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1.  Transcobalamin II Receptor Polymorphisms Are Associated with Increased Risk for Neural Tube Defects 
Journal of medical genetics  2010;47(10):677-685.
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. We evaluated inherited variants in the TCblR gene as NTD risk factors.
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:
We found two tightly linked variants associated with NTDs in a recessive model: TCblR rs2336573 (G220R) (pcorr=0.0080, corrected for multiple hypothesis testing) and TCblR rs9426 (pcorr =0. 0279). These variants were also associated with NTDs in a family-based test prior to 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)). We describe a copy number variant (CNV) distal to TCblR and two previously unreported exonic insertion-deletion polymorphisms.
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 one thousand controls, indicating this NTD risk factor may be of low frequency and high penetrance. Nine other variants are in perfect LD with the associated SNPs. 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.
doi:10.1136/jmg.2009.073775
PMCID: PMC4112773  PMID: 20577008
neural tube defects; spina bifida; transcobalamin II receptor (TCblR); cobalamin; vitamin B12; copy number variant (CNV)
2.  Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects 
BMC Medical Genetics  2012;13:62.
Background
Neural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk.
Methods
A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case–control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects.
Results
Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003–0.0023) were found in nine genes (MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury)) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing.
Conclusions
To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive correction. We have produced a ranked list of variants with the strongest association signals. Variants in the highest rank of associations are likely to include true associations and should be high priority candidates for further study of NTD risk.
doi:10.1186/1471-2350-13-62
PMCID: PMC3458983  PMID: 22856873
Neural tube defects; Spina bifida; Folic acid; One-carbon metabolism; Candidate gene
3.  Maternal vitamin levels in pregnancies affected by congenital malformations other than neural tube defects 
Background
Periconceptional use of folic acid prevents most neural tube defects (NTDs). Whether folic acid and/or multivitamins can prevent other congenital anomalies is not clear. This study tested whether maternal blood levels of folate and vitamin B12 in pregnancies affected by congenital malformations excluding NTDs are lower when compared to non-affected pregnancies.
Methods
We measured pregnancy red cell folate (RCF), vitamin B12, and homocysteine (tHcy) concentrations in blood samples taken at the first antenatal clinic in Dublin maternity hospitals in 1986–1990 when vitamin supplementation was rare. The cases were mothers who delivered a baby with a congenital malformation other than NTD identified by the Dublin EUROCAT Registry; controls were a systematic sample of mothers of offspring without congenital malformations from the same hospitals in the same time period.
Results
The median maternal levels of RCF and tHcy did not differ significantly between cases and controls for any of the congenital malformation groups examined (RCF: all malformations 275.9 ug/L v controls 271.2; p=0.77; tHcy: all malformations 7.5 umol/L v controls 7.6; p=0.57). In an unadjusted analysis vitamin B12 was significantly higher in case-mothers whose babies had cleft palate only (p=0.006), musculoskeletal malformations (p=0.034) and midline defects (p=0.039) but not after adjustment for multiple testing.
Conclusions
Our data suggest that low maternal folate and B12 levels or high tHcy levels in early pregnancy are not associated with all congenital malformations excluding NTDs. Fortification with folic acid or B12 may not have a beneficial effect in the prevention of these anomalies.
doi:10.1002/bdra.20817
PMCID: PMC3372895  PMID: 21591245
4.  Construction of a High Resolution Linkage Disequilibrium Map to Evaluate Common Genetic Variation in TP53 and Neural Tube Defect Risk in an Irish Population 
Genetic and environmental factors contribute to the etiology of neural tube defects (NTDs). While periconceptional folic acid supplementation is known to significantly reduce the risk of NTDs, folate metabolic pathway related factors do not account for all NTDs. Evidence from mouse models indicates that the tumor protein p53 (TP53) is involved in implantation and normal neural tube development. To determine whether genetic variation in the TP53 might contribute to NTD risk in humans, we constructed a high resolution linkage disequilibrium (LD) map of the TP53 genomic region based on genotyping 21 markers in an Irish population. We found that nine of these variants can be used to capture the majority of common variation in the TP53 genomic region. In contrast, the 3-marker haplotype commonly reported in the TP53 literature offers limited coverage of the variation in the gene. We used the expanded set of polymorphisms to measure the influence of TP53 on NTDs using both case-control and family-based tests of association. We also assayed a functional variant in the p53 regulator MDM2 (rs2279744). Alleles of three noncoding TP53 markers were associated with NTD risk. A case effect was seen with the GG genotype of rs1625895 in intron 6 (OR = 1.37 [1.04-1.79], p=0.02). A maternal effect was seen with the 135/135 genotype of the intron 1 VNTR (OR = 1.86 [1.16-2.96], p=0.01) and the TT genotype of rs1614984 (RR = 0.58 [0.37-0.91], p=0.02). As multiple comparisons were made, these cannot be considered definitive positive findings and additional investigation is required.
