Human immunodeficiency virus-related polyneuropathy remains a painful condition resulting from damaged nerve endings. HIV infection strongly associates with a predominantly polyneuropathy that is attributed to HIV infection itself, or a toxic neuropathy associated with combination antiretroviral therapy (CART). In non-HIV-infected individuals, both deficiency and high intake of vitamins have been associated with polyneuropathy. For that reason, clinicians recommend vitamin supplements before and during CART. Although some, but not all, HIV-related vitamin deficiencies may replete during treatment with CART, it is predictable that high vitamin supplement intakes may contribute to nerve disorders. In resource-limited settings where the diagnosis of polyneuropathy heavily relies on symptoms, data on risk factors for polyneuropathy including vitamin status, alcohol consumption, and co-infections are limited. In addition, studies on genetic influence on the concentration of micronutrients in the blood of long-term users of CART are scarce. Possible sources of high intakes of vitamins could arise from the fact that a number of HIV-infected persons self-medicate. In addition, since HIV-infected individuals have an increased lifespan, relying on symptoms alone to specifically diagnose HIV-associated neuropathies could be a barrier to effective treatment in recourse-poor settings. This paper reviews evidence on single nucleotide polymorphisms (SNPs) with the potential to influence bioavailability of vitamins in HIV-infected patients. Genome-wide association studies have reported SNPs in alkaline phosphatase, fucosyltransferase 2, cubilin, transcobalamin 1, and tumor necrosis factor as potential determinants of various blood levels of vitamin B-6, B-12 and E. As long term CART increasingly become, personalized, future research should focus on SNPs, which influence vitamin blood levels, and with potential to augment long-term treatment with CART.
KeywordsHuman Immunodeficiency VirusCombination Antiretroviral TherapySingle Nucleotide Polymorphisms and Polyneuropathy
Kupka, R., Msamanga, G.I., Spiegelman, D., et al. (2004) Selenium Status Is Associated with Accelerated HIV Disease Progression among HIV-1-Infected Pregnant Women in Tanzania. Journal of Nutrition, 134, 2556-2560.
Lawn, S.D., Harries, A.D., Anglaret, X., Myer, L. and Wood, R. (2008) Early Mortality among Adults Accessing Antiretroviral Treatment Programmes in Sub-Saharan Africa. AIDS, 22, 1897-1908. https://doi.org/10.1097/QAD.0b013e32830007cd
May, M., Boulle, A., Phiri, S., et al. (2010) Prognosis of Patients with HIV-1 Infection Starting Antiretroviral Therapy in Sub-Saharan Africa: A Collaborative Analysis of Scale-Up Programmes. Lancet, 376, 449-457. https://doi.org/10.1016/S0140-6736(10)60666-6
Zachariah, R., Harries, K., Moses, M., et al. (2009) Very Early Mortality in Patients Starting Antiretroviral Treatment at Primary Health Centres in Rural Malawi. Tropical Medicine & International Health, 14, 713-721. https://doi.org/10.1111/j.1365-3156.2009.02291.x
Tagliati, M., Grinnell, J., Godbold, J. and Simpson, D.M. (1999) Peripheral Nerve Function in HIV Infection: Clinical, Electrophysi-Ologic, and Laboratory Findings. Archives of Neurology, 56, 84-89. https://doi.org/10.1001/archneur.56.1.84
Van der Watt, J.J. (2013) HIV-Associated Sensory Neuropathy in an African Cohort; a Longitudinal Study of Risk Factors Predisposing to Antiretroviral Induced Painful Neuropathy. Ph.D. Thesis, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa.
Boulle, A., Orrel, C., Kaplan, R., et al. (2007) Substitutions Due to Antiretroviral Toxicity or Contraindication in the First 3 Years of Antiretroviral Therapy in a Large South African Cohort. Antiviral Therapy, 12, 753-760.
