Transcobalamin II receptor polymorphisms are associated with increased risk for neural tube defects

Area of Science:

• Genetics
• Human Health
• Biochemistry

Background:

• Low cobalamin (vitamin B12) levels in pregnant women increase the risk of neural tube defects (NTDs) in offspring.
• The transcobalamin II receptor (TCblR) is crucial for cellular uptake of cobalamin.

Purpose of the Study:

• To investigate inherited variants in the TCblR gene as potential risk factors for NTDs.
• To evaluate the association between common TCblR variations and NTD occurrence.

Main Methods:

• Employed case-control and family-based association tests to screen for TCblR genetic variations.
• Utilized a large Irish cohort and confirmatory NTD trios for robust analysis.

Main Results:

• Identified two linked TCblR variants, rs2336573 (G220R) and rs9426, significantly associated with NTDs in a recessive model (p(corr)=0.0080 and p(corr)=0.0279, respectively).
• Family-based tests confirmed the association, showing a strong risk ratio for these variants.
• Described a copy number variant and two novel exonic insertion-deletion polymorphisms in the TCblR region.

Conclusions:

• TCblR variants rs2336573 (G220R) and rs9426 are significant risk factors for NTDs in the Irish population.
• The high penetrance and low frequency of the homozygous risk genotype in controls suggest a potent, albeit rare, NTD risk factor.
• TCblR gene variation likely influences cobalamin metabolism and plays a role in NTD susceptibility.