Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

248 Applying Pharmacogenomics in Therapeutics
Cobalamin transfer protein–vitamin B 12 complex is recognized by specific receptors
on the cell membrane and transported into the cell, and unbound vitamin B 12 and
haptocorrin–vitamin B 12 complexes cannot be recognized and absorbed. Therefore,
cobalamin transfer protein gene polymorphism may affect the functionality of vitamin
B 12 complex cellular uptake process. The commonly seen mutation in cobalamin
is 776C>G (proline is replaced by arginine). Carriers of the 776G/G variant
account for 20% of the general population; wild-type homozygotes (776C/C) and
mutant 776C/G heterozygotes account for 30% and 50% of the general population,
respectively. Research has found that 776C>G mutation not only affects the affinity
between cobalamin and vitamin B 12 , but also affects the transportation capacity of
the cobalamin–vitamin B 12 complex. Miller and colleagues have found that carriers
of 776G/G variant had significantly lower levels of haptocorrin–vitamin B 12 complex,
lower percentage of binding of total vitamin B12 and cobalamin, and significantly
higher concentrations of plasma methylmalonic acid (MMA) compared with
the C/C genotype. 7 These results have shown that 776C>G gene polymorphism can
change the way the cells take vitamin B 12 , exacerbating the deficiency of vitamin B 12 .
Kristina et al. have found that in 359 young women, 776G/G homozygotes had significantly
lower levels of plasma cobalamin–vitamin B 12 complex, compared with the
wild-type 776C/C individuals (74 vs. 87 pmol/L, p = 0.02). The 776 C>G mutation
affects alterations in the homocysteine levels in the body by changing the plasma
cobalamin–vitamin B 12 complex concentration, thus further affecting the occurrence
of cardiovascular and other diseases. 7
Vitamin C
Vitamin C is a potent antioxidant in the human body, and it is used to relieve ascorbate
peroxidase substrate oxidative stress. Many important biosynthetic processes
also require involvement of vitamin C. For example, through anti-oxidation and
improvement of endothelial function, vitamin C plays an important role in cardioprotection
and collagen synthesis. Vitamin C deficiency leads to the reduction
of the collagen in atherosclerotic plaques, easily leading to plaque rupture, and in
severe cases leading to blood clots and even death. The normal function of sodiumdependent
vitamin C transporters (SVCT, encoded by gene SLC23A2) 1 and 2 help
maintain the homeostasis of vitamin C in vivo. SVCT1 is mainly distributed in the
intestine and kidney, controlling the intake and discharge of vitamin C; SVCT2
is mainly distributed in metabolically highly active tissue, ensuring the intracellular
inverse concentration gradient accumulation of ascorbic acid in the aorta and
other specific tissues. Ascorbic acid is the key factor for artery wall and plaque cap
collagen synthesis, and it reduces endothelial dysfunction and inflammation, protecting
and stabilizing the vascular plaques. Human SVCT2 gene polymorphism is
associated with premature birth and a variety of tumors. The two polymorphic loci
rs6139591 and rs2681116 of SVCT2 are associated with the changes in vitamin C
intake and the concentrations of circulating vitamin C. A case–cohort study of
57,053 subjects with a 6.4-year follow-up has found that women carrying rs6139591
T/T gene absorbed less vitamin C from food, having a 5.39-fold increased risk
of suffering from acute coronary syndrome (ACS), compared with carriers of the