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Population distribution of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C risk alleles for methotrexate toxicity in Israel

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Abstract

Methylenetetrahydrofolate reductase (MTHFR) is a central regulatory enzyme in the folate pathway. Two non-synonymous single nucleotide polymorphisms in MTHFR, C677T (rs1801133) and A1298C (rs1801131) have been associated with reduced MTHFR enzyme activity. These polymorphisms, especially C677T, appear to be linked with methotrexate-related toxicity, particularly hepatotoxicity; thus, pretreatment identification of individuals carrying these polymorphisms may be of clinical relevance. The purpose of this study was to determine the frequency and distribution of MTHFR polymorphic variants, known to functionally impair MTHFR activity, in the highly heterogeneous Israeli population. MTHFR genotyping was carried out in the representatives of three major demographic groups in Israel by PCR–restriction fragment length polymorphism and high-resolution melting. The relative distribution of variant alleles 677T and 1298C was found to be similar in individuals of Jewish, Druze and Arab Moslem descent (p = 0.09). However, Ashkenazi Jews displayed a 1.9-fold higher frequency of variant 677T and a 1.8-fold lower frequency of variant 1298C compared to non-Ashkenazi Jews (p < 0.001). Distinct differences in the relative frequencies of both polymorphisms were also found between Ashkenazi Jews and Druze (p < 0.01 for C677T, p < 0.01 for A1298C) or Ashkenazi Jews and Arab Moslem (p < 0.01 for C677T, p < 0.05 for A1298C). These data underscore the importance of geographic genetic analysis for a better understanding of human pharmacotherapy and personalized medicine.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Center for Translational Genetics, B. Rappaport Institute for Research in the Medical Sciences, Faculty of Medicine, Technion-Israel Institute of Technology and Rambam Health Care Campus, Haifa, Israel

    Edna Efrati, Hela Elkin & Sagi Nahum

  2. Clinical Pharmacology Institute, Rambam Health Care Campus and Faculty of Medicine, Technion, Haifa, Israel

    Edna Efrati & Norberto Krivoy

  3. B. Rappaport Faculty of Medicine, Haifa, Israel

    Norberto Krivoy

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  1. Edna Efrati
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  2. Hela Elkin
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  4. Norberto Krivoy
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Correspondence to Norberto Krivoy.

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Efrati, E., Elkin, H., Nahum, S. et al. Population distribution of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C risk alleles for methotrexate toxicity in Israel. Rheumatol Int 33, 1001–1004 (2013). https://doi.org/10.1007/s00296-012-2494-1

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  • DOI: https://doi.org/10.1007/s00296-012-2494-1

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