Molecular Biology Reports

, Volume 40, Issue 8, pp 4685–4689 | Cite as

Betaine–homocysteine methyltransferase 742G>A polymorphism and risk of down syndrome offspring in a Brazilian population

  • Márcia R. Amorim
  • Cláudia M. Moura
  • Aline D. Gomes
  • Hazel N. Barboza
  • Roberta B. Lopes
  • Márcia G. Ribeiro
  • Marcelo A. Costa LimaEmail author


Down syndrome (DS) is the most common form of mental retardation of genetic etiology. Several polymorphisms in genes involved with the folic acid cycle have been associated to the risk of bearing a DS child; however, the results are controversial. Betaine-homocysteine methyltransferase (BHMT) is a key enzyme of folate pathway, and catalyzes the remethylation of homocysteine into methionine. Recent studies suggest that the polymorphism BHMT 742G>A may be associated with a decreased risk of having a DS child. We herein investigate the association of this polymorphism with the occurrence of DS in a Brazilian population. We have genotyped 94 mothers of DS infants (DSM) and 134 control mothers (CM) for this polymorphism through PCR–RFLP, and found significant differences for both BHMT 742G>A genotype (P = 0.04) and allele (P = 0.03) frequencies between DSM and CM. The observed genotypic frequencies were GG = 0.45; GA = 0.45 and AA = 0.10 in CM, and GG = 0.54; GA = 0.38 and AA = 0.02 in DSM. Allelic frequencies were G = 0.68 and A = 0.32 in CM and G = 0.78 and A = 0.22 in DSM. The presence of the mutant BHMT 742 A allele decreases 40 % the risk of bearing a DS child (OR = 0.61; 95 % CI: 0.40–0.93; P = 0.03), and the risk is diminished up to >80 % in association with the homozygous genotype (OR = 0.17; 95 % CI: 0.04–0.80; P = 0.01). Our results indicate that women harboring the single nucleotide polymorphism BHMT 742G>A have a decreased risk of a DS pregnancy, and further studies are necessary to confirm this protective effect.


Down syndrome BHMT 742G>A Folic acid metabolism Homocysteine remethylation 



We are grateful to the families that participate in this study and the IPPMG Pediatrics Clinic professionals. This study was supported by Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ E-26/110.427/2011).


