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Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide
  1. B Wilcken1,
  2. F Bamforth2,
  3. Z Li3,
  4. H Zhu3,
  5. A Ritvanen4,
  6. M Redlund5,
  7. C Stoll6,
  8. Y Alembik6,
  9. B Dott6,
  10. A E Czeizel7,
  11. Z Gelman-Kohan8,
  12. G Scarano9,
  13. S Bianca10,
  14. G Ettore10,
  15. R Tenconi11,
  16. S Bellato12,
  17. I Scala13,
  18. O M Mutchinick14,
  19. M A López14,
  20. H de Walle15,
  21. R Hofstra15,
  22. L Joutchenko16,
  23. L Kavteladze16,
  24. E Bermejo17,
  25. M L Martínez-Frías18,
  26. M Gallagher19,*,
  27. J D Erickson20,*,
  28. S E Vollset21,*,
  29. P Mastroiacovo22,*,
  30. G Andria13,*,
  31. L D Botto20,*
  1. 1Children’s Hospital at Westmead, Sydney, Australia
  2. 2University of Alberta, Edmonton, Canada
  3. 3National Centre for Maternal and Infant Health, Peking University, Beijing, China
  4. 4The National Research and Development Centre for Welfare and Health, STAKES, Finland
  5. 5Department of Paediatrics, Helsinki University Central Hospital, Finland
  6. 6University of Strasbourg, Strasbourg, France
  7. 7Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary
  8. 8Kaplan Medical Centre, Rehovot, Israel
  9. 9Division of Medical Genetics, AO “G Rummo”, Benevento, and Birth Defects Registry of Campania, Italy
  10. 10Sicily Congenital Malformation Registry, Sicily, Italy
  11. 11Department of Paediatrics, University of Padova, Veneto, Italy
  12. 12Paediatrics Unit, Arzignano Hospital, Vicenza, Veneto, Italy
  13. 13University Federico II, Naples, Italy
  14. 14Departamento de Genética, RYVEMCE, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, DF
  15. 15University of Groningen, The Netherlands
  16. 16Moscow Birth Defects Registry, Moscow, Russia
  17. 17ECEMC and Instituto de Salud Carlos III, Madrid, Spain
  18. 18ECEMC, Instituto de Salud Carlos III, and Universidad Complutense, Madrid, Spain
  19. 19National Center on Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
  20. 20National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
  21. 21University of Bergen, Bergen, Norway
  22. 22International Centre on Birth Defects, Rome, Italy
  1. Correspondence to:
 Dr L D Botto, National Center on Birth Defects and Developmental Disabilities, Mailstop F-45, Centers for Disease Control and Prevention, 4770 Buford Highway NE, Atlanta, GA 30341, USA; 

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Since its biochemical characterisation in 19911 and its genetic identification in 1995,2 677C>T allele (T allele) of the 5,10 methylenetetrahydrofolate reductase (MTHFR) gene has been a focus of increasing interest from researchers world wide. The expanding spectrum of common conditions linked with the 677C>T allele now includes certain adverse birth outcomes (including birth defects), pregnancy complications, cancers, adult cardiovascular diseases, and psychiatric disorders.3–8 Although several of these associations remain unconfirmed or controversial,4 their scope is such that it becomes of interest to explore the geographical and ethnic distribution of the allele and associated genotypes.9 Accurate information on such distribution can contribute to studies of gene-disease associations (by providing reference population data) and population genetics (by highlighting geographical and ethnic variations suggestive of evolutionary pressures),10 as well as help to evaluate health impact (by allowing estimates of population attributable fraction).

Current population data, however, show gaps and even for some ethnic groups or large geographical areas (for example, China) few data are available.3 Our aim was to supplement the available data by collecting a large and diverse sample of newborns from different geographical areas and ethnic groups, and to examine international variations in the distribution of the 677C>T allele. We present findings relating to more than 7000 newborns from 16 areas around the world.


The study was conducted under the auspices of the International Clearinghouse for Birth Defect Monitoring Systems (ICBDMS) and was coordinated through its head office, the International Center on Birth Defects (ICBD).

Sample selection

Participating programmes, in consultation with the coordinating group, identified a population sampling approach that would be simple yet minimise sampling bias with respect to the MTHFR genotype. We made an explicit attempt to sample systematically the newborn population. Details of each programme’s approach are listed below, and further …

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  • Authors are listed by alphabetical order of country with coordinating group and corresponding author last.

  • * Coordinating group.

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