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Mark Levine - One of the best experts on this subject based on the ideXlab platform.
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temporo spacial microanatomical distribution of the murine sodium dependent ascorbic acid transporters slc23a1 and SLC23A2 in the kidney throughout development
Biochemistry and Cell Biology, 2017Co-Authors: Peter Eck, Christopher Corpe, Mark LevineAbstract:The two membrane transporters Slc23a1 and SLC23A2 mediate ascorbic acid uptake into cells. We recently determined the key role of Slc23a1 in renal re-absorption of ascorbic acid in a knockout mouse...
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identification and functional characterization of an alternative 5 exon of the sodium dependent ascorbic acid transporter slc23a1 818 5
The FASEB Journal, 2014Co-Authors: Mandana Amir Shaghaghi, Mark Levine, Natalia Yurkova, Peter EckAbstract:Vitamin C, an essential micronutrient and a critical cofactor for several intracellular enzymatic reactions, is actively transported across epithelial barriers through the sodium-dependent ascorbic acid transporter 1 (SLC23A1). The SLC23A1 gene encodes SLC23A1 transporter and is located on human chromosome 5q31.2 (138702885-138719039 compl.; NC_000005.9). Previously, the SLC23A1 transcript has been described as containing 15 exons, stretching over 16 kilobases; however, no alternative splice variant has been described yet. Variations in SLC23A1 gene would impact vitamin C dietary requirements and/or susceptibility to common complex diseases. We have, therefore, evaluated the existence of additional SLC23A1 transcripts in silico and examined the function of new transcript through Xenopus laevis oocytes injection. Here, we characterized a novel alternative first exon encoding a SLC23A1 isoform which is exclusive to human and is expressed in the small intestine. The novel SLC23A1 protein isoform adds 36 N-te...
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the human sodium dependent ascorbic acid transporters slc23a1 and SLC23A2 do not mediate ascorbic acid release in the proximal renal epithelial cell
Physiological Reports, 2013Co-Authors: Peter Eck, Oran Kwon, Shenglin Chen, Omar Y Mian, Mark LevineAbstract:Sodium-dependent ascorbic acid membrane transporters SLC23A1 and SLC23A2 mediate ascorbic acid (vitamin C) transport into cells. However, it is unknown how ascorbic acid undergoes cellular release, or efflux. We hypothesized that SLC23A1 and SLC23A2 could serve a dual role, mediating ascorbic acid cellular efflux as well as uptake. Renal reabsorption is required for maintaining systemic vitamin C concentrations. Because efflux from nephron cells is necessary for reabsorption, we studied whether SLC23A1 and SLC23A2 mediate efflux of ascorbic acid in the human renal nephron. We found high gene expression of SLC23A1 but no expression of SLC23A2 in the proximal convoluted and straight tubules of humans. These data rule out SLC23A2 as the ascorbic acid release protein in the renal proximal tubular epithelia cell. We utilized a novel dual transporter-based Xenopus laevis oocyte system to investigate the function of the SLC23A1 protein, and found that no ascorbate release was mediated by SLC23A1. These findings were confirmed in mammalian cells overexpressing SLC23A1. Taken together, the data for SLC23A1 show that it too does not have a role in cellular release of ascorbic acid across the basolateral membrane of the proximal tubular epithelial cell, and that SLC23A1 alone is responsible for ascorbic acid uptake across the apical membrane. These findings reiterate the physiological importance of proper functioning of SLC23A1 in maintaining vitamin C levels for health and disease prevention. The ascorbate efflux mechanism in the proximal tubule of the kidney remains to be characterized.
