Comparison of the genomic structure and variation in the two human sodium-dependent Vitamin C transporters, SLC23A1 and SLC23A2

Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Human Genetics (Impact Factor: 4.82). 10/2004; 115(4):285-94. DOI: 10.1007/s00439-004-1167-x
Source: PubMed


Vitamin C (L-ascorbic acid) is an essential co-factor for eight mammalian enzymes and quenches reactive oxygen species. Sodium-dependent vitamin C transport is mediated by two transporters, SVCT 1 and SVCT 2, encoded by SLC23A1 and SLC23A2. We characterized the genomic structures of SLC23A1 and SLC23A2, determined the extent of genetic variation and linkage disequilibrium across each gene, analyzed nucleotide diversity to estimate the effect of selective pressure, and compared sequence variation across species. In SLC23A1, the majority of single nucleotide polymorphisms (SNPs) are population-specific in either African Americans or Caucasians, including three of four non-synonymous SNPs. In contrast, most SNPs in SLC23A2 are shared between African Americans and Caucasians, and there are no non-synonymous SNPs in SLC23A2. Our analysis, combined with previous in vitro and in vivo studies, suggests that non-synonymous variation appears to be tolerated in SLC23A1 but not SLC23A2, and that this may be a consequence of different selective pressures following past gene duplication of the sodium-dependent vitamin C transporters. Genetic association studies of these two genes will need to account for the differences in haplotype structure and the population-specific variants. Our data represent a fundamental step toward the application of genetics to refining nutrient recommendations, specifically for vitamin C, and may serve as a paradigm for other vitamins.

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Available from: Peter Eck, Oct 05, 2015
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    • "In the present study, we showed that rs4987219 in intron 8 and the synonymous rs1110277 in exon 11 were associated with the severe acute leukopenia and stomatitis, respectively. In 2004, the genomic structure and variations in human SLC23A1 and SLC23A2 gene was clarified by Eck et al. 32. SLC23A2 gene was found to be 158,398 bp long, containing 17 exons, but several large introns resulted in transcript of 7,421 bp 32. "
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    ABSTRACT: Objective: Definitive chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and cisplatin (CDDP) is one of the standard therapies for esophageal squamous cell carcinoma (ESCC); however, inter-individual variations in clinical outcomes have yet to be investigated. In the present study, single nucleotide polymorphisms (SNPs) in SLC23A2 gene were retrospectively evaluated in 49 Japanese patients with ESCC who were treated with a definitive 5-FU/CDDP-based CRT, and the predictive values for the clinical response, severe acute toxicities, and long-term survival were assessed. Methods: A course consisted of the continuous infusion of 5-FU at 400 mg/m2/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m2/day on days 1 and 8, and radiation at 2 Gy/day on days 1 to 5, 8 to 12, and 15 to 19, with a second course being repeated after a 2-week interval. The SLC23A2 SNPs rs2681116, rs13037458, rs1715364, rs4987219, and rs1110277 were evaluated. Results: The rs2681116 and rs13037458 had a tendency to predict the clinical response (p=0.144 and 0.085, respectively) and long-term survival (p=0.142 and 0.056, respectively). The rs4987219 and rs1110277 correlated with severe acute leukopenia (p=0.025) and stomatitis (p=0.019), respectively. Conclusions: Further investigations with a larger number of patients or an in vitro study are needed to confirm the predictive values of genetic polymorphisms in SLC23A2.
    International journal of medical sciences 02/2014; 11(4):321-6. DOI:10.7150/ijms.7654 · 2.00 Impact Factor
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    • "Our study identified one SNP marker (and haplotypes) in association with GC risk from the SLC23A2 gene, the homologous gene found in rat gastric tissue. Little is known about the distribution of these proteins in humans, but the genes are highly conserved in humans and rodents, indicating a common ancestral gene (Eck et al. 2004; Savini et al. 2008). Little is known about the possible functions of the SNP markers for which we and others have observed associations (Chen et al. 2009; Erichsen et al. 2006; Wright et al. 2009; Skibola et al. 2008), but discrepancies across studies could also reflect different expression patterns for these genes in different tissues. "
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    ABSTRACT: Vitamin C is known to protect mucosal tissues from oxidative stress and inhibit nitrosamine formation in the stomach. High consumption of fruits, particularly citrus, and higher circulating vitamin C concentrations may be inversely associated with gastric cancer (GC) risk. We investigated 20 polymorphisms in vitamin C transporter genes SCL23A1 and SCL23A2 and GC risk in 365 cases and 1,284 controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. We also evaluated the association between these polymorphisms and baseline plasma vitamin C levels in a subset of participants. Four SNPs were predictors of plasma vitamin C levels (SLC23A1 rs11950646 and rs33972313; SLC23A2 rs6053005 and rs6133175) in multivariable linear regression models. One SNP (SLC23A2 rs6116569) was associated with GC risk, in particular non-cardia GC (OR = 1.63, 95 % CI = 1.11-2.39, based on 178 non-cardia cases), but this association was attenuated when plasma vitamin C was included in the logistic regression model. Haplotype analysis of SLC23A1 yielded no associations with GC. In SLC23A2, one haplotype was associated with both overall and non-cardia GC, another haplotype was associated with GC overall, and a third was associated with intestinal-type GC. Common variants in SLC23A1 and SLC23A2 may influence plasma vitamin C concentration independent of dietary intake, and variation in SLC23A2 may influence GC risk. Additional prospective studies in large populations and consortia are recommended. Investigation of variation in vitamin C transporter genes may shed light on the preventative properties of vitamin C in gastric carcinogenesis.
    Genes & Nutrition 06/2013; 8(6). DOI:10.1007/s12263-013-0346-6 · 2.79 Impact Factor
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    • "Another explanation for the absence of a positive correlation between vitamin C intake and plasma vitamin C values in periodontal patients may be a different genetic make-up. Vitamin C can be actively transported across membranes against its concentration gradient by two sodium-dependent vitamin C transporter proteins (Stratakis et al. 2000) encoded by two separate genes and for both genetic polymorphisms have been demonstrated (Eck et al. 2004). In a recent study, it was confirmed that genetic variation in vitamin C "
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    ABSTRACT: To test the hypothesis that vitamin C concentrations in plasma, polymorphonuclear neutrophilic leucocytes (PMNs) and peripheral blood mononuclear cells (PBMCs) are lower in periodontitis patients compared with healthy controls. Twenty-one untreated periodontal patients and 21 healthy controls matched for age, gender, race and smoking habits were selected. Dietary vitamin C intake was assessed by a self-administered dietary record. Fasting blood samples were obtained and analysed for vitamin C concentrations in plasma, PMNs and PBMCs by means of high-pressure liquid chromatography (HPLC). Plasma vitamin C was lower in periodontitis patients compared with controls (8.3 and 11.3 mg/l, respectively, p = 0.03). Only in the control group a positive correlation was present between vitamin C intake and plasma values. No differences could be assessed between patients and controls regarding vitamin C dietary intake and levels in PMNs and PBMCs. In the patient group, pocket depth appeared to be negatively associated with the vitamin C concentration in PMNs. Although the relationship between low plasma vitamin C levels and periodontitis is clear, the disease cannot be explained by insufficient vitamin C storage capacity of leucocytes; the question remains through which mechanism low plasma vitamin C levels are related to periodontitis.
    Journal Of Clinical Periodontology 06/2012; 39(10):905-12. DOI:10.1111/j.1600-051X.2012.01927.x · 4.01 Impact Factor
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