Gene–gene interaction in folate-related genes and risk of neural tube defects in a UK population
- C L Relton1,4,
- C S Wilding2,
- M S Pearce1,
- A J Laffling2,
- P A Jonas3,4,
- S A Lynch4,
- E J Tawn2,
- J Burn4
- 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
- 2Genetics Department, Westlakes Research Institute, Westlakes Science and Technology Park, Moor Row, Cumbria, CA24 3JY, UK
- 3West Cumberland Hospital, Whitehaven, Cumbria, CA28 8JG, UK
- 4Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle-upon-Tyne, NE1 3BZ, UK
- 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;
- Accepted 8 January 2004
- Revised 19 December 2003
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.
- Hcy, homocysteine
- NTD, neural tube defects
- SNP, single nucleotide polymorphism
- TDT, transmission disequilibrium testing
This research was funded by BNFL and the Birth Defects Foundation.
Conflict of interest: none declared.