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genetic variation in sodium dependent vitamin c transporters slc23a1 and SLC23A2 and risk of advanced colorectal adenoma
Nutrition and Cancer, 2008Co-Authors: Hans Christian Erichsen, Mark Levine, Peter Eck, Robert Welch, Meredith Yeager, Ulrike Peters, Robert E Schoen, Richard B Hayes, Stephen J ChanockAbstract:Previous observational studies suggest that vitamin C may reduce risk of colorectal cancer. Vitamin C transport is facilitated by membrane bound sodium-dependent transporters, SVCT1 (encoded by SLC23A1) and SVCT2 (encoded by SLC23A2). To investigate if common genetic variants in these two genes are associated with risk of colorectal tumor development, we conducted a case-control study of 656 Caucasian advanced distal colorectal adenoma cases and 665 Caucasian sigmoidoscopy-negative controls nested within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The analysis of common single nucleotide polymorphisms in SLC23A1 revealed no association. For SLC23A2, overall, there was no association with haplotypes, but two SNPs located in intron 8 and exon 11 could be associated (odds ratio = 0.49, 95% confidence interval = 0.25-0.95 for haplotype G-C vs. haplotype C-C). The findings should be confirmed in follow-up studies, and further investigation is required to probe the functional basis of this finding.
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genomic and functional analysis of the sodium dependent vitamin c transporter slc23a1 svct1
Genes and Nutrition, 2007Co-Authors: Christopher Corpe, Peter Eck, Hans Christian Erichsen, Stephen J Chanock, James G. Taylor, Mark LevineAbstract:Vitamin C, an essential co-factor for at least eight enzymatic reactions, might also be involved in development or treatment of cancer, cardiovascular diseases, diabetes, and stroke. Ascorbic acid, the reduced form of vitamin C is transported across epithelial barriers by the sodium dependent vitamin C transporters 1 (SVCT1). SVCT1 is encoded by SLC23A1 and mapped to 5q31.2 [1, 2]. Recently, the pattern of common genetic variants has been characterized for both ascorbic acid transporters, SLC23A1 and SLC23A2, which share common intron/exon borders, are 58% similar in sequence across the coding region, but differ greatly in size and linkage disequilibrium patterns [3]. Here we characterize the genetic variation in the less constrained SLC23A1 gene in more detail and test for functional consequences. SLC23A1 is expressed in tissues critical for absorption and reabsorption of vitamin C (kidney, intestinal, and hepatic tissues) [4]. Therefore functional consequences of variations in SVCT1 would impact on dietary requirements and recommendations.
Peter Eck - One of the best experts on this subject based on the ideXlab platform.
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temporo spacial microanatomical distribution of the murine sodium dependent ascorbic acid transporters slc23a1 and SLC23A2 in the kidney throughout development
Biochemistry and Cell Biology, 2017Co-Authors: Peter Eck, Christopher Corpe, Mark LevineAbstract:The two membrane transporters Slc23a1 and SLC23A2 mediate ascorbic acid uptake into cells. We recently determined the key role of Slc23a1 in renal re-absorption of ascorbic acid in a knockout mouse...
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identification and functional characterization of an alternative 5 exon of the sodium dependent ascorbic acid transporter slc23a1 818 5
The FASEB Journal, 2014Co-Authors: Mandana Amir Shaghaghi, Mark Levine, Natalia Yurkova, Peter EckAbstract:Vitamin C, an essential micronutrient and a critical cofactor for several intracellular enzymatic reactions, is actively transported across epithelial barriers through the sodium-dependent ascorbic acid transporter 1 (SLC23A1). The SLC23A1 gene encodes SLC23A1 transporter and is located on human chromosome 5q31.2 (138702885-138719039 compl.; NC_000005.9). Previously, the SLC23A1 transcript has been described as containing 15 exons, stretching over 16 kilobases; however, no alternative splice variant has been described yet. Variations in SLC23A1 gene would impact vitamin C dietary requirements and/or susceptibility to common complex diseases. We have, therefore, evaluated the existence of additional SLC23A1 transcripts in silico and examined the function of new transcript through Xenopus laevis oocytes injection. Here, we characterized a novel alternative first exon encoding a SLC23A1 isoform which is exclusive to human and is expressed in the small intestine. The novel SLC23A1 protein isoform adds 36 N-te...
