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J Med Genet. 2004 Apr;41(4):256-60.

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

Author information

  • 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. c.l.relton@ncl.ac.uk

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, CbetaS 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/CbetaS; MTHFR 677/MTRR) and one combination in case mothers (CbetaS/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.

PMID:
15060097
[PubMed - indexed for MEDLINE]
PMCID:
PMC1735724
Free PMC Article
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