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Cited by 107Genetic Associations and EpidemiologyVitamin C and Antioxidants ResearchNutrition, Genetics, and Disease

Genetic variation at the SLC23A1 locus is associated with circulating concentrations of l-ascorbic acid (vitamin C): evidence from 5 independent studies with >15,000 participants

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Timpson, Nicholas J, Forouhi, Nita G, Brion, Marie-Jo, Harbord, Roger M, Cook, Derek G, Johnson, Paul, McConnachie, Alex, Morris, Richard W +12 more·2010·The American Journal of Clinical Nutrition
DOI 10.3945/ajcn.2010.29438PMC PMC3605792
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Abstract

Background L-ascorbic acid is an essential part of the human diet and has been associated with a wide range of chronic complex diseases, including cardiovascular outcomes. To date, there are no confirmed genetic correlates of circulating concentrations of L-ascorbic acid. Objective We aimed to confirm the existence of an association between common variation at the SLC23A1 gene locus and circulating concentrations of L-ascorbic acid. Design We used a 2-stage design, which included a discovery cohort (the British Women's Heart and Health Study), a series of follow-up cohorts, and meta-analysis (totaling 15,087 participants) to assess the relation between variation at SLC23A1 and circulating concentrations of L-ascorbic acid. Results In the discovery cohort, variation at rs33972313 was associated with a reduction in circulating concentrations of L-ascorbic acid (-4.15 micromol/L; 95% CI: -0.49, -7.81 micromol/L; P = 0.03 reduction per minor allele). Pooled analysis of the relation between rs33972313 and circulating L-ascorbic acid across all studies confirmed this and showed that each additional rare allele was associated with a reduction in circulating concentrations of L-ascorbic acid of -5.98 micromol/L (95% CI: -8.23, -3.73 micromol/L; P = 2.0 x 10(-7) per minor allele). Conclusions A genetic variant (rs33972313) in the SLC23A1 vitamin C active transporter locus was identified that is reliably associated with circulating concentrations of L-ascorbic acid in the general population. This finding has implications more generally for the epidemiologic investigation of relations between circulating L-ascorbic acid and health outcomes.

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  • An elevation of vitamin C levels was also seldomly described.

    “However, an elevation of vitamin C levels was also seldomly described [80,82,83].”

    From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [82]

    The Results (page unavailable) report increased circulating vitamin C levels associated with two genetic variants. The paper does not say that elevations are seldom described, so it supports the occurrence of an elevation but not the claim about how rarely it has been reported. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The strongest evidence to decrease circulating vitamin C levels was found for several common SNPs of SLC23A1 due to reduced renal reabsorption.

    “The strongest evidence to decrease circulating vitamin C levels was found for several common SNPs of SLC23A1 due to reduced renal reabsorption.”

    From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [82]

    The Results (page not provided) identify one rare SLC23A1 allele, rs33972313, associated with lower circulating vitamin C; two other SNPs were associated with increases, not decreases. The Discussion (page not provided) says impaired transport is assumed, notes SVCT1 activity in the kidney, and says functional assays of the variant were not performed. It does not establish reduced renal reabsorption as the mechanism. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • SNPs of SLC23A1 are more common in African and African-American populations than others, while SNPs of Slc23A2 are of similar frequency in Caucasian and African populations.

    “These SNPs are more common in the African and African-American populations over others, while SNPs of Slc23A2 are of a similar frequency in the Caucasian and African populations [80,82,84].”

    From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [82]

    The Introduction (page unavailable) says SLC23A2 variation is consistent across European and African populations, supporting the comparison for that gene. It does not say SLC23A1 SNPs are more common in African or African-American populations; the Discussion (page unavailable) limits this study’s findings to populations of European descent. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 41