Ellis, R.J., Rosario, D., Clifford, D.B., et al. (2010) Continued High Prevalence and Adverse Clinical Impact of Human Immuno-Deficiency Virus-Associated Sensory Neuropathy in the Era of Combination Antiretroviral Therapy: The Chapter Study. Archives of Neurology, 67, 552-558. https://doi.org/10.1001/archneurol.2010.76
Moyle, G.J. and Sadler, M. (1998) Polyneuropathy with Nucleoside Antiretroviral: Risk Factors, Incidence and Management. Drug Safety, 19, 481-494. https://doi.org/10.2165/00002018-199819060-00005
Barohn, R.J., Gronseth, G.S., Leforce, B.R., et al. (1993) Peripheral Nervous System Involvement in a Large Cohort of Human Immunodeficiency Virus-Infected Individuals. Archives of Neurology, 50, 167-171. https://doi.org/10.1001/archneur.1993.00540020045016
So, Y.T., Holtzman, D.M., Abrams, D.I. and Olney, R.K. (1988) Peripheral Neuropathy Associated with Acquired Immunodeficiency Syndrome. Prevalence and Clinical Features from a Population-Based Survey. Archives of Neurology, 45, 945-994. https://doi.org/10.1001/archneur.1988.00520330023005
Mehta, S.A., Ahmed, A., Laverty, M., Holzman, R.S., Valentine, F. and Sivapalasingam, S. (2011) Sex Differences in the Incidence of Peripheral Neuropathy among Kenyans Initiating Antiretroviral Therapy. Clinical Infectious Diseases, 53, 490-496. https://doi.org/10.1093/cid/cir432
Mullin, S., Temu, A., Kalluvya, S., Grant, A. and Manji, H. (2011) High Prevalence of Distal Sensory Polyneuropathy in Antiretroviral-Treated and Untreated People with HIV in Tanzania. Tropical Medicine & International Health, 16, 1291-1296. https://doi.org/10.1111/j.1365-3156.2011.02825.x
Shurie, J.S. and Deribew, A. (2010) Assessment of the Prevalence of Distal Symmetrical Polyneuropathy and Its Risk Factors among HAART-Treated and Untreated HIV Infected Individuals. Ethiopian Medical Journal, 48, 85-93.
Bygrave, H., Ford, N., Van Cutsem, G., et al. (2011) Implementing a Tenofovir-Based First-Line Regimen in Rural Lesotho: Clinical Outcomes and Toxicities after Two Years. Journal of Acquired Immune Deficiency Syndromes, 56, e75-e78. https://doi.org/10.1097/QAI.0b013e3182097505
Hung, C.F., Gibson, S.A., Letendre, S.L., et al. (2008) Impact of Long-Term Treatment with Neurotoxic Dideoxynucleoside Antiretrovirals: Implications for Clinical Care In Resource-Limited Settings. HIV Medicine, 9, 731-737. https://doi.org/10.1111/j.1468-1293.2008.00615.x
Pasupthi, P., Ramachandran, T., Sindhu, P.J., Saravanan, G. and Bakthavathsalam, G. (2009) Enhanced Oxidative Stress Markers and Antioxidant Imbalance in HIV Infection and AIDS Patients. Journal of Scientific Research, 1, 370-380. https://doi.org/10.3329/jsr.v1i2.2295
Coaccioli, S., Grapa, G., Fantera, M., et al. (2010) Oxidant/Antioxidant Status in Patients with Chronic HIV Infection. Clinical Therapeutics, 161, 55-58.
Awodele, O., Olayemi, S.O., Nwite, J.A. and Adeyemo, T.A. (2012) Investigation of the Levels of Oxidative Stress Parameters in HIV and HIV-TB Co-Infected Patients. Journal of Infection in Developing Countries, 6, 79-85. https://doi.org/10.3855/jidc.1906
Gil del Valle, L., Hernández, R.G. and Avila, J.P. (2013) Oxidative Stress Associated to Disease Progression and Toxicity during Antiretroviral Therapy in Human Immunodeficiency Virus Infection. Journal of Virology and Microbiology, 1-15. https://doi.org/10.5171/2013.279685
Winter, H. (1996) Gastrointestinal Tract Function and Malnutrition in HIV-Infected Children. Journal of Nutrition, 126, 2620S-2622S.
Shevitz, A.H. and Knox, T.A. (2001) Nutrition in the Era of Highly Active Antiretroviral Therapy. Clinical Infectious Diseases, 32, 1769-1775. https://doi.org/10.1086/320761
Miller, T.L. (2003) Nutritional Aspects of HIV-Infected Children Receiving Highly Active Antiretroviral Therapy. AIDS, 17, S130-S140.
