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1.  Anorectal atresia and variants at predicted regulatory sites in candidate genes 
Annals of human genetics  2012;77(1):31-46.
SUMMARY
Anorectal atresia is a serious birth defect of largely unknown etiology but candidate genes have been identified in animal studies and human syndromes. Because alterations in the activity of these genes might lead to anorectal atresia, we selected 71 common variants predicted to be in transcription factor binding sites, CpG windows, splice sites, and miRNA target sites of 25 candidate genes, and tested for their association with anorectal atresia. The study population comprised 150 anorectal atresia cases and 623 control infants without major malformations. Variants predicted to affect transcription factor binding, splicing, and DNA methylation in WNT3A, PCSK5, TCF4, MKKS, GLI2, HOXD12, and BMP4 were associated with anorectal atresia based on a nominal P value <0.05. The GLI2 and BMP4 variants are reported to be moderately associated with gene expression changes (Spearman’s rank correlation coefficients between −0.260 and 0.226). We did not find evidence for interaction between maternal pre-pregnancy obesity and variants in MKKS, a gene previously associated with obesity, on the risk of anorectal atresia. Our results for MKKS support previously suggested associations with anorectal malformations. Our findings suggest that more research is needed to determine whether altered GLI2 and BMP4 expression is important in anorectal atresia in humans.
doi:10.1111/j.1469-1809.2012.00734.x
PMCID: PMC3535506  PMID: 23127126
anorectal malformations; imperforate anus; hindgut; congenital abnormalities
2.  Evaluation of Genes Involved in Limb Development, Angiogenesis, and Coagulation as Risk Factors for Congenital Limb Deficiencies 
We conducted a population-based case-control study of single nucleotide polymorphisms (SNPs) in selected genes to find common variants that play a role in the etiology of limb deficiencies (LD)s. Included in the study were 389 infants with LDs of unknown cause and 980 unaffected controls selected from all births in New York State (NYS) for the years 1998 to 2005. We used cases identified from the NYS Department of Health (DOH) Congenital Malformations Registry. Genotypes were obtained for 132 SNPs in genes involved in limb development (SHH, WNT7A, FGF4, FGF8, FGF10, TBX3, TBX5, SALL4, GREM1, GDF5, CTNNB1, EN1, CYP26A1, CYP26B1), angiogenesis (VEGFA, HIF1A, NOS3), and coagulation (F2, F5, MTHFR). Genotype call rates were >97% and SNPs were tested for departure from Hardy-Weinberg expectations by race/ethnic subgroups. For each SNP, odds ratios (OR)s and confidence intervals (CI)s were estimated and corrected for multiple comparisons for all LDs combined and for LD subtypes. Among non-Hispanic white infants, associations between FGF10 SNPs rs10805683 and rs13170645 and all LDs combined were statistically significant following correction for multiple testing (OR=1.99; 95% CI=1.43-2.77; uncorrected p=0.000043 for rs10805683 heterozygous genotype, and OR=2.37; 95% CI=1.48-3.78; uncorrected p=0.00032 for rs13170645 homozygous minor genotype). We also observed suggestive evidence for associations with SNPs in other genes including CYP26B1 and WNT7A. Animal studies have shown that FGF10 induces formation of the apical ectodermal ridge and is necessary for limb development. Our data suggest that common variants in FGF10 increase the risk for a wide range of non-syndromic limb deficiencies.
doi:10.1002/ajmg.a.35565
PMCID: PMC3448837  PMID: 22965740
limb deficiencies; polymorphisms; FGF10
3.  Hirschsprung’s disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation 
Journal of human genetics  2012;57(8):485-493.
