12.9%, 38.4%, and 49.5%, respectively, whereas in case group distribution was 32.9%, 10.2%, 47.2%, and 42.6%, respectively. The T allele prevalence in the control and T2DM groups was 32.1% and 37.8%, 15.0% and 22.0%, and 52.2% and 42.0%, in Caucasians, Asians and Blacks.
- The main analysis investigating the association between the T allele and T2DM risk revealed extreme heterogeneity (I2 = 77; P < 0.00001) and the random effect pooled OR was marginally significant (OR 1.28, 95% CI 1.01, 1.63; P = 0.04). A weakly positive result was found in the dominant model for the T allele (OR 1.52, 95% CI 1.19, 1.94; P = 0.0008). Analysis for the recessive model revealed no significant differences (OR 1.06, CI 0.69, 1.64; P = 0.78).
- No evidence for association between the rs841853 SNP and T2DM risk in allele contrast and recessive models was found in subgroup analyses for Caucasians (OR 1.21, 95% CI 0.94, 1.58, P = 0.14; and OR 1.19, CI 0.71, 2.00, P = 0.50, respectively), whereas a marginal positive result was revealed in the dominant model (OR 1.42, CI 1.17, 1.73, P = 0.0005). In contrast with Caucasians, positive results were found for Asians in all genetic models with the pooled OR fluctuating from 1.83 to 2.24, indicating that this genetic mutation may increase T2DM risk in Asians. rs841853 was found to be a protective factor against T2DM for Blacks in the allele contrast model, with the combined OR of 0.72.
[PMID 18613291] Association of glucose transporter 1 polymorphisms with type 2 diabetes in the Tunisian population
273 T2DM subjects (cases) and 343 healthy subjects (controls) from Tunisia were genotyped using the PCR restriction fragment length polymorphism and three SNPs of SLC2A1 were isolated. Results showed that the GT genotype of rs841853 could increase the risk of susceptibility to T2DM (OR 2.4, 95% CI 1.7, 3.4). The combination defined by the three SNPs (HpyCH4V SNP/Enh2 SNP1/XbaI SNP), showed that the TAT haplotype conferred the highest risk of T2DM (OR 3.4, 95% CI 2.4, 4.8).
[PMID 15682272] Association between the GLUT1 gene polymorphism and the risk of diabetic nephropathy: a meta-analysis
Studies included 710 cases with DN and 750 control diabetic patients without nephropathy. 5 of 6 studies included Caucasian populations, and only one involved an Asian population In the control group, the T allele prevalence, TT genotype, TG genotype and GG genotype distribution of the rs841853 SNP was 34%, 11%, 46% and 43% respectively, whereas in the case group distribution was 38%, 14%, 49% and 38%.
- The main analysis, investigating the association between the T allele and DN risk, revealed heterogeneity (I2 = 68; P < 0.01) and the random effect pooled OR was not significant (OR 1.26, 95% CI 0.93, 1.69; P = 0.04).
- The genotype contrast of the homozygotes derived significant association only for the studies in Hardy-Weinberg equilibrium (fixed effects (OR 1.70, 95% CI 1.15, 2.53) and random effects (OR 1.91, 95% CI 1.00, 3.46)). The dominant model and allele contrast model for the T allele produced the same pattern of results, and the recessive model produced no significant associations. The T allele could be dominant for DN.
[PMID 22509097] Multicenter cohort association study of SLC2A1 single nucleotide polymorphisms and age-related macular degeneration
This study examines the potential association between single nucleotide polymorphisms (SNPs) in the glucose transporter 1 (SLC2A1) gene and AMD. 22 SNPs of SLC2A1 gene were genotyped in 375 cases and 199 controls from an initial discovery cohort (the Amsterdam-Rotterdam-Netherlands study). Replication testing was performed in 5 large independent (Caucasian) cohorts (4,860 cases and 4,004 controls). Subjects from all cohorts underwent ophthalmic examination and fundus photograph for diagnosis of AMD. SNPs were selected on criteria such as functional relevance, MAF>10%, coverage of the main LD blocks, and tagging of the most common haplotypes (LD tagging criterion of r2>0.8).
- Three out of the 22 SNPs showed a significant allelic association with AMD: rs841853 (p=0.0006), rs3754219 (p=0.0011) and rs4660687 (p=0.0157), the former two passing the gene-wise significance threshold (p-value/total number of SNPs) as well as the positive control (complement factor 3 (C3) polymorphisms) association threshold. rs841853 shows a risk increasing effect with highest ORs seen for homozygous carriers of the risk alleles (OR 2.24; 95% CI 1.13–4.41).
- On replication, significant association between rs841853 with AMD was only seen in one cohort (OR 2.07; 95% CI 1.14–3.76), whereas on subtype analysis of AMD, significant association was seen with CNV cases (AMD “wet” form).
- The between-study heterogeneity for rs841853 was significant: all AMD cases combined (p=0.008; I2=68%), CNV (p=0.0005; I2=80%) and late AMD cases compared to the controls (p=0.002; I2=74%).
- The genotype frequencies were found to be significantly different for the controls and/or cases among the six individual populations (p value=0.024). rs841853 MAF ranged from 25% to 33% in the control groups, and varied from 30% to 35% in cases.
[PMID 20679470] The XbaI G>T polymorphism of the glucose transporter 1 gene modulates 18F-FDG uptake and tumor aggressiveness in breast cancer
This study found that the rs841853 SNP is associated with an increased (18)F-FDG uptake and a more advanced tumor grade or growth in breast cancer. A diagnostic PET/CT scan was obtained from 52 Caucasian individuals with breast cancer, and the standardized uptake value was determined as a measure of (18)F-FDG uptake. GLUT1 polymorphisms were isolated using PCR techniques.
- The GG genotype of rs841853 was associated with increased tumor uptake of (18)F-FDG, with a mean standardized uptake value of 11.7 (TT/GT genotypes, 5.9; P = 0.03).
- The GG genotype was positively related to enhanced tumor proliferation (mitotic count, P = 0.01). The GG genotype was absent in grade 1 carcinomas and increasingly prevalent in tumors with higher malignancy (grade 2, 28.0%; grade 3, 50%; P = 0.04). Thus rs841853 may favor aggressive phenotypes by modulating the efficiency of cancer cells to recruit glucose and escalate growth rate, suggesting the rs841853 SNP is a proliferation-related prognostic factor.
[PMID 21247498] Genetic variation of Glucose Transporter-1 (GLUT1) and albuminuria in 10,278 European Americans and African Americans: a case-control study in the Atherosclerosis Risk in Communities (ARIC) Study
[PMID 22707195] Relationship between five GLUT1 gene single nucleotide polymorphisms and diabetic nephropathy: a systematic review and meta-analysis
[PMID 19587357] A systematic meta-analysis of genetic association studies for diabetic retinopathy.
[PMID 23631762] Genotyping analysis and 18FDG uptake in breast cancer patients: a preliminary research