  1. 1.
    Allen EG, Freeman SB, Druschel C, Hobbs CA, O’Leary LA, Romitti PA, Royle MH, Torfs CP, Sherman SL (2009) Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects. Hum Genet 125:41–52PubMedCrossRefGoogle Scholar
  2. 2.
    James SJ, Pogribna M, Pogribny IP, Melnyk S, Hine RJ, Gibson JB, Yi P, Tafoya DL, Swenson DH, Wilson VL, Gaylor DW (1999) Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. Am J Clin Nut 70:495–501Google Scholar
  3. 3.
    Guéant JL, Guéant-Rodriguez RM, Anello G, Bosco P, Brunaud L, Romano C, Ferri R, Romano A, Candito M, Namour B (2003) Genetic determinants of folate and vitamin B12 metabolism: a common pathway in neural tube defect and Down syndrome? Clin Chem Lab Med 11:1473–1477Google Scholar
  4. 4.
    McKeever MP, Weir DG, Molloy A, Scott JM (1991) Betaine-homocysteine methyltransferase: organ distribution in man, pig and rat and subcellular distribution in the rat. Clin Sci 81:551–556Google Scholar
  5. 5.
    Lever M, Slow S (2010) The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism. Clin Biochem 43:732–744PubMedCrossRefGoogle Scholar
  6. 6.
    Lu SC (2000) S-Adenosylmethionine. Int J Biochem Cell Biol 32:391–395PubMedCrossRefGoogle Scholar
  7. 7.
    Sunden SL, Renduchintala MS, Park EI, Miklasz SD, Garrow TA (1997) Betaine-homocysteine methyltransferase expression in porcine and human tissues and chromosomal localization of the human gene. Arch Biochem Biophys 345:171–174CrossRefGoogle Scholar
  8. 8.
    Morin I, Platt R, Weisberg I, Sabbaghian N, Wu Q, Garrow TA, Rozen R (2003) Common variant in betaine-homocysteine methyltransferase (BHMT) and risk for spina bifida. Am J Med Genet 119A:172–173PubMedCrossRefGoogle Scholar
  9. 9.
    Li F, Feng Q, Lee C, Wang S, Pelleymounter LL, Moon I, Eckloff BW, Wieben ED, Schaid DJ, Yee V, Weinshilboum RM (2008) Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: common gene sequence variation and functional characterization. Mol Genet Metab 94(3):326–335PubMedCrossRefGoogle Scholar
  10. 10.
    Weisberg IS, Park E, Ballman KV, Berger P, Nunn M, Suh DS, Breksa AP, Garrow TA, Rozen R (2003) Investigations of a common genetic variant in betaine-homocysteine methyltransferase (BHMT) in coronary artery disease. Atherosclerosis 167:205–214PubMedCrossRefGoogle Scholar
  11. 11.
    Shaw GM, Lu W, Zhu H, Yang W, Briggs FB, Carmichael SL, Barcellos LF, Lammer EJ, Finnell RH (2009) 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects. BMC Med Genet 10:49PubMedCrossRefGoogle Scholar
  12. 12.
    Mostowska A, Hozyasz KK, Wojcicki P, Dziegelewska M, Jagodzinski PP (2010) Associations of folate and choline metabolism gene polymorphisms with orofacial clefts. J Med Genet 47:809–815CrossRefGoogle Scholar
  13. 13.
    Mostowska A, Myka M, Lianeri M, Roszak A, Jagodziński PP (2011) Folate and choline metabolism gene variants and development of uterine cervical carcinoma. Clin Biochem 44:596–600CrossRefGoogle Scholar
  14. 14.
    Koushik A, Kraft P, Fuchs CS, Hankinson SE, Willett WC, Giovannucci EL, Hunter DJ (2006) Nonsynonymous polymorphisms in genes in the one-carbon metabolism pathway and associations with colorectal cancer. Cancer Epidemiol Biomarkers Prev 15:2408–2417CrossRefGoogle Scholar
  15. 15.
    Boyles AL, Billups AV, Deak KL, Siegel DG, Mehltretter L, Slifer SH, Bassuk AG, Kessler JA, Reed MC, Nijhout HF, George TM, Enterline DS, Gilbert JR, Speer MC, NTD Collaborative Group (2006) Neural tube defects and folate pathway genes: family-based association tests of gene–gene and gene–environment interactions. Environ Health Perspect 114:1547–1552PubMedCrossRefGoogle Scholar
  16. 16.
    Singh PR, Lele SS, Mukherjee MS (2011) Gene polymorphisms and low dietary intake of micronutrients in coronary artery disease. J Nutrigenet Nutrigenom 4(4):203–209CrossRefGoogle Scholar
  17. 17.
    Mills JL, Carter TC, Kay DM, Browne ML, Brody LC, Liu A, Romitti PA, Caggana M, Druschel CM (2012) Folate and vitamin B12-related genes and risk for omphalocele. Hum Genet 131:739–746PubMedCrossRefGoogle Scholar
  18. 18.
    Heil SG, Lievers KJ, Boers GH, Verhoef P, den Heijer M, Trijbels FJ, Blom HJ (2000) Betainehomocysteine methyltransferase (BHMT): genomic sequencing and relevance to hyperhomocysteinemia and vascular disease in humans. Mol Genet Metab 71:511–519PubMedCrossRefGoogle Scholar
  19. 19.
    Zhu H, Curry S, Wen S, Wicker NJ, Shaw GM, Lammer EJ, Yang W, Jafarov T, Finnell RH (2005) Are the betaine-homocysteine methyltransferase (BHMT and BHMT2) genes risk factors for spina bifida and orofacial clefts? Am J Med Genet 135A:274–277CrossRefGoogle Scholar
  20. 20.
    Giusti B, Saracini C, Bolli P, Magi A, Sestini I, Sticchi E, Pratesi G, Pulli R, Pratesi C, Abbate R (2008) Genetic analysis of 56 polymorphisms in 17 genes involved in methionine metabolism in patients with abdominal aortic aneurysm. J Med Genet 45:721–730PubMedCrossRefGoogle Scholar
  21. 21.