Hirschsprung’s disease (HSCR) results from failed colonization of the embryonic gut by enteric neural crest cells (ENCCs); colonization requires RET proto-oncogene (RET) signaling. We sequenced RET to identify coding and splice-site variants in a population-based case group and we tested for associations between HSCR and common variants in RET and candidate genes (ASCL1, HOXB5, L1CAM, PHOX2B, PROK1, PROKR1) chosen because they are involved in ENCC proliferation, migration, and differentiation in animal models. We conducted a nested case-control study of 304 HSCR cases and 1 215 controls. Among 38 (12.5%) cases with 34 RET coding and splice-site variants, 18 variants were previously unreported. We confirmed associations with common variants in HOXB5 and PHOX2B but the associations with variants in ASCL1, L1CAM, and PROK1 were not significant after multiple comparisons adjustment. RET variants were strongly associated with HSCR (P values between 10−3 and 10−31) but this differed by race/ethnicity: associations were absent in African-Americans. Our population-based study not only identified novel RET variants in HSCR cases, it showed that common RET variants may not contribute to HSCR in all race/ethnic groups. The findings for HOXB5 and PHOX2B provide supportive evidence that genes regulating ENCC proliferation, migration, and differentiation could be risk factors for HSCR.
doi:10.1038/jhg.2012.54
PMCID: PMC3503526  PMID: 22648184
congenital abnormalities; enteric nervous system; Hirschsprung disease; RET
4.  Folate and Vitamin B12 Related Genes and Risk for Omphalocele 
Human Genetics  2011;131(5):739-746.
Both taking folic acid-containing vitamins around conception and consuming food fortified with folic acid have been reported to reduce omphalocele rates. Genetic factors are etiologically important in omphalocele as well; our pilot study showed a relationship with the folate metabolic enzyme gene methylenetetrahydrofolate reductase (MTHFR). We studied 169 non-aneuploid omphalocele cases and 761 unaffected, matched controls from all New York State births occurring between 1998 and 2005 to look for associations with single nucleotide polymorphisms (SNPs) known to be important in folate, vitamin B12, or choline metabolism. In the total study population, variants in the transcobalamin receptor gene (TCblR), rs2232775 (Q8R), and the MTHFR gene, rs1801131 (1298A>C), were significantly associated with omphalocele. In African-Americans significant associations were found with SNPs in genes for the vitamin B12 transporter (TCN2) and the vitamin B12 receptor (TCblR). A SNP in the homocysteine-related gene, betaine-homocysteine S-methyltransferase (BHMT), rs3733890 (R239Q), was significantly associated with omphalocele in both African-Americans and Asians. Only the TCblR association in the total population remained statistically significant if Bonferroni correction was applied. The finding that transcobalamin receptor (TCblR) and transporter (TCN2) SNPs and a BHMT SNP were associated with omphalocele suggests that disruption of methylation reactions, in which folate, vitamin B12, and homocysteine play critical parts, may be a risk factor for omphalocele. Our data, if confirmed, suggest that supplements containing both folic acid and vitamin B12 may be beneficial in preventing omphaloceles.
doi:10.1007/s00439-011-1117-3
PMCID: PMC3374579  PMID: 22116453
omphalocele; folate; vitamin B12; homocysteine; transcobalamin; transcobalamin receptor
5.  Caffeine, Selected Metabolic Gene Variants, and Risk for Neural Tube Defects 
Background
Investigations of maternal caffeine intake and neural tube defects (NTDs) have not considered genetic influences. Caffeine metabolism gene effects were examined in the National Birth Defects Prevention Study.
Methods
Average daily caffeine was summed from self-reported coffee, tea, soda, and chocolate intake for mothers of 768 NTD cases and 4143 controls delivered from 1997–2002. A subset of 306 NTD and 669 control infants and their parents were genotyped for CYP1A2*1F, NAT2 481C>T and NAT2 590G>A. CYP1A2*1F was classified by fast or slow oxidation status and NAT2 variants were categorized into rapid or slow acetylation status. Case-control logistic regression analyses, family-based transmission/disequilibrium tests and log-linear analyses, and hybrid log-linear analyses were conducted to produce odds ratios (OR) or relative risks (RR) and 95% confidence intervals (CI) for caffeine intake and maternal and infant gene variants, and to examine interaction effects