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


METHODS
Case-control association study.


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


METHODS
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.


CONCLUSIONS
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.
Relton
C L
CL
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@ncl.ac.uk
Wilding
C S
CS
Pearce
M S
MS
Laffling
A J
AJ
Jonas
P A
PA
Lynch
S A
SA
Tawn
E J
EJ
Burn
J
J
D016022:Case-Control Studies; D004843:Epistasis, Genetic; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D008297:Male; D009436:Neural Tube Defects / Q000235:genetics*; D011110:Polymorphism, Genetic; D006113:United Kingdom
D006710:Homocysteine; D005492:Folic Acid