  1. [1]Nishikimi M Koshizaka T Ozawa T Yagi K Occurrence in humans and guinea pigs of the gene related to their missing enzyme L-gulono-gamma-lactone oxidase Archives of Biochemistry & Biophysics 1988 267 842 6 3214183
  2. [2]Nishikimi M Fukuyama R Minoshima S Shimizu N Yagi K Cloning and chromosomal mapping of the human nonfunctional gene for L-gulono-gamma-lactone oxidase, the enzyme for L-ascorbic acid biosynthesis missing in man Journal of Biological Chemistry 1994 269 13685 8 8175804
  3. [3]Levine M Rumsey SC Daruwala R Park JB Wang Y Criteria and recommendations for vitamin C intake JAMA 1999 1415 1423 10217058
  4. [5]Khaw KT Bingham S Welch A Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study Lancet 2001 357 657 663 11247548
  5. [6]McRae MP Vitamin C supplementation lowers serum low-density lipoprotein cholesterol and triglycerides: a meta-analysis of 13 randimised controlled trials Journal of Chiropractic Medicine 2008 7 48 58 19674720 PMC2682928
  6. [7]Padayatty SJ Katz A Wang Y Vitamin C as an antioxidant: evaluation of its role in disease prevention Journal of the American College of Nutrition 2003 22 18 35 12569111
  7. [8]Padayatty SJ Levine M Padayatty SJ Levine M Fruit and vegetables: think variety, go ahead, eat American Journal of Clinical Nutrition 2008 87 5 7 18175730
  8. [9]Harding AH Wareham NJ Bingham SA Plasma vitamin C level, fruit and vegetable consumption, and the risk of new-onset type 2 diabetes mellitus: the European prospective investigation of cancer--Norfolk prospective study Archives of Internal Medicine 2008 168 1493 9 18663161
  9. [10]Britton JR Pavord ID Richards KA Dietary antioxidant vitamin intake and lung function in the general population American Journal of Respiratory & Critical Care Medicine 1995 151 1383 7 7735589
  10. [11]Schwartz J Weiss ST Relationship between dietary vitamin C intake and pulmonary function in the First National Health and Nutrition Examination Survey (NHANES I) American Journal of Clinical Nutrition 1994 59 110 4 8279390
  11. [12]Mandl J Szarka A Banhegyi G Vitamin C: update on physiology and pharmacology British Journal of Pharmacology 2009 157 1097 1110 19508394 PMC2743829
  12. [13]Polidori MC Mecocci P Levine M Short-term and long-term vitamin C supplementation in humans dose-dependently increases the resistance of plasma to ex vivo lipid peroxidation Archives of Biochemistry & Biophysics 2004 423 109 15 14871474
  13. [14]Balkan J Dogru-Abbasoglu S Aykac-Toker G Uysal M Serum pro-oxidant-antioxidant balance and low-density lipoprotein oxidation in healthy subjects with different cholesterol levels Clinical & Experimental Medicine 2004 3 237 42 15103515
  14. [15]Jialal I Vega GL Grundy SM Physiologic levels of ascorbate inhibit the oxidative modification of low density lipoprotein Atherosclerosis 1990 82 185 91 2375783
  15. [18]Wideman GL Baird GH Bolding OT Ascorbic acid deficiency and premature rupture of fetal membranes American Journal of Obstetrics & Gynecology 1964 88 592 5 14128191
  16. [19]Rebouche CJ Ascorbic acid and carnitine biosynthesis American Journal of Clinical Nutrition 1991 54 1147S 1152S 1962562
  17. [20]Li Y Schellhorn HE Li Y Schellhorn HE New developments and novel therapeutic perspectives for vitamin C Journal of Nutrition 2007 137 2171 84 17884994
  18. [21]Wilson JX Regulation of vitamin C transport Annual Review of Nutrition 2005 25 6.1 6.21 16011461
  19. [22]Takanaga H Mackenzie B Hediger MA Takanaga H Mackenzie B Hediger MA Sodium-dependent ascorbic acid transporter family SLC23 Pflugers Archiv - European Journal of Physiology 2004 447 677 82 12845532
  20. [23]Stratakis CA Taymans SE Daruwala R Song J Levine M Mapping of the human genes (SLC23A2 and SLC23A1) coding for vitamin C transporters 1 and 2 (SVCT1 and SVCT2) to 5q23 and 20p12, respectively Journal of Medical Genetics 2000 37 E20 10978367 PMC1734702
  21. [24]Maulen NP Henriquez EA Kempe S Up-regulation and polarized expression of the sodium-ascorbic acid transporter SVCT1 in post-confluent differentiated CaCo-2 cells Journal of Biological Chemistry 2003 278 9035 41 12381735
  22. [25]Bowers-Komro DM McCormick DB Characterization of ascorbic acid uptake by isolated rat kidney cells Journal of Nutrition 1991 121 57 64 1992058
  23. [26]Lee JH Oh CS Mun GH Immunohistochemical localization of sodium-dependent L-ascorbic acid transporter 1 protein in rat kidney Histochemistry & Cell Biology 2006 126 491 4 16673096
  24. [27]Savini I Rossi A Pierro C Avigliano L Catani MV SVCT1 and SVCT2: key proteins for vitamin C uptake Amino Acids 2008 34 347 55 17541511
  25. [28]Eck P Erichsen HC Taylor JG Comparison of the genomic structure and variation in the two human sodium-dependent vitamin C transporters, SLC23A1 and SLC23A2 Human Genetics 2004 115 285 94 15316768
  26. [29]Lawlor DA Bedford C Taylor M Ebrahim S Geographical variation in cardiovascular disease, risk factors, and their control in older women: British Women’s Heart and Health Study Journal of Epidemiology & Community Health 2003 57 134 40 12540690 PMC1732392
  27. [30]Lawlor DA Ebrahim S Davey Smith G British women’s h, health s Socioeconomic position in childhood and adulthood and insulin resistance: cross sectional survey using data from British women’s heart and health study Bmj 2002 325 805 12376440 PMC128946
  28. [33]Day NE Oakes S R L EPIC-Norfolk: study design and characteristics of the cohort: European Prospective Investigation of Cancer British Journal of Cancer 1999 80 95 103 10466767
  29. [34]Hart CL MacKinnon PL Watt GC The Midspan studies International Journal of Epidemiology 2005 34 28 34 15705739
  30. [35]Whincup PH Gilg JA Owen CG British South Asians aged 13-16 years have higher fasting glucose and insulin levels than Europeans Diabetic Medicine 2005 22 1275 7 16108862
  31. [36]Whincup PH Owen CG Sattar N Cook DG School dinners and markers of cardiovascular health and type 2 diabetes in 13-16 year olds: cross sectional study Bmj 2005 331 1060 1 16210251 PMC1283186
  32. [37]Walker M Whincup PH Shaper AG The British Regional Heart Study 1975-2004 International Journal of Epidemiology 2004 33 1185 92 15319395
  33. [38]Guo SW Thompson EA Performing the exact test of Hardy-Weinberg proportion for multiple alleles Biometrics 1992 48 361 72 1637966
  34. [39]Armitage P Berry G Statistical methods in medical research 1994 Blackwell Scientific Publications Oxford Third ed
  35. [40]Higgins JP Thompson SG Deeks JJ Altman DG Measuring inconsistency in meta-analyses BMJ 2003 327 557 560 12958120 PMC192859
  36. [42]Davey Smith G Ebrahim S Mendelian Randomisation: prospects, pitfalls and limitations International Jounal of Epidemiology 2003 33 30 42 15075143
  37. [43]Lawlor DA Harbord RM Sterne JAC Timpson NJ Davey Smith G Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology Statistics in Medicine 2008 27 1133 1163 17886233
  38. [45]MacDonald L Thumser AE Sharp P MacDonald L Thumser AE Sharp P Decreased expression of the vitamin C transporter SVCT1 by ascorbic acid in a human intestinal epithelial cell line British Journal of Nutrition 2002 87 97 100 11895172
  39. [46]Tsukaguchi H Tokui T Mackenzie B A family of mammalian Na+− dependent L-ascorbic acid transporters Nature 1999 399 70 5 10331392
  40. [47]Jin SN Mun GH Lee JH Immunohistochemical study on the distribution of sodium-dependent vitamin C transporters in the respiratory system of adult rat Microscopy Research & Technique 2005 68 360 7 16358281
  41. [48]Boyer JC Campbell CE Sigurdson WJ Polarized localization of vitamin C transporters, SVCT1 and SVCT2, in epithelial cells Biochemical & Biophysical Research Communications 2005 334 150 6 15993839