    Xu X, Gammon MD, Zeisel SH, Lee YL, Wetmur JG, Teitelbaum SL, Bradshaw PT, Neugut AI, Santella RM, Chen J (2008) Choline metabolism and risk of breast cancer in a population-based study. FASEB J 22:2045–2052PubMedCrossRefGoogle Scholar
  22. 22.
    Szczepańska M, Mostowska A, Wirstlein P, Lianeri M, Marianowski P, Skrzypczak J, Jagodziński PP (2011) Polymorphic variants of folate and choline metabolism genes and the risk of endometriosis-associated infertility. Eur J Obstet Gynecol Reprod Biol 157:67–72CrossRefGoogle Scholar
  23. 23.
    Boyles AL, Wilcox AJ, Taylor JA, Shi M, Weinberg CR, Meyer K, Fredriksen A, Ueland PM, Johansen AM, Drevon CA, Jugessur A, Trung TN, Gjessing HK, Vollset SE, Murray JC, Christensen K, Lie RT (2009) Oral facial clefts and gene polymorphisms in metabolism of folate/one-carbon and vitamin A: a pathway-wide association study. Genet Epidemiol 33:247–255PubMedCrossRefGoogle Scholar
  24. 24.
    Hu Y, Chen E, Mu Y, Li J, Chen R (2011) BHMT gene polymorphisms as risk factors for cleft lip and cleft palate in a Chinese population. Biomed Environ Sci 24:89–93PubMedGoogle Scholar
  25. 25.
    Hozyasz KK, Mostowska A, Szaflarska-Poplawska A, Lianeri M, Jagodzinski PP (2012) Polymorphic variants of genes involved in homocysteine metabolism in celiac disease. Mol Biol Rep 39:3123–3130PubMedCrossRefGoogle Scholar
  26. 26.
    Pawlik P, Mostowska A, Lianeri M, Sajdak S, Kędzia H, Jagodzinski PP (2012) Folate and choline metabolism gene variants in relation to ovarian cancer risk in the Polish population. Mol Biol Rep 39:5553–5560PubMedCrossRefGoogle Scholar
  27. 27.
    Zampieri BL, Biselli JM, Goloni-Bertollo EM, Vannucchi H, Carvalho VM, Cordeiro JA, Pavarino EC (2012) Maternal risk for Down syndrome is modulated by genes involved in folate metabolism. Dis Markers 32:73–81PubMedCrossRefGoogle Scholar
  28. 28.
    Zampieri BL, Biselli JM, Goloni-Bertollo EM, Pavarino EC (2012) BHMT G742A and MTHFD1 G1958A polymorphisms and Down syndrome risk in the Brazilian population. Genet Test Mol Biomarkers 16:628–631PubMedCrossRefGoogle Scholar
  29. 29.
    Aidar M, Line SRP (2007) A simple and cost-effective protocol for DNA isolation from buccal epithelial cells. Braz Dent J 18:148–152PubMedCrossRefGoogle Scholar
  30. 30.
    Ananth CV, Elsasser DA, Kinzler WL, Peltier MR, Getahun D, Leclerc D, Rozen RR, New Jersey Placental Abruption Study Investigators (2007) Polymorphisms in methionine synthase reductase and betaine-homocysteine S-methyltransferase genes: risk of placental abruption. Mol Genet Metab 91:104–110CrossRefGoogle Scholar
  31. 31.
    Zintzaras E (2007) Maternal gene polymorphisms involved in folate metabolism and risk of Down syndrome offspring: a meta-analysis. J Hum Genet 52:943–953PubMedCrossRefGoogle Scholar
  32. 32.
    Costa Lima MA, Amorim MR, Orioli IM (2013) Association of methylenetetrahydrofolate reductase gene 677C>T polymorphism and Down syndrome. Mol Biol Rep 40:2115–2125CrossRefGoogle Scholar
  33. 33.
    Amorim MR, Costa Lima MA (2013) MTRR 66G>A polymorphism as maternal risk factor for Down syndrome: a meta-analysis. Genet Test Mol Biom 17:69–73CrossRefGoogle Scholar
  34. 34.
    Hazra A, Wu K, Kraft P, Fuchs CS, Giovannucci EL, Hunter DJ (2007) Twenty-four non-synonymous polymorphisms in the one-carbon metabolic pathway and risk of colorectal adenoma in the Nurses’ Health Study. Carcinogenesis 28(7):1510–1519PubMedCrossRefGoogle Scholar
  35. 35.
    Popp RA, Farcas MF, Trifa AP, Crisan TO, Militaru MS, Pop IV (2012) Association of betaine-homocysteine S-methyltransferase gene G742A SNP and male infertility. Rev Rom Med Labor 20:57–62Google Scholar
  36. 36.
    Ying H, ErJun C, Yue M, JinLu L, RenJi C (2011) BHMT gene polymorphisms as risk factors for cleft lip and cleft palate in a Chinese population. Biomed Environ Sci 24:89–93Google Scholar
  37. 37.
    da Silva LMR, Galbiatti AL, Ruiz MT, Raposo LS, Maniglia JV, Pavarino EC, Bertollo EMG (2012) MTHFD1 G1958A, BHMT G742A, TC2 C776G and TC2 A67G polymorphisms and head and neck squamous cell carcinoma risk. Mol Biol Rep 39:887–893PubMedCrossRefGoogle Scholar
  38. 38.
    Barkai G, Arbuzova S, Berkenstadt M, Heifetz S, Cuckle H (2003) Frequency of Down’s syndrome and neural-tube defects in the same family. Lancet 361:1331–1335PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Márcia R. Amorim
    • 1
  • Cláudia M. Moura
    • 2
  • Aline D. Gomes
    • 2
  • Hazel N. Barboza
    • 1
  • Roberta B. Lopes
    • 1
  • Márcia G. Ribeiro
    • 3
  • Marcelo A. Costa Lima
    • 2
    Email author
  1. 1.Departamento de Biologia GeralInstituto de Biologia, Universidade Federal FluminenseNiteróiBrazil
  2. 2.Laboratório de Genética Molecular Humana, Departamento de GenéticaInstituto de Biologia Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro (UERJ)Rio de JaneiroBrazil
  3. 3.Instituto de Puericultura e Pediatria Martagão Gesteira, Universidade Federal do Rio de Janeiro, Cidade UniversitáriaRio de JaneiroBrazil

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