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the human sodium dependent ascorbic acid transporters slc23a1 and SLC23A2 do not mediate ascorbic acid release in the proximal renal epithelial cell
Physiological Reports, 2013Co-Authors: Peter Eck, Oran Kwon, Shenglin Chen, Omar Y Mian, Mark LevineAbstract:Sodium-dependent ascorbic acid membrane transporters SLC23A1 and SLC23A2 mediate ascorbic acid (vitamin C) transport into cells. However, it is unknown how ascorbic acid undergoes cellular release, or efflux. We hypothesized that SLC23A1 and SLC23A2 could serve a dual role, mediating ascorbic acid cellular efflux as well as uptake. Renal reabsorption is required for maintaining systemic vitamin C concentrations. Because efflux from nephron cells is necessary for reabsorption, we studied whether SLC23A1 and SLC23A2 mediate efflux of ascorbic acid in the human renal nephron. We found high gene expression of SLC23A1 but no expression of SLC23A2 in the proximal convoluted and straight tubules of humans. These data rule out SLC23A2 as the ascorbic acid release protein in the renal proximal tubular epithelia cell. We utilized a novel dual transporter-based Xenopus laevis oocyte system to investigate the function of the SLC23A1 protein, and found that no ascorbate release was mediated by SLC23A1. These findings were confirmed in mammalian cells overexpressing SLC23A1. Taken together, the data for SLC23A1 show that it too does not have a role in cellular release of ascorbic acid across the basolateral membrane of the proximal tubular epithelial cell, and that SLC23A1 alone is responsible for ascorbic acid uptake across the apical membrane. These findings reiterate the physiological importance of proper functioning of SLC23A1 in maintaining vitamin C levels for health and disease prevention. The ascorbate efflux mechanism in the proximal tubule of the kidney remains to be characterized.
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vitamin c transporter slc23a1 links renal reabsorption vitamin c tissue accumulation and perinatal survival in mice
Journal of Clinical Investigation, 2010Co-Authors: Christopher Corpe, Yaohui Wang, Peter Eck, Jin Wang, Robert Faulhaberwalter, Jurgen Schnermann, Sam Margolis, Sebastian J Padayatty, He Sun, Robert L NussbaumAbstract:Levels of the necessary nutrient vitamin C (ascorbate) are tightly regulated by intestinal absorption, tissue accumulation, and renal reabsorption and excretion. Ascorbate levels are controlled in part by regulation of transport through at least 2 sodium-dependent transporters: Slc23a1 and SLC23A2 (also known as Svct1 and Svct2, respectively). Previous work indicates that SLC23A2 is essential for viability in mice, but the roles of Slc23a1 for viability and in adult physiology have not been determined. To investigate the contributions of Slc23a1 to plasma and tissue ascorbate concentrations in vivo, we generated Slc23a1-/- mice. Compared with wild-type mice, Slc23a1-/- mice increased ascorbate fractional excretion up to 18-fold. Hepatic portal ascorbate accumulation was nearly abolished, whereas intestinal absorption was marginally affected. Both heterozygous and knockout pups born to Slc23a1-/- dams exhibited approximately 45% perinatal mortality, and this was associated with lower plasma ascorbate concentrations in dams and pups. Perinatal mortality of Slc23a1-/- pups born to Slc23a1-/- dams was prevented by ascorbate supplementation during pregnancy. Taken together, these data indicate that ascorbate provided by the dam influenced perinatal survival. Although Slc23a1-/- mice lost as much as 70% of their ascorbate body stores in urine daily, we observed an unanticipated compensatory increase in ascorbate synthesis. These findings indicate a key role for Slc23a1 in renal ascorbate absorption and perinatal survival and reveal regulation of vitamin C biosynthesis in mice.
