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

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250 Applying Pharmacogenomics in TherapeuticsVitamin E is transported by triglycerides (TG)-rich lipoprotein in vivo.Apolipoprotein A5 (APOA5) gene polymorphism can significantly affect the occurrenceof hypertriglyceridemia; therefore, the transport of vitamin E in vivo can beregulated by APOA5. In 169 patients with type 2 diabetes, researchers found that thevitamin E levels in patients with APOA5-1131T/C genotype was about 13% higherthan that in the normal population, and the T/C genotype probability in the populationwith higher vitamin E level was about 2.6 times of the probability in the normalpopulation. 12Plasminogen activator inhibitor type 1 (PAI-1) is an independent risk factor forcardiovascular diseases. Its expression is increased in type 2 diabetic patients. PAI-1gene 4G/5G polymorphism can regulate the expression of PAI-1 protein, thus affectingcardiovascular diseases. Vitamin E can effectively lower PAI-1 levels. Testa et al.gave 500 IU of vitamin E per day to 93 type 2 diabetic patients for 10 consecutiveweeks and then detected the 4G/5G polymorphism and PAI-1 level. They found thatthe PAI-1 levels started to drop in the 10th week in 4G/5G and 4G/4G patients whilethe levels started to drop in the 5th week in 5G/5G patients and 4G/5G patients(p < 0.01). The results have shown that the 4G alleles of PAI-1 affects the pharmacologicalfunction of vitamin E. Vitamin E has a faster onset in patients with 5G/5Ggenotype, indicating that vitamin E may have a better effect on cardiovascular diseaseprevention in these patients. 13Vitamin KVitamin K is vital for blood coagulation and bone growth. Its key features include thefollowing: (1) Blood clotting: It is a blood coagulation factor of gamma-carboxylasecofactor. Synthesis of coagulation factors VII, IX, and X is also dependent on vitaminK. (2) Bone metabolism: It is involved in the synthesis of vitamin K– dependentprotein, which can regulate the synthesis of calcium phosphate in the bone. Plasmavitamin K levels and bone density of elderly people are positively correlated.Outcomes of treatment of excessive anticoagulation using vitamin K in clinicalpractice also show significant differences among individuals. Vitamin K epoxidereductase complex subunit 1 (VKORC1) may be used to partially explain thisphenomenon. In excessive anticoagulation patients (international normalized ratio[INR] ≥ 4), 2.5–5 mg vitamin K was given to the patients based on their INRvalues. The INR value was rechecked at 3, 6, 24, and 72 hours after the treatment.Researchers noticed that patients with VKORC1-1639G/A mutation had significantlylower INR 3 hours after taking vitamin K, compared with carriers ofthe A/A genotype (p < 0.001). These results have shown that VKORC1-1639G>Agene polymorphism is significantly associated with an acute procoagulant effectof vitamin K. 14Folic AcidFolic acid, as an important carbon carrier, plays a critical role in the nucleotidesynthesis, re-methylation of homocysteine, and other important physiological functions,especially in the rapid cell division and growth processes (such as infant development
Pharmacogenomics and Alternative Medicine251and pregnancy). Folic acid can promote immature cells in the bone marrow to formmorphologically normal red blood cells, thus avoiding anemia.Meta-analysis has shown that the 677T/T genotype in the gene MTHFR encodingmethylenetetrahydrofolate reductase (MTHFR) was associated with 14–21% higherrisk of developing cardiovascular diseases compared with carriage of 677 C allele. 15Maria et al. have found that folic acid interacts with MTHFR 677C/T polymorphism,affecting the incidence of colorectal cancer (p = 0.037): if folic acid level is low andwith MTHFR 677T/T genotype, patients would be at higher risk for colorectal cancer(OR = 2.4), indicating that the body’s folic acid levels are more important for patientswith the MTHFR 677T/T genotype. 16Reduced folate carrier (RFC-1, encoded by the gene SLC19A1) is a folic acidtransporter in vivo, and it is involved in folic acid transport across the placenta,blood–brain barrier, renal, and other physiological processes. Folic acid deficiencycan cause intracellular DNA methylation abnormalities, ultimately leading to congenitaldiseases, cancer, cardiovascular diseases, and neuropsychiatric diseases.RFC-1 gene 80A/G polymorphism and increased plasma homocysteine levels areassociated with decreased folic acid levels, likely causing congenital disorders.A meta-analysis involving 930 mothers of Down syndrome (DS) children and 1240mothers of normal controls has shown that RFC-1 gene 80G/G genotype has a 1.27-fold higher risk of DS. The single G allele is associated with a 1.14-fold increasedrisk of DS. 17 This result shows that RFC-1 gene polymorphism can affect the neuralsystem development of the fetus by regulating the transportation of folic acidin vivo.MINERALS AND TRACE ELEMENTSMinerals are a general name for a variety of elements that constitute human tissuesand maintain normal physiological functions. Minerals are also essential nutrientsfor the human body. Carbon, oxygen, hydrogen, nitrogen, and other elements aremainly in the form of organics, and the remaining 60 elements are often referred toas minerals (inorganics) in the human body.Calcium, magnesium, potassium, sodium, phosphorus, sulfur, and chlorineaccount for approximately 60–80% of total minerals in the body. Therefore, theseseven elements are called macroelements. Iron, copper, iodine, zinc, selenium, manganese,molybdenum, cobalt, chromium, tin, vanadium, silicon, nickel, and fluorineaccount for less than 0.005% of total minerals in the body; therefore, these 14 elementsare called microelements or trace elements. Although minerals cannot provideenergy, they play an important role in human physiology. Human bodies areunable to synthesize these minerals and must get them from the outside environment.Minerals are the staples that make up the organs and tissues. For example, calcium,phosphorus, and magnesium are the main ingredients of bones and teeth. Mineralsare also necessary for normal osmotic pressure and acid–base balance of the body.Synthesis of some specific biological molecules, such as hemoglobin and thyroidhormone, requires iodine. The interactions between human gene polymorphism andminerals/trace elements may affect the normal physiological functions of the humanbody and the occurrence of diseases.
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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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