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J Med Genet 41:256-260 doi:10.1136/jmg.2003.010694
  • Original article

Gene–gene interaction in folate-related genes and risk of neural tube defects in a UK population

  1. C L Relton1,4,
  2. C S Wilding2,
  3. M S Pearce1,
  4. A J Laffling2,
  5. P A Jonas3,4,
  6. S A Lynch4,
  7. E J Tawn2,
  8. J Burn4
  1. 1Paediatric and Lifecourse Epidemiology Research Group, School of Clinical Medical Sciences, Newcastle University, Sir James Spence Institute, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK
  2. 2Genetics Department, Westlakes Research Institute, Westlakes Science and Technology Park, Moor Row, Cumbria, CA24 3JY, UK
  3. 3West Cumberland Hospital, Whitehaven, Cumbria, CA28 8JG, UK
  4. 4Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle-upon-Tyne, NE1 3BZ, UK
  1. Correspondence to:
 Dr C L Relton
 Paediatric and Lifecourse Epidemiology Research Group, School of Clinical Medical Sciences, Newcastle University, Sir James Spence Institute, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK; c.l.reltonncl.ac.uk
  • Accepted 8 January 2004
  • Revised 19 December 2003

Abstract

Objective: To investigate the contribution of polymorphic variation in genes involved in the folate-dependent homocysteine pathway in the aetiology of neural tube defects (NTD).

Design: Case-control association study.

Subjects: A total of 530 individuals from families affected by NTD, 645 maternal controls, and 602 healthy newborn controls from the northern UK.

Main outcome measures: Seven polymorphisms in six genes coding for proteins in the folate-dependent homocysteine pathway (MTHFR 677C→T, MTHFR 1298A→C, MTRR 66A→G, SHMT 1420C→T, CβS 844ins68, GCPII 1561C→T, RFC-1 80G→A). The impact of each polymorphism and the effect of gene–gene interactions (epistasis) upon risk of NTD were assessed using logistic regression analysis.

Results: The MTHFR 677C→T polymorphism was shown to represent a risk factor in NTD cases (CC v CT+TT odds ratio (OR) 2.03 [95% confidence interval (CI) 1.09, 3.79] p = 0.025) and the MTRR 66A→G polymorphism was shown to exert a protective effect in NTD cases (AA v AG+GG OR 0.31 [95% CI 0.10, 0.94] p = 0.04). When statistical tests for interaction were conducted, three genotype combinations in cases (MTRR/GCPII; MTHFR 677/CβS; MTHFR 677/MTRR) and one combination in case mothers (CβS/RFC-1) were shown to elevate NTD risk. Maternal–fetal interaction was also detected when offspring carried the MTHFR 677C→T variant and mothers carried the MTRR 66A→G variant, resulting in a significantly elevated risk of NTD.

Conclusion: Both independent genetic effects and gene–gene interaction were observed in relation to NTD risk. Multi-locus rather than single locus analysis might be preferable to gain an accurate assessment of genetic susceptibility to NTD.

Footnotes

  • This research was funded by BNFL and the Birth Defects Foundation.

  • Conflict of interest: none declared.