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Authors
Timpson, N. J., Forouhi, N. G., Brion, M.-J., Harbord, R. M., Cook, D. G., Johnson, P., McConnachie, A., Morris, R. W., Rodriguez, S., Luan, J., Ebrahim, S., Padmanabhan, S., Watt, G., Bruckdorfer, K. R., Wareham, N. J., Whincup, P. H., Chanock, S., Sattar, N., Lawlor, D. A., & Davey Smith, G.
Affiliations
  • University of Bristol (GB)
  • Medical Research Council (GB)
  • Addenbrooke's Hospital (GB)
  • University of Glasgow (GB)
  • University College London (GB)
  • National Cancer Institute (US)
ORCID
Venue
The American Journal of Clinical Nutrition
Publisher
Elsevier BV
Published
2010-08
Volume
92
Issue
2
Pages
375-382
ISSN
0002-9165 (ISSN-L)
DOI
10.3945/ajcn.2010.29438
PMC
PMC3605792
OpenAlex
W2161822077
Cited by
107
References
7
Citations by year
2026: 1 · 2025: 8 · 2024: 4 · 2023: 2 · 2022: 7 · 2021: 8 · 2020: 13 · 2019: 3 · 2018: 9 · 2017: 3 · 2016: 4 · 2015: 8 · 2014: 4 · 2013: 13 · 2012: 8
FWCI
1.12
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal of Clinical Nutrition (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Bristol Research (University of Bristol) (submittedVersion)
  • Explore Bristol Research (submittedVersion)
Funders
  • London School of Hygiene and Tropical Medicine
  • Wellcome Trust (085515, 051187/Z/97/A)
  • National Institute for Health and Care Research
  • British Heart Foundation (RG/08/013/25942, FS/05/095/19937), PG97027, FS05/125, PG/97012, G0600705)
  • University College London
  • University of Glasgow
  • University of Bristol (G0600705)
  • Medical Research Council (G0600705)
  • National Cancer Institute
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
Keywords
SLC23A1, vitamin C, genetic association, vitamin C transporter, genetic variation, vitamin C metabolism
MeSH terms
Adult, Aged, Ascorbic Acid, Female, Genetics, Population, Genotype, Humans, Male, Middle Aged, Cohort Studies, Linear Models, Polymorphism, Single Nucleotide, Symporters, Organic Anion Transporters, Sodium-Dependent, Sodium-Coupled Vitamin C Transporters

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