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genetic variation in sodium dependent vitamin c transporters slc23a1 and SLC23A2 and risk of advanced colorectal adenoma
Nutrition and Cancer, 2008Co-Authors: Hans Christian Erichsen, Mark Levine, Peter Eck, Robert Welch, Meredith Yeager, Ulrike Peters, Robert E Schoen, Richard B Hayes, Stephen J ChanockAbstract:Previous observational studies suggest that vitamin C may reduce risk of colorectal cancer. Vitamin C transport is facilitated by membrane bound sodium-dependent transporters, SVCT1 (encoded by SLC23A1) and SVCT2 (encoded by SLC23A2). To investigate if common genetic variants in these two genes are associated with risk of colorectal tumor development, we conducted a case-control study of 656 Caucasian advanced distal colorectal adenoma cases and 665 Caucasian sigmoidoscopy-negative controls nested within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The analysis of common single nucleotide polymorphisms in SLC23A1 revealed no association. For SLC23A2, overall, there was no association with haplotypes, but two SNPs located in intron 8 and exon 11 could be associated (odds ratio = 0.49, 95% confidence interval = 0.25-0.95 for haplotype G-C vs. haplotype C-C). The findings should be confirmed in follow-up studies, and further investigation is required to probe the functional basis of this finding.
Stephen J Chanock - One of the best experts on this subject based on the ideXlab platform.
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genetic variation in sodium dependent vitamin c transporters slc23a1 and SLC23A2 and risk of advanced colorectal adenoma
Nutrition and Cancer, 2008Co-Authors: Hans Christian Erichsen, Mark Levine, Peter Eck, Robert Welch, Meredith Yeager, Ulrike Peters, Robert E Schoen, Richard B Hayes, Stephen J ChanockAbstract:Previous observational studies suggest that vitamin C may reduce risk of colorectal cancer. Vitamin C transport is facilitated by membrane bound sodium-dependent transporters, SVCT1 (encoded by SLC23A1) and SVCT2 (encoded by SLC23A2). To investigate if common genetic variants in these two genes are associated with risk of colorectal tumor development, we conducted a case-control study of 656 Caucasian advanced distal colorectal adenoma cases and 665 Caucasian sigmoidoscopy-negative controls nested within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The analysis of common single nucleotide polymorphisms in SLC23A1 revealed no association. For SLC23A2, overall, there was no association with haplotypes, but two SNPs located in intron 8 and exon 11 could be associated (odds ratio = 0.49, 95% confidence interval = 0.25-0.95 for haplotype G-C vs. haplotype C-C). The findings should be confirmed in follow-up studies, and further investigation is required to probe the functional basis of this finding.
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genomic and functional analysis of the sodium dependent vitamin c transporter slc23a1 svct1
Genes and Nutrition, 2007Co-Authors: Christopher Corpe, Peter Eck, Hans Christian Erichsen, Stephen J Chanock, James G. Taylor, Mark LevineAbstract:Vitamin C, an essential co-factor for at least eight enzymatic reactions, might also be involved in development or treatment of cancer, cardiovascular diseases, diabetes, and stroke. Ascorbic acid, the reduced form of vitamin C is transported across epithelial barriers by the sodium dependent vitamin C transporters 1 (SVCT1). SVCT1 is encoded by SLC23A1 and mapped to 5q31.2 [1, 2]. Recently, the pattern of common genetic variants has been characterized for both ascorbic acid transporters, SLC23A1 and SLC23A2, which share common intron/exon borders, are 58% similar in sequence across the coding region, but differ greatly in size and linkage disequilibrium patterns [3]. Here we characterize the genetic variation in the less constrained SLC23A1 gene in more detail and test for functional consequences. SLC23A1 is expressed in tissues critical for absorption and reabsorption of vitamin C (kidney, intestinal, and hepatic tissues) [4]. Therefore functional consequences of variations in SVCT1 would impact on dietary requirements and recommendations.