Van Lettow, M., Fawzi, W.W. and Semba, R.D. (2003) Triple Trouble: The Role of Malnutrition in Tuberculosis and Human Immunodeficiency Virus Co-Infection. Nutrition Reviews, 61, 81-90. https://doi.org/10.1301/nr.2003.marr.81-90
Kumar, N. (2007) Nutritional Neuropathies. Neurologic Clinics, 25, 209-255. https://doi.org/10.1016/j.ncl.2006.11.001
Tang, A.M., Graham, N.M., Semba, R.D., et al. (1997) Association between Serum Vitamin A and E Levels and HIV-1 Disease Progression. AIDS, 11, 613-620. https://doi.org/10.1097/00002030-199705000-00009
Kanter, A.S., Spencer, D.C., Steinberg, M.H., et al. (1999) Supplemental Vitamin B and Progression to AIDS and Death in Black South African Patients Infected with HIV. Journal of Acquired Immune Deficiency Syndromes, 21, 252-253. https://doi.org/10.1097/00126334-199907010-00011
Faintuch, J., Soeters, P.B. and Osmo, H.G. (2006) Nutritional and Metabolic Abnormalities in Pre-AIDS HIV Infection. Nutrition, 22, 683-690. https://doi.org/10.1016/j.nut.2006.03.011
WHO (2003) Nutrient Requirements for People Living with HIV/AIDS. Report of a Technical Consultation, WHO, Geneva.
Isanaka, S., Mugusi, F. and Hawkins, C. (2012) Effect of High-Dose vs Standard-Dose Multivitamin Supplementation at the Initiation of HAART on HIV Disease Progression and Mortality in Tanzania: A Randomized Controlled Trial. JAMA, 308, 1535-1544. https://doi.org/10.1001/jama.2012.13083
Ames, B.N. (2004) Delaying the Mitochondrial Decay of Aging. Annals of the New York Academy of Sciences, 1019, 406-411. https://doi.org/10.1196/annals.1297.073
Arendt, B.M., Aghdassi, E., Mohammed, S.S., et al. (2008) Dietary Intake and Physical Activity in a Canadian Population Sample of Male Patients with HIV Infection and Metabolic Abnormalities. Current HIV Research, 6, 82-90. https://doi.org/10.2174/157016208783571973
Depeint, F., Bruce, W.R., Shangari, N., Mehta, R. and O’Brien, P.J. (2006) Mitochondrial Function and Toxicity: Role of the B Vitamin Family on Mitochondrial Energy Metabolism. Chemico-Biological Interactions, 163, 94-112. https://doi.org/10.1016/j.cbi.2006.04.014
Thompson, J. (2007) Vitamins, Minerals and Supplements. 7: Minerals. Community Practitioner, 80, 38-40.
Dreyfuss, M.L. and Fawzi, W.W. (2002) Micronutrients and Vertical Transmission of HIV-1. The American Journal of Clinical Nutrition, 75, 959-970.
Drain, P.K., Kupka, R., Mugusi, F. and Fawzi, W.W. (2007) Micronutrients in HIV-Positive Persons Receiving Highly Active Antiretroviral Therapy. The American Journal of Clinical Nutrition, 85, 333-345.
Singhal, N. and Austin, J.A. (2002) A Clinical Review of Micronutrients in HIV Infection. Journal of the International Association of Physicians in AIDS Care, 1, 63-75. https://doi.org/10.1177/154510970200100205
Higdon, J. (2000) Thiamin. Micronutrient Information Center, Oregon State University, USA. http://lpi.oregonstate.edu/infocenter/minerals
Butterworth, R.F. (2006) Thiamin. In: Shils, M.E., Shike, M., Ross, A.C., Caballero, B. and Cousins, R.J., Eds., Modern Nutrition in Health and Disease, 10th Edition, Lippincott Williams & Wilkins, Baltimore.
Spinazzi, M., Angelini, C. and Patrini, C. (2010) Subacute Sensory Ataxia and Optic Neuropathy with Thiamine Deficiency. Nature Reviews Neuroscience, 6, 288-293. https://doi.org/10.1038/nrneurol.2010.16
Hammond, N., Wang, Y., Dimachkie, M. and Barohn, R. (2013) Nutritional Neuropathies. Neurologic Clinics, 31, 477-489. https://doi.org/10.1016/j.ncl.2013.02.002
Renwick, A.G. (2006) Toxicology of Micronutrients: Adverse Effects and Uncertainty. Journal of Nutrition, 136, 493S-501S.
Lyn Patrick, N.D. (2000) Nutrients and HIV: Part 2—Vitamins A and E, Zinc, B-Vitamins, and Magnesium. Alternative Medicine Review, 5, 39-51.
