OBJECTIVE: Women who have low cobalamin (vitamin B(12)) 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: Case-control 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; p(corr)=0.0080, corrected for multiple hypothesis testing) and TCblR rs9426 (p(corr)=0.0279). 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; RR=6.59, p=0.0037) and rs9426 (RR=6.71, p=0.0035)). A copy number variant distal to TCblR and two previously unreported exonic insertion-deletion 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.
OBJECTIVE:Women who have low cobalamin (vitamin B(12)) 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: Case-control 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; p(corr)=0.0080, corrected for multiple hypothesis testing) and TCblRrs9426 (p(corr)=0.0279). 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; RR=6.59, p=0.0037) and rs9426 (RR=6.71, p=0.0035)). A copy number variant distal to TCblR and two previously unreported exonic insertion-deletion polymorphisms were described. CONCLUSIONS:TCblR rs2336573 (G220R) and TCblRrs9426 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.
Authors: Peadar N Kirke; James L Mills; Anne M Molloy; Lawrence C Brody; Valerie B O'Leary; Leslie Daly; Sharon Murray; Mary Conley; Philip D Mayne; Owen Smith; John M Scott Journal: BMJ Date: 2004-05-21
Authors: E W Weekes; T Tamura; R O Davis; R Birch; W H Vaughn; J C Franklin; C Barganier; P Cosper; S C Finley; W H Finley Journal: Biol Neonate Date: 1992
Authors: Pascal M W Groenen; Iris A L M van Rooij; Petronella G M Peer; Rob H Gooskens; Gerhard A Zielhuis; Régine P M Steegers-Theunissen Journal: Am J Obstet Gynecol Date: 2004-07 Impact factor: 8.661
Authors: James L Mills; Tonia C Carter; Denise M Kay; Marilyn L Browne; Lawrence C Brody; Aiyi Liu; Paul A Romitti; Michele Caggana; Charlotte M Druschel Journal: Hum Genet Date: 2011-11-25 Impact factor: 4.132
Authors: Julia E VanderMeer; Tonia C Carter; Faith Pangilinan; Adam Mitchell; Emma Kurnat-Thoma; Peadar N Kirke; James F Troendle; Anne M Molloy; Ronald G Munger; Marcia L Feldkamp; Maria A Mansilla; James L Mills; Jeff C Murray; Lawrence C Brody Journal: Am J Med Genet A Date: 2016-01-20 Impact factor: 2.802
Authors: Laurel E Murphy; James L Mills; Anne M Molloy; Cong Qian; Tonia C Carter; Helena Strevens; Dag Wide-Swensson; Aleksander Giwercman; Richard J Levine Journal: Asian J Androl Date: 2011-08-22 Impact factor: 3.285
Authors: Aneliya Velkova; Jennifer E L Diaz; Faith Pangilinan; Anne M Molloy; James L Mills; Barry Shane; Erica Sanchez; Conal Cunningham; Helene McNulty; Cheryl D Cropp; Joan E Bailey-Wilson; Alexander F Wilson; Lawrence C Brody Journal: Hum Mol Genet Date: 2017-12-15 Impact factor: 6.150
Authors: Tonia C Carter; Faith Pangilinan; James F Troendle; Anne M Molloy; Julia VanderMeer; Adam Mitchell; Peadar N Kirke; Mary R Conley; Barry Shane; John M Scott; Lawrence C Brody; James L Mills Journal: Am J Med Genet A Date: 2010-12-10 Impact factor: 2.802