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genetic variation in the sodium dependent vitamin c transporters slc23a1 and SLC23A2 and risk for preterm delivery
American Journal of Epidemiology, 2006Co-Authors: Hans Christian Erichsen, Mark Levine, Peter Eck, Stephanie M Engel, Robert Welch, Meredith Yeager, Anna Maria Siegariz, Andrew F Olshan, Stephen J ChanockAbstract:Vitamin C has been the focus of epidemiologic investigation in preterm delivery (<37 weeks' gestation), which is a leading cause of neonatal mortality and birth-related morbidity. There are two sodium-dependent membrane transporters encoded by SLC23A1 and SLC23A2, which have key roles in human vitamin C metabolism and which control dietary uptake, reabsorption, and tissue distribution of vitamin C. Using maternal DNA, the authors evaluated common single-nucleotide polymorphisms (SNPs) in SLC23A1 and SLC23A2 in a nested case-control analysis of the Pregnancy, Infection, and Nutrition Study (1995-2000) cohort. Of the associations observed for both haplotypes in SLC23A 1 and individual SNPs in SLC23A2, the most robust finding is with an intron 2 variant in SLC23A2. Heterozygotes and homozygotes for this variant had a 1.7-fold (95% confidence interval: 0.9, 3.3) and a 2.7-fold (95% confidence interval: 1.2, 6.3) elevation in the risk of spontaneous preterm birth, respectively. Semi-Bayesian hierarchical regression analysis, which simultaneously adjusted for multiple SNPs within the same gene, gave comparable results. The authors' findings link genetic variants in the vitamin C transporters to spontaneous preterm birth, which may explain previous dietary associations. If the findings from this study are confirmed, they may serve as the foundation for genetic risk assessment of nutritional pathways in preterm birth.
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Comparison of the genomic structure and variation in the two human sodium-dependent vitamin C transporters, SLC23A1 and SLC23A2
Human Genetics, 2004Co-Authors: Peter Eck, Mark Levine, Hans Christian Erichsen, Meredith Yeager, James G. Taylor, Austin L. Hughes, Stephen J ChanockAbstract: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.
Astrid E. Fletcher - One of the best experts on this subject based on the ideXlab platform.
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polymorphisms in sodium dependent vitamin c transporter genes and plasma aqueous humor and lens nucleus ascorbate concentrations in an ascorbate depleted setting
Experimental Eye Research, 2014Co-Authors: Srinivasan Senthilkumari, Badri Talwar, Kuppamuthu Dharmalingam, Ravilla D Ravindran, Ramamurthy Jayanthi, Charu Saravanan, Ian S Young, Periasamy Sundaresan, Alan D Dangour, Astrid E. FletcherAbstract:Abstract We have previously reported low concentrations of plasma ascorbate and low dietary vitamin C intake in the older Indian population and a strong inverse association of these with cataract. Little is known about ascorbate levels in aqueous humor and lens in populations habitually depleted of ascorbate and no studies in any setting have investigated whether genetic polymorphisms influence ascorbate levels in ocular tissues. Our objectives were to investigate relationships between ascorbate concentrations in plasma, aqueous humor and lens and whether these relationships are influenced by Single Nucleotide Polymorphisms (SNPs) in sodium-dependent vitamin C transporter genes (SLC23A1 and SLC23A2). We enrolled sixty patients (equal numbers of men and women, mean age 63 years) undergoing small incision cataract surgery in southern India. We measured ascorbate concentrations in plasma, aqueous humor and lens nucleus using high performance liquid chromatography. SLC23A1 SNPs (rs4257763, rs6596473) and SLC23A2 SNPs (rs1279683 and rs12479919) were genotyped using a TaqMan assay. Patients were interviewed for lifestyle factors which might influence ascorbate. Plasma vitamin C was normalized by a log 10 transformation. Statistical analysis used linear regression with the slope of the within-subject associations estimated using beta ( β ) coefficients. The ascorbate concentrations (μmol/L) were: plasma ascorbate, median and inter-quartile range (IQR), 15.2 (7.8, 34.5), mean (SD) of aqueous humor ascorbate, 1074 (545) and lens nucleus ascorbate, 0.42 (0.16) (μmol/g lens nucleus wet weight). Minimum allele frequencies were: rs1279683 (0.28), rs12479919 (0.30), rs659647 (0.48). Decreasing concentrations of ocular ascorbate from the common to the rare genotype were observed for rs6596473 and rs12479919. The per allele difference in aqueous humor ascorbate for rs6596473 was −217 μmol/L, p p β coefficients for the regression of log 10 plasma ascorbate on aqueous humor ascorbate were higher for the GG genotype of rs6596473: GG, β = 1460 compared to carriage of the C allele, CG, β = 1059, CC, β = 1132, p interaction = 0.1. In conclusion we found that compared to studies in well-nourished populations, ascorbate concentrations in the plasma, aqueous humor and lens nucleus were low. We present novel findings that polymorphisms in SLC23A1/2 genes influenced ascorbate concentration in aqueous humor and lens nucleus.
