Pangilinan F, Mitchell A, Vandermeer J, Molloy AM, Troendle J, Conley M, Kirke PN, Sutton M, Sequeira JM, Quadros EV, Scott JM, Mills JL, Brody LC, Transcobalamin II receptor polymorphisms are associated with increased risk for neural tube defects., Journal of Medical Genetics, 47, 10, 2010, 677 - 685
Journal of Medical Genetics 47 10
Objective Women who have low cobalamin (vitamin B12)
levels are at increased risk for having children with neural
tube defects (NTDs). The transcobalamin II receptor (TCblR)
mediates uptake of cobalamin into cells. Inherited variants
in the TCblR gene as NTD risk factors were evaluated.
Methods Caseecontrol and family-based tests of
association were used to screen common variation in
TCblR as genetic risk factors for NTDs in a large Irish
group. A confirmatory group of NTD triads was used to
test positive findings.
Results 2 tightly linked variants associated with NTDs in
a recessive model were found: TCblR rs2336573 (G220R;
pcorr¼0.0080, corrected for multiple hypothesis testing)
and TCblR rs9426 (pcorr¼0.0279). These variants were
also associated with NTDs in a family-based test before
multiple test correction (log-linear analysis of a recessive
model: rs2336573 (G220R; RR¼6.59, p¼0.0037) and
rs9426 (RR¼6.71, p¼0.0035)). A copy number variant
distal to TCblR and two previously unreported exonic
insertionedeletion polymorphisms were described.
Conclusions TCblR rs2336573 (G220R) and TCblR
rs9426 represent a significant risk factor in NTD cases in
the Irish population. The homozygous risk genotype was
not detected in nearly 1000 controls, indicating that this
NTD risk factor may be of low frequency and high
penetrance. 9 other variants are in perfect linkage
disequilibrium with the associated single nucleotide
polymorphisms. Additional work is required to identify the
disease-causing variant. Our data suggest that variation in
TCblR plays a role in NTD risk and that these variants may
modulate cobalamin metabolism.
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