doi:10.1002/ajmg.a.32504
PMCID: PMC2836760  PMID: 18798306
neural tube defects; spina bifida; p53; TP53; MDM2; linkage disequilibrium
5.  Uncoupling Protein 2 Polymorphisms as Risk Factors for Neural Tube Defects 
BACKGROUND:
Both environmental and genetic factors are involved in the etiology of neural tube defects (NTDs). Inadequate folate intake and obesity are important environmental risk factors. Several folate-related genetic variants have been identified as risk factors; however, little is known about how genetic variants relate to the increased risk seen in obese women. Uncoupling Protein 2 (UCP2) is an attractive candidate to screen for NTD risk because of its possible role in obesity as well as energy metabolism, type-2 diabetes, and the regulation of reactive oxygen species. Interestingly, a previous study found that a common UCP2 compound homozygous genotype was associated with a threefold increase in NTD risk.
METHODS:
We evaluated three polymorphisms, −866G>A, A55V, and the 3′UTR 45bp insertion/deletion, as risk factors for NTDs in Irish NTD cases (N=169), their mothers (N=163), their fathers (N=167) and normal control subjects (N=332).
RESULTS:
Allele and genotype frequencies were not significantly different when comparing NTD mothers, NTD fathers, or affected children to controls. Additionally, the previously reported risk genotype (combined homozygosity of 55VV and 3′UTR 45bp deletion/deletion) was not present at a higher frequency in any NTD group when compared to controls.
CONCLUSIONS:
In our Irish study population, UCP2 polymorphisms do not influence NTD risk. Moreover, the prevalence of this allele in other populations was similar to the Irish prevalence but far lower than reported in the previous NTD study, suggesting that this previous finding of an association with NTDs might have been due to an unrepresentative study sample.
doi:10.1002/bdra.20520
PMCID: PMC2724655  PMID: 19137581
neural tube defects; spina bifida; UCP2; obesity
6.  Eye Malformations in Children with Heavy Alcohol Exposure in Utero 
The Journal of pediatrics  2008;153(3):391-395.
Objective
To determine whether children who do not develop fetal alcohol syndrome (FAS) despite heavy alcohol exposure are at risk for eye abnormalities
Study design
We screened 9628 pregnant women and identified 101 women who were drinking ≥ 2 ounces of absolute alcohol per day and 101 non-drinking control women. We followed 43 exposed and 55 control offspring ages 4 to 9 years and performed masked, standardized ophthalomologic exams.
Results
The groups did not differ in their rates of impaired visual acuity, refractory errors, ptosis, epicanthal folds, or short palpebral fissures. Biomicroscopy examinations were normal in all exposed subjects; two (4%) controls and no exposed had cataracts. Seven (16%) exposed subjects versus 8 (15%) controls had arterial tortuosity. No subjects had optic nerve hypoplasia.
Conclusions
Previous research has reported that children with FAS have a high incidence of serious ophthalmologic defects; our data show that the risk is limited to children with FAS, not children exposed to high levels of alcohol prenatally but who do not develop FAS. Eye examinations are unlikely to clarify the diagnosis in children suspected of having alcohol related damage.
doi:10.1016/j.jpeds.2008.04.024
PMCID: PMC2570183  PMID: 18571671
Fetal Alcohol Syndrome; visual acuity; ocular malformations; birth defects; alcohol; eye; optic nerve hypoplasia

Results 1-7 (7)