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Increased Resistance to Malaria in Mice with Methylenetetrahydrofolate Reductase ( M thfr ) Deficiency Suggests a Mechanism for Selection of the MTHFR 677 C > T (c.665 C > T ) Variant
Author(s) -
Meadows Danielle N.,
Pyzik Michal,
Wu Qing,
Torre Sabrina,
Gros Philippe,
Vidal Silvia M.,
Rozen Rima
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22533
Subject(s) - methylenetetrahydrofolate reductase , biology , reductase , medicine , immunology , endocrinology , genotype , genetics , enzyme , biochemistry , gene
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 M editerranean regions, where malaria was historically endemic and may have conferred a selective advantage for other mutations. We infected Mthfr ‐deficient ( Mthfr + /− ) and MTHFR overexpressing ( MTHFR Tg ) mice with P lasmodium berghei ANKA to induce cerebral malaria. Mthfr +/− mice survived longer ( P < 0.02, log‐rank test), and MTHFR Tg mice died earlier ( P < 0.05, log‐rank test) after infection compared with wild‐type littermates. Flow cytometry revealed increased lymphocyte populations and increased CCR 4 + NK cells in spleen of Mthfr + /− mice; MTHFR Tg 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.