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polymorphisms in sodium dependent vitamin c transporter genes and plasma aqueous humor and lens nucleus ascorbate concentrations in an ascorbate depleted setting
Experimental Eye Research, 2014Co-Authors: Srinivasan Senthilkumari, Badri Talwar, Kuppamuthu Dharmalingam, Ravilla D Ravindran, Ramamurthy Jayanthi, Charu Saravanan, Ian S Young, Periasamy Sundaresan, Alan D Dangour, Astrid E. FletcherAbstract:We have previously reported low concentrations of plasma ascorbate and low dietary vitamin C intake in the older Indian population and a strong inverse association of these with cataract. Little is known about ascorbate levels in aqueous humor and lens in populations habitually depleted of ascorbate and no studies in any setting have investigated whether genetic polymorphisms influence ascorbate levels in ocular tissues. Our objectives were to investigate relationships between ascorbate concentrations in plasma, aqueous humor and lens and whether these relationships are influenced by Single Nucleotide Polymorphisms (SNPs) in sodium-dependent vitamin C transporter genes (SLC23A1 and SLC23A2). We enrolled sixty patients (equal numbers of men and women, mean age 63 years) undergoing small incision cataract surgery in southern India. We measured ascorbate concentrations in plasma, aqueous humor and lens nucleus using high performance liquid chromatography. SLC23A1 SNPs (rs4257763, rs6596473) and SLC23A2 SNPs (rs1279683 and rs12479919) were genotyped using a TaqMan assay. Patients were interviewed for lifestyle factors which might influence ascorbate. Plasma vitamin C was normalized by a log10 transformation. Statistical analysis used linear regression with the slope of the within-subject associations estimated using beta (β) coefficients. The ascorbate concentrations (μmol/L) were: plasma ascorbate, median and inter-quartile range (IQR), 15.2 (7.8, 34.5), mean (SD) of aqueous humor ascorbate, 1074 (545) and lens nucleus ascorbate, 0.42 (0.16) (μmol/g lens nucleus wet weight). Minimum allele frequencies were: rs1279683 (0.28), rs12479919 (0.30), rs659647 (0.48). Decreasing concentrations of ocular ascorbate from the common to the rare genotype were observed for rs6596473 and rs12479919. The per allele difference in aqueous humor ascorbate for rs6596473 was -217 μmol/L, p < 0.04 and a per allele difference in lens nucleus ascorbate of -0.085 μmol/g, p < 0.02 for rs12479919. The β coefficients for the regression of log10 plasma ascorbate on aqueous humor ascorbate were higher for the GG genotype of rs6596473: GG, β = 1460 compared to carriage of the C allele, CG, β = 1059, CC, β = 1132, p interaction = 0.1. In conclusion we found that compared to studies in well-nourished populations, ascorbate concentrations in the plasma, aqueous humor and lens nucleus were low. We present novel findings that polymorphisms in SLC23A1/2 genes influenced ascorbate concentration in aqueous humor and lens nucleus.
Hans Christian Erichsen - One of the best experts on this subject based on the ideXlab platform.
