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

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246 Applying Pharmacogenomics in TherapeuticsTABLE 10.2Effects of Genetic Polymorphisms on Aqueous-Soluble VitaminsVitamin Gene PolymorphismsB 12TCN2C776Grs1801198Effects of Genetic Polymorphismson VitaminsG allele: Decreased transcriptionand concentrations of cellular andplasma transcobalamin.DiseasePerniciousanemiaCFolicacidFUT2 rs602662 A allele: Increased vitamin B 12HaptoglobinSerum vitamin C concentrationsHp2-2were associated with haptoglobintype, showing lowest values inserum from Hp2-2 subjects.Vitamin C rs6139591 A higher rate of l-ascorbic acidtransporter rs1776964 oxidation in Hp2-2 carriers.SLC23A1 rs33972313 The rs6139591 TT genotype and alower than median dietary vitamin Cintake had a higher risk of acutecoronary syndrome.Reduction in circulating concentrationsof l-ascorbic acid per minor allele.MTRA2756GMTHFR677C→Trs1805087rs1801133G allele: Increased Hcyconcentration.T/T: Elevated plasma homocysteineconcentrations.Capillaryfragility;gumsbleedingCardiovasculardiseasethe girl experienced sudden loss of consciousness, followed by myoclonus of rightlimbs, lasting for about 30 minutes. Electroencephalogram revealed spikes and slowwaves in the left occipital and left posterior temporal. Paroxysmal limbs tremblingand seizures were presented from the age of 3. Intracranial calcification was notedby CT. At the age of 5, mental regression, lower-extremity weakness, and sleepingproblems were observed. Her plasma folate decreased to 4.49 nmol/L (normalvalue >6.8 nmol/L). Plasma total homocysteine elevated to 28.11 μmol/L (normalvalue <15 μmol/L). Folate and 5-methyltetrahydrofolate in cerebrospinal fluid (CSF)were significantly decreased to an undetectable level.Folinic calcium (15 mg per day, p.o.) was initiated at the age of 5. One week later,she showed hematological normalization. Blood HGB, MCV, folate, and total homocysteinereturned to normal. One month after treatment, intermittent limb tremor andepileptic seizures disappeared. Sleeping difficulties and irritability disappeared oneyear after treatment. Progressive improvement in mental development was observed.However, leg weakness was observed when going up and down stairs. SLC46A1 geneencoding proton-coupled folate transporter (PCFT) was the only gene responsible forhereditary folate malabsorption. On SLC46A1 gene, a novel mutation, c.1A>T (M1L),and a reported mutation c.194-195insG (p.Cys66LeufsX99) were identified, supportedthe diagnosis of hereditary folate malabsorption. Each parent carried one of the twomutations. Folinic calcium supplement resulted in rapid clinical improvement. She iscurrently six years old with normal development and routine blood features. 5,6
Pharmacogenomics and Alternative Medicine247Vitamin B 12Vitamin B 12 is also called cobalamin, existing in the human body mainly in the form ofadenosine cobalamin and methyl-cobalamin, both of which participate in two types ofimportant biochemical reaction processes. As a methyl malonyl coenzyme A mutase,adenosylcobalamin transforms methyl malonyl coenzyme A into succinyl coenzymeA; and as the coenzyme of methionine synthetase, methyl- cobalamin turns the methylationof homocysteine to methionine. Vitamin B 12 in the human body comes mainlyfrom food through microbial biosynthesis in the digestive tract, and then through theabsorption, transportation, and cell uptake by haptocorrin (HC); intrinsic factor (IF);and cobalamin transfer protein II (TCII). Vitamin B 12 is involved in erythrocytes formation,DNA synthesis, and other in vivo critical processes, such as maintenance ofthe nerve sheath. Vitamin B 12 deficiency leads to body immune defects, megaloblasticanemia, coronary heart disease, and gastrointestinal and nervous system diseases.Vitamin B 12 deficiency can also lead to hyperhomocysteinemia, which is an independentrisk factor for cardiovascular diseases, and is also associated with type 2 diabetes,end-stage renal disease, nerviduct defect, and Alzheimer disease.Beef, pork, fish, and chicken are rich in vitamin B 12 . Vegetarians have a higherrisk of vitamin B 12 deficiency compared to nonvegetarians. Atrophic gastritis canalso cause vitamin B 12 malabsorption. In recent years, through the candidate genesand genome-wide association study (GWAS), it has been confirmed that a numberof gene polymorphisms are significantly associated with levels and metabolism ofvitamin B 12 and corresponding diseases.Fucosyltransferase (FUT2) gene polymorphism is related to the plasma level ofvitamin B 12 . The involvement of sites such as rs602662 (G772A) and rs492602 hasbeen confirmed. Notably, rs602662, which has been studied repeatedly by GWAS,is significantly associated with changes in vitamin B 12 plasma levels. In 1146 AsianIndian people, a research (which used a single base extension method for FUT2 genotypingand regression analysis, taking into account age, sex, dietary habits, and associateddiseases such as coronary heart disease, high blood pressure, and diabetes) hasshown that people homozygous for the rs602662-A/A had an average plasma vitaminB 12 level of 175.3 pmol/L, while people with the G/G genotype had a mean vitamin B 12level of 149.5 pmol/L. The reduction ratio is approximately 0.15. For people with theG/A genotype, the level is 152.7 pmol/L. The results showed a characteristic gene–dose effect (p = 4.0 × 10 −5 ). The research also found that in vegetarians, 772G/Ghad a 20% lower vitamin B 12 level in plasma than 772A/A (140.7 vs. 174.2 pmol/L).This research has shown that besides vegetarianism, a significant reduction in plasmavitamin B 12 is also most likely caused by FUT2 gene polymorphism. 3The form of methyl-cobalamin of vitamin B 12 , as a coenzyme of methionine synthase,can transfer the methyl group from 5-methyl-tetrahydrofolate. Vitamin B 12deficiency leads to blockade of re-methylation of homocysteine into methionine andraises the level of homocysteine in blood circulation, probably causing cardiovasculardisease, abnormal pregnancy, and other clinical illness. In the blood, vitaminB 12 mainly binds to haptocorrin and transcobalamin. Haptocorrin binds 80%of the plasma vitamin B 12 and is not involved in cell vitamin uptake, whereas transcobalaminbinds 20% of plasma vitamin B 12 and is critical to the vitamin uptake.
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DedicationWe dedicate this book to
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viiiContentsChapter 10 Pharmacogeno
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EditorsXiaodong Feng, PhD, PharmD,
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ContributorsWeiguo Chen, PhDDepartm
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Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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