Aggarwal, B.B., Sundaram, C., Prasad, S. and Kannappan, R. (2010) Tocotrienols, the Vitamin E of the 21st Century: Its Potential against Cancer and Other Chronic Diseases. Biochemical Pharmacology, 80, 1613-1631. https://doi.org/10.1016/j.bcp.2010.07.043
Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and Interpretation and Uses of DRIs, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, et al. (2000) Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Institute of Medicine, The National Academies Press.
Meydani, S., Wu, D., Santos, M. and Hayek, M. (1995) Antioxidants and Immune Response in the Aged: Overview of Present Evidence. The American Journal of Clinical Nutrition, 62, 1462S-1476S.
USAID (2000) HIV/AIDS and Nutrition. A Review of the Literature and Recommendations for Nutritional Care and Support in Sub-Saharan Africa.
Tanphaichitr, V. (1999) Thiamin. In: Shils, M.E., Olsen, J.A. and Shike, M., et al., Eds., Modern Nutrition in Health and Disease, 9th Edition, Lippincott Williams & Wilkins, Baltimore.
So, Y.T.S. and Roger, P. (2008) Deficiency Diseases of the Nervous System. In: Bradley, W.B., Daroff, R.B., Fenichel, G.M. and Jankovic, J., Eds., Neurology in Clinical Practice, Butterworth-Heinemann, Oxford, 1643-1656.
Gdynia, H.J., Muueller, T., Sperfeld, A.D., et al. (2008) Severe Sensorimotor Neuropathy after Intake of Highest Dosages of Vitamin B6. Neuromuscular Disorders, 18, 156-158.
Simpson, J.L., Bailey, L.B., Pietrzik, K., Shane, B. and Holzgreve, W. (2010) Micronutrients and Women of Reproductive Potential: Required Dietary Intake and Consequences of Dietary Deficiency or Excess. Part I—Folate, Vitamin B12, Vitamin B6. The Journal of Maternal-Fetal & Neonatal Medicine, 23, 1323-1343. https://doi.org/10.3109/14767051003678234
Leishear, K., Boudreau, R.M., Studenski, S.A., et al. (2012) Relationship between Vitamin B12 and Sensory and Motor Peripheral Nerve Function in Older Adults. Journal of the American Geriatrics Society, 60, 1057-1063. https://doi.org/10.1111/j.1532-5415.2012.03998.x
Vitamin, E. (2009) Review of Natural Products. Facts & Comparisons 4.0. Wolters Kluwer Health, Inc., St. Louis, MO.
Visser, M.E., Maartens, G., Kossew, G. and Hussey, G.D. (2003) Plasma Vitamin and Zinc Concentrations in HIV-Infected Adults in Cape Town, South Africa. British Journal of Nutrition, 89, 475-482. https://doi.org/10.1079/BJN2002806
Beisel, W.R. (1996) Nutrition in Paediatric HIV Infection: Setting the Research Agenda. Nutrition and Immune Function: Overview. Journal of Nutrition, 126, 2611S-2615S.
The Italian Paediatric Intestinal/HIV Study Group (1993) Intestinal Malabsorption of HIV-Infected Children: Relationship to Diarrhoea, Failure to Thrive, Enteric Micro-Organisms and Immune Impairment. The Italian Paediatric Intestinal/HIV Study Group. AIDS, 7, 1435-1440. https://doi.org/10.1097/00002030-199311000-00005
Semba, R.D. and Tang, A.M. (1999) Micronutrients and the Pathogenesis of Human Immunodeficiency Virus Infection. British Journal of Nutrition, 81, 181-189. https://doi.org/10.1017/S0007114599000379
Henderson, R.A., Talusan, K., Hutton, N., Yolken, R.H. and Caballero, B. (1999) Whole Body Protein Turnover in Children with Human Immunodeficiency Virus (HIV) Infection. Nutrition, 15, 189-194. https://doi.org/10.1016/S0899-9007(98)00178-6
Campa, A., Shor-Posner, G., Indacochea, F., et al. (1999) Mortality Risk in Selenium-Deficient HIV-Positive Children. Journal of Acquired Immune Deficiency Syndromes, 20, 508-513.
