Increased Resistance to Malaria in Mice with Methylenetetrahydrofolate Reductase (Mthfr) Deficiency Suggests a Mechanism for Selection of the MTHFR 677C>T (c.665C>T) Variant |
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| Authors: | Danielle N. Meadows Michal Pyzik Qing Wu Sabrina Torre Philippe Gros Silvia M. Vidal Rima Rozen |
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| Affiliation: | 1. Department of Human Genetics, McGill University, McGill University Health Center, Montreal, Quebec, Canada;2. Complex Traits Group, McGill University, McGill University Health Center, Montreal, Quebec, Canada;3. Department of Pediatrics, McGill University, McGill University Health Center, Montreal, Quebec, Canada;4. Department of Biochemistry, McGill University, Montreal, Quebec, Canada;5. Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada |
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| Abstract: | The polymorphism 677C>T (NM_005957.4:c.665C>T/p.Ala222Val, rs1801133:C>T) in methylenetetrahydrofolate reductase (MTHFR) results in mild enzymatic deficiency and increased risk for several complex traits including adverse reproductive outcomes, birth defects, and heart disease. Despite these deleterious effects, homozygosity is high (5%–15%) in many populations, and among the highest in Mediterranean regions, where malaria was historically endemic and may have conferred a selective advantage for other mutations. We infected Mthfr‐deficient (Mthfr+/?) and MTHFR overexpressing (MTHFRTg) mice with Plasmodium berghei ANKA to induce cerebral malaria. Mthfr+/? mice survived longer (P < 0.02, log‐rank test), and MTHFRTg mice died earlier (P < 0.05, log‐rank test) after infection compared with wild‐type littermates. Flow cytometry revealed increased lymphocyte populations and increased CCR4+ NK cells in spleen of Mthfr+/? mice; MTHFRTg animals had decreased numbers of these NK cells. Interferon‐γ and interleukin‐10 immunoreactive proteins were increased and decreased, respectively, in brain of Mthfr+/? mice compared with wild‐type. We suggest that mild MTHFR deficiency protects against malarial infection and that this phenomenon may have led to the high frequency of the 677C>T/c.665C>T variant in human populations. |
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| Keywords: | MTHFR folate infection cerebral malaria genetic selection |
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