Human genetic variation influences vitamin C homeostasis by altering vitamin C transport and antioxidant enzyme function

Abstract

New evidence for the regulation of vitamin C homeostasis has emerged from several studies of human genetic variation. Polymorphisms in the genes encoding sodium-dependent vitamin C transport proteins are strongly associated with plasma ascorbate levels and likely impact tissue cellular vitamin C status. Furthermore, genetic variants of proteins that suppress oxidative stress or detoxify oxidatively damaged biomolecules, i.e., haptoglobin, glutathione-S-transferases, and possibly manganese superoxide dismutase, affect ascorbate levels in the human body. There also is limited evidence for a role of glucose transport proteins. In this review, we examine the extent of the variation in these genes, their impact on vitamin C status, and their potential role in altering chronic disease risk. We conclude that future epidemiological studies should take into account genetic variation in order to successfully determine the role of vitamin C nutriture or supplementation in human vitamin C status and chronic disease risk.

Figure 1

Vitamin C homeostasis. Vitamin C levels in the circulation and tissues are influenced by several regulatory mechanisms in the body. Proteins involved in vitamin C homeostasis fall under the general-categories transporters (blue) that transport vitamin C across cell membranes and those that modulate oxidative stress (red) and would interact with ascorbate due to its antioxidant properties. GLUT, glucose transporter protein; GST, glutathione S-transferase; MnSOD, manganese superoxide dismutase; SVCT, sodium-dependent vitamin C transporter.

Figure 2

Tissue distribution of vitamin C and its transport proteins in the human body. Ascorbate concentrations are from limited human data and are represented as mg/100 g wet weight for tissues and molarity (mM or μM) for intracellular and extracellular fluids. Asterisk indicates that the tissue concentrations of ascorbate in the small intestine are heavily dependent on recent dietary intake. Sodium-dependent vitamin C transporter (SVCT) distribution is based on mRNA expression data in animals and human tissues. Republished with permission from Saunders/Elsevier, from Michels, A and Frei B, Vitamin C, in Biochemical, Physiological, and Molecular Aspects of Human Nutrition, third edition, ed. MH Stipanuk, MA Caudill, pp. 626–54, copyright 2012 (62).

Figure 3

SLC23A1 activity and human genetic variation. (a) Distribution of SLC23A1 in kidney nephron segments by Serial Analysis of Gene Expression (SAGE) libraries containing expression data from microdissected glomeruli and six different nephron segments; values are expressed as tags per million. (b) Effect of SLC23A1 SNPs on ascorbate transport. Xenopus laevis oocytes were microinjected with the following SLC23A1 cRNAs: common type; sham injected; human deletion construct; and SNPs A652G (rs34521685), G790A (rs33972313), A772G (rs35817838), and C180T (rs6886922). (c) Population prevalences of SLC23A1 polymorphisms. Shown are averaged minor allelic frequencies of SLC23A1 genotypes in African (n = 48), American African (n = 438), and white (n = 1,874) individuals, using pooled genotype data. (d) Modeled effects of SLC23A1 polymorphisms on plasma ascorbate concentrations in humans. Values in healthy young women for common type SLC23A1 are measured and calculated fasting steady-state plasma ascorbate concentrations. For women with SNPs, values are calculated from wild-type data comparisons to transport data in panel b. Reprinted with permission of the American Society for Clinical Investigations, from Corpe C.P., Tu H., Eck P., Wang J., Faulhaber-Walter R., Schnermann J., Margolis S., Padayatty S., Sun H., Wang Y., Nussbaum R.L., Espey, M.G., and Levine, M. Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. April 1:120(4). Copyright 2010 (17).

Figure 4

Haptoglobin phenotypes. Haptoglobin is translated as a single polypeptide chain that undergoes posttranslational processing and cleavage to form a light chain (α subunit) and a heavy chain (β subunit). The α subunit of haptoglobin also binds to other α chains through disulfide bridges (55). The haptoglobin protein encoded by HP¹ has a cysteine residue in the α chain that binds a cysteine residue in an adjacent α chain. The α chain encoded by the HP² variant allele has an additional cysteine residue and hence binds two other α chain cysteine residues. The resulting phenotypes are a combination of those two α chains forming a tetrameric protein (Hp1-1), or different sizes of linear (Hp2-1) or cyclic (Hp2-2) haptoglobin polymers.