Srinivas, A. and Dias, B.F. (2008) Antioxidants in HIV Positive Children. Indian Journal of Pediatrics, 75, 347-350. https://doi.org/10.1007/s12098-008-0036-3
Semba, R.D., Shah, N., Strathdee, S.A. and Vlahov, D. (2002) High Prevalence of Iron Deficiency and Anaemia among Female Injection Drug Users with and without HIV Infection. Journal of Acquired Immune Deficiency Syndromes, 29, 142-144.
Cos, P., Maes, L., Berghe, D.V., Hermans, N., Pieters, L. and Vlietinck, A. (2004) Plant Substances as Anti-HIV Agents Selected According to Their Putative Mechanism of Action. Journal of Natural Products, 167, 284-293. https://doi.org/10.1021/np034016p
Anabwani, G. and Navario, P. (2005) Nutrition and HIV/AIDS in Sub-Saharan Africa: An Overview. Nutrition, 21, 96-99. https://doi.org/10.1016/j.nut.2004.09.013
Safadi, Y.E., Vivet-Boudou, V. and Marquet, R. (2007) HIV-1 Reverse Transcriptase Inhibitors. Applied Microbiology and Biotechnology, 75, 723-737. https://doi.org/10.1007/s00253-007-0919-7
Cote, H.C., Brumme, Z.L., Craib, K.J., et al. (2002) Changes in Mitochondrial DNA as a Marker of Nucleoside Toxicity in HIV Patients. The New England Journal of Medicine, 346, 811-820. https://doi.org/10.1056/NEJMoa012035
Drain, P.K., Kupka, R., Mugusi, F. and Fawzi, W.W. (2007) Micronutrients in HIV-Positive Persons Receiving Highly Active Antiretroviral Therapy. The American Journal of Clinical Nutrition, 85, 333-345.
De Clercq, E. (2009) The History of Antiretrovirals: Key Discoveries over the Past 25 Years. Reviews in Medical Virology, 19, 287-299. https://doi.org/10.1002/rmv.624
Schramm, C., Wanitschke, R. and Galle, P.R. (1999) Thiamine for the Treatment of Nucleoside Analogue-Induced Severe Lactic Acidosis. European Journal of Anaesthesiology, 16, 733-735. https://doi.org/10.1046/j.1365-2346.1999.00586.x
Fouty, B., Frerman, F. and Reves, R. (1998) Riboflavin to Treat Nucleoside Analogue Induced Lactic Acidosis. The Lancet, 352, 291-292. https://doi.org/10.1016/S0140-6736(05)60266-8
Gavrila, A., Sotirios, T., Doweiko, J., et al. (2003) Exercise and Vitamin E Intake Are Independently Associated with Metabolic Abnormalities in Human Immunodeficiency Virus-Positive Subjects: A Cross-Sectional Study. Clinical Infectious Diseases, 36, 1593-1601. https://doi.org/10.1086/375225
Villamor, E., Mugusi, F., Urassa, W., et al. (2008) A Trial of the Effect of Micronutrient Supplementation on Treatment Outcome, T Cell Counts, Morbidity, and Mortality in Adults with Pulmonary Tuberculosis. The Journal of Infectious Diseases, 197, 1499-1505. https://doi.org/10.1086/587846
Lehmann, H.C., Chen, W., Borzan, J., Mankowski, J.L. and Hoke, A. (2011) Mitochondrial Dysfunction in Distal Axons Contributes to Human Immunodeficiency Virus Sensory Neuropathy. Annals of Neurology, 69, 100-110. https://doi.org/10.1002/ana.22150
Hulgan, T., Haas, D.W., Haines, J.L., et al. (2005) Mitochondrial Haplogroups and Peripheral Neuropathy during Antiretroviral Therapy: An Adult AIDS Clinical Trials Group Study. AIDS, 19, 1341-1349. https://doi.org/10.1097/01.aids.0000180786.02930.a1
Canter, J.A., Robbins, G.K. and Selph, D. (2010) African Mitochondrial DNA Subhaplogroups and Peripheral Neuropathy during Antiretroviral Therapy. The Journal of Infectious Diseases, 201, 1703-1707. https://doi.org/10.1086/652419
Tanaka, T., Scheet, P., Giusti, B., et al. (2009) Genome-Wide Association Study of Vitamin B6, Vitamin B12, Folate, and Homo-Cysteine Blood Concentrations. The American Journal of Human Genetics, 84, 477-482. https://doi.org/10.1016/j.ajhg.2009.02.011
Frosst, P., Blom, H.J., Milos, R., et al. (1995) A Candidate Genetic Risk Factor for Vascular Disease: A Common Mutation in Methylenetetrahydrofolate Reductase. Nature Genetics, 10, 111-113. https://doi.org/10.1038/ng0595-111
Klerk, M., Verhoef, P., Clarke, R., Blom, H.J., Kok, F.J. and Schouten, E.G. (2002) MTHFR 677C→T Polymorphism and Risk of Coronary Heart Disease: A Meta-Analysis. JAMA, 288, 2023-2031. https://doi.org/10.1001/jama.288.16.2023
McCully, K.S. (2007) Homocysteine, Vitamins, and Vascular Disease Prevention. The American Journal of Clinical Nutrition, 86, 1563S-1568S.