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genetic variation in sodium dependent vitamin c transporters slc23a1 and SLC23A2 and risk of advanced colorectal adenoma
Nutrition and Cancer, 2008Co-Authors: Hans Christian Erichsen, Mark Levine, Peter Eck, Robert Welch, Meredith Yeager, Ulrike Peters, Robert E Schoen, Richard B Hayes, Stephen J ChanockAbstract:Previous observational studies suggest that vitamin C may reduce risk of colorectal cancer. Vitamin C transport is facilitated by membrane bound sodium-dependent transporters, SVCT1 (encoded by SLC23A1) and SVCT2 (encoded by SLC23A2). To investigate if common genetic variants in these two genes are associated with risk of colorectal tumor development, we conducted a case-control study of 656 Caucasian advanced distal colorectal adenoma cases and 665 Caucasian sigmoidoscopy-negative controls nested within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The analysis of common single nucleotide polymorphisms in SLC23A1 revealed no association. For SLC23A2, overall, there was no association with haplotypes, but two SNPs located in intron 8 and exon 11 could be associated (odds ratio = 0.49, 95% confidence interval = 0.25-0.95 for haplotype G-C vs. haplotype C-C). The findings should be confirmed in follow-up studies, and further investigation is required to probe the functional basis of this finding.
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genomic and functional analysis of the sodium dependent vitamin c transporter slc23a1 svct1
Genes and Nutrition, 2007Co-Authors: Christopher Corpe, Peter Eck, Hans Christian Erichsen, Stephen J Chanock, James G. Taylor, Mark LevineAbstract:Vitamin C, an essential co-factor for at least eight enzymatic reactions, might also be involved in development or treatment of cancer, cardiovascular diseases, diabetes, and stroke. Ascorbic acid, the reduced form of vitamin C is transported across epithelial barriers by the sodium dependent vitamin C transporters 1 (SVCT1). SVCT1 is encoded by SLC23A1 and mapped to 5q31.2 [1, 2]. Recently, the pattern of common genetic variants has been characterized for both ascorbic acid transporters, SLC23A1 and SLC23A2, which share common intron/exon borders, are 58% similar in sequence across the coding region, but differ greatly in size and linkage disequilibrium patterns [3]. Here we characterize the genetic variation in the less constrained SLC23A1 gene in more detail and test for functional consequences. SLC23A1 is expressed in tissues critical for absorption and reabsorption of vitamin C (kidney, intestinal, and hepatic tissues) [4]. Therefore functional consequences of variations in SVCT1 would impact on dietary requirements and recommendations.
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genetic variation in the sodium dependent vitamin c transporters slc23a1 and SLC23A2 and risk for preterm delivery
American Journal of Epidemiology, 2006Co-Authors: Hans Christian Erichsen, Mark Levine, Peter Eck, Stephanie M Engel, Robert Welch, Meredith Yeager, Anna Maria Siegariz, Andrew F Olshan, Stephen J ChanockAbstract:Vitamin C has been the focus of epidemiologic investigation in preterm delivery (<37 weeks' gestation), which is a leading cause of neonatal mortality and birth-related morbidity. There are two sodium-dependent membrane transporters encoded by SLC23A1 and SLC23A2, which have key roles in human vitamin C metabolism and which control dietary uptake, reabsorption, and tissue distribution of vitamin C. Using maternal DNA, the authors evaluated common single-nucleotide polymorphisms (SNPs) in SLC23A1 and SLC23A2 in a nested case-control analysis of the Pregnancy, Infection, and Nutrition Study (1995-2000) cohort. Of the associations observed for both haplotypes in SLC23A 1 and individual SNPs in SLC23A2, the most robust finding is with an intron 2 variant in SLC23A2. Heterozygotes and homozygotes for this variant had a 1.7-fold (95% confidence interval: 0.9, 3.3) and a 2.7-fold (95% confidence interval: 1.2, 6.3) elevation in the risk of spontaneous preterm birth, respectively. Semi-Bayesian hierarchical regression analysis, which simultaneously adjusted for multiple SNPs within the same gene, gave comparable results. The authors' findings link genetic variants in the vitamin C transporters to spontaneous preterm birth, which may explain previous dietary associations. If the findings from this study are confirmed, they may serve as the foundation for genetic risk assessment of nutritional pathways in preterm birth.
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Comparison of the genomic structure and variation in the two human sodium-dependent vitamin C transporters, SLC23A1 and SLC23A2
Human Genetics, 2004Co-Authors: Peter Eck, Mark Levine, Hans Christian Erichsen, Meredith Yeager, James G. Taylor, Austin L. Hughes, Stephen J ChanockAbstract: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.