ORIGINAL ARTICLE

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

C L Relton^1,4, C S Wilding², M S Pearce¹, A J Laffling², P A Jonas^3,4, S A Lynch⁴, E J Tawn² and J Burn⁴

¹ 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
² Genetics Department, Westlakes Research Institute, Westlakes Science and Technology Park, Moor Row, Cumbria, CA24 3JY, UK
³ West Cumberland Hospital, Whitehaven, Cumbria, CA28 8JG, UK
⁴ Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle-upon-Tyne, NE1 3BZ, UK

Correspondence to:
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.relton{at}ncl.ac.uk

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 677CT, MTHFR 1298AC, MTRR 66AG, SHMT 1420CT, CßS 844ins68, GCPII 1561CT, RFC-1 80GA). 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 677CT 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 66AG 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/CßS; MTHFR 677/MTRR) and one combination in case mothers (CßS/RFC-1) were shown to elevate NTD risk. Maternal–fetal interaction was also detected when offspring carried the MTHFR 677CT variant and mothers carried the MTRR 66AG 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.

Keywords: epistasis; folate; neural tube defects; polymorphisms

Abbreviations: Hcy, homocysteine; NTD, neural tube defects; SNP, single nucleotide polymorphism; TDT, transmission disequilibrium testing

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