Fredriksen, A., Meyer, K., Ueland, P.M., Vollset, S.E., Grotmol, T. and Schneede, J. (2007) Large-Scale Population-Based Metabolic Phenotyping of Thirteen Genetic Polymorphisms Related to One-Carbon Metabolism. Human Mutation, 28, 856-865. https://doi.org/10.1002/humu.20522
Mornet, E. (2000) Hypophosphatasia: The Mutations in the Tissue-Nonspecific Alkaline Phosphatase Gene. Human Mutation, 15, 309-315. https://doi.org/10.1002/(SICI)1098-1004(200004)15:4 3.0.CO;2-C
Yuan, X., Waterworth, D., Perry, J.R., et al. (2008) Population-Based Genome-Wide Association Studies Reveal Six Loci Influencing Plasma Levels of Liver Enzymes. American Journal of Human Genetics, 83, 520-528. https://doi.org/10.1016/j.ajhg.2008.09.012
Kaptan, K., Beyan, C., Ural, A.U., et al. (2000) Helicobacter pylori—Is It a Novel Causative Agent in Vitamin B12 Deficiency? Archives of Internal Medicine, 160, 1349-1353.
Kelly, R.J., Rouquier, S., Giorgi, D., Lennon, G.G. and Lowe, J.B. (1995) Sequence and Expression of a Candidate for the Human Secretor Blood Group α(1,2) Fucosyltransferase Gene (FUT2). Homozygosity for an Enzyme-Inactivating Nonsense Mutation Commonly Correlates with the Non-Secretor Phenotype. Journal of Biological Chemistry, 270, 4640-4649. https://doi.org/10.1074/jbc.270.9.4640
Hazra, A., Kraft, P., Selhub, J., et al. (2008) Common Variants of FUT2 Are Associated with Plasma Vitamin B12 Levels. Nature Genetics, 40, 1160-1162. https://doi.org/10.1038/ng.210
Serpa, J., Mendes, N., Reis, C.A., et al. (2004) Two New FUT2 (Fucosyltransferase 2 Gene) Missense Polymorphisms, 739G→A and 839T→C, Are Partly Responsible for Non-Secretor Status in a Caucasian Population from Northern Portugal. Biochemical Journal, 383, 469-474. https://doi.org/10.1042/BJ20040803
Tanner, S.M., Li, Z., Perko, J.D., et al. (2005) Hereditary Juvenile Cobalamin Deficiency Caused by Mutations in the Intrinsic Factor Gene. Proceedings of the National Academy of Sciences of the United States of America, 102, 4130-4133. https://doi.org/10.1073/pnas.0500517102
Tanner, S.M., Li, Z., Bisson, R., et al. (2004) Genetically Heterogeneous Selective Intestinal Malabsorption of Vitamin B12: Founder Effects, Consanguinity, and High Clinical Awareness Explain Aggregations in Scandinavia and the Middle East. Human Mutation, 23, 327-333. https://doi.org/10.1002/humu.20014
Belisle, S.E., Leka, L.S., Delgado-Lista, J., Jacques, P.F., Ordovas, J.M. and Meydani, S.N. (2009) Polymorphisms at Cytokine Genes May Determine the Effect of Vitamin E on Cytokine Production in the Elderly. Journal of Nutrition, 139, 1855-1860. https://doi.org/10.3945/jn.109.112268
Major, J.M., Yu, K., Chung, C.C., et al. (2012) Genome-Wide Association Study Identifies Three Common Variants Associated with Serologic Response to Vitamin E Supplementation in Men. Journal of Nutrition, 142, 866-871. https://doi.org/10.3945/jn.111.156349