Vitamin C (VC, L-ascorbic acid) transport is mediated by specific transporters, such as sodium-dependent vitamin C transporter (SVCT) 1 and 2. SVCT1 and 2 have a functional role in secondary active transport of VC from the outside to the inside of cells at the expense of sodium electrochemical gradient across the cell membrane. Recent studies revealed that the effect of SVCTs gene polymorphisms on risk of preterm birth and any diseases. Moreover, some paper reported that the effect of SVCTs gene polymorphisms on VC concentration in human blood and interactions with other antioxidant related genes. In this paper, we review recent insights into the relationships between SVCTs gene polymorphisms and health and disease risk.

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Haptoglobin, which is encoded by Hp gene, is a hemoglobin-binding protein that has antioxidative properties. This protein has a common polymorphism that consists of two different alleles: Hp1 and Hp2. As haptoglobin phenotypes, Hp1-1, Hp2-1 and Hp2-2 exist. The frequencies of these three haptoglobin phenotypes show marked geographical differences in the world. It has been reported that the haptoglobin phenotypes (genotypes) has a significant effect on vitamin C metabolism in Caucasians and Mongoloids. Serum vitamin C concentration was the lowest in Hp2-2 subjects compared with Hp1-1 and Hp2-1. A lower stability of L-ascorbic acid in blood from Hp2-2 subjects was shown by in vitro experiments. From these studies, it is suggested that individuals with Hp2-2 phenotype has an increased risk of vitamin C deficiency.

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There are many gene polymorphisms for glutathione S-transferases (GSTs). The relationship between vitamin C (VC) and gene polymorphisms for GSTs was first explored in 2001 in a study of middle-aged men in Slovakia which found that GSTM1-null genotype was related with increasing circulating VC levels. This was also observed in a more recent study in a US cohort, where individuals with the highest serum VC levels were more likely to be GSTM1-null than to have a functional copy of GSTM1. However, this relationship between blood VC levels and the presence of GSTM1 has not been universally observed. Two studies, one in a Chinese cohort and another with nonsmoking adults in Canada, showed no differences in blood VC status associated with GSTM1 genotype. In a study of factory workers in Slovakia, an overall decline in plasma VC levels was found to be associated with GSTM1-null genotype. Thus, it appears that there are interactions between blood VC levels and gene polymorphisms for GSTs, but overall conclusions are difficult to reach. Therefore, further studies are needed to clarify the relationship between blood VC levels and gene polymorphisms for GSTs.

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Vitamin D binding protein (DBP), which is also known as a group-specific component (GC)-globulin, is a major plasma carrier protein for vitamin D and its metabolites. DBP is also known as an actin scavenger and a precursor of GC protein-derived macrophage activating factor (GC-MAF). This multifunction protein plays a role in the determination of serum 25-hydroxyvitamin D levels and regulation of the immune system. Therefore, genetic variants of DBP may affect risks of various diseases related with vitamin D levels and the immune system. Until now, various protein and genetic polymorphisms of DBP have been identified. Especially, Gc1S, Gc1F and Gc2 are well-known polymorphisms characterized by isoelectrophoresis, which are derived from two missense variants of DBP gene encoding D432E (rs7041) and T436K (rs4588). In this review, we discuss some relationships between DBP genotypes and common disease risk including osteoporosis, cancer and diabetes.

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1,25-Dihydroxyvitamin D_3, an active form of vitamin D_3, which plays a central role in the regulation of calcium and bone homeostasis through vitamin D receptor (VDR). In 1994, Morrison and colleagues first reported that bone mineral density was associated with single nucleotide polymorphisms (SNPs) in the intron 8 of human VDR gene. In 1997, we clarified the whole structure of the human VDR genome and reported the relationship between FokI and Cdx-2 SNPs in the human VDR gene and bone density in Japanese women. Osteoporosis is known as one of multifactorial genetic diseases and its occurrence is associated with not only genetic factors but also environmental factors, lifestyle such as diet and exercise, aging, and abnormal bone mineral metabolism. Therefore, it can be expected that the identification of osteoporosis-related genes including the VDR gene will lead to the development of new methods to treat and to protect against osteoporosis, although there are several statistical problems for data analysis.

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CYP2R1 catalyzes conversion of vitamin D_3 to 25-hydroxyvitamin D_3 (25OHD3), while CYP27B1 catalyzes conversion of 25OHD_3 to 1α, 25-dihydroxyvitamin D_3 (1,25(OH)2D3), the active form of vitamin D_3 On the contrary, CYP24A1 inactivates 1,25(OH)2D3 by multi-step monooxygenation reactions. More than 30 CYP27B1 mutations containing missense and nonsense mutations have been found in vitaminD-dependent rickets type I (VDDR1) patients, while 3 types of CYP2R1 mutation were found in VDDR1 patients. Recently, more than 20 CYP24A1 mutations were found, and a clear relationship was revealed between CYP24A1 mutations and idiopathic infantile hypercalcemia. These findings clearly demonstrate that deficiency of one of the three CYPs could cause hypo- or hypervitaminnosis D, resulting in disruption of calcium homeostasis. Recently, several reports on CYP2R1 and/or CYP27B1 genes polymorphisms and susceptibility to type I diabetes were published. GG genotype of (G>A)(rs10741657) CYP2R1 polymorphism and CC genotype of -1260C>A (rs10877012) CYP27B1 polymorphism increased the risk of type I diabetes. In the immune system, 1,25(OH)2D3 has been shown to suppress Th1-type immune responses. Low levels of 25OHD3 and/or 1,25(OH)2D3 in GG type of CYP2R1 and CC type of CYP27B1 may explain the excessive Th1-type responses to result in an autoimmune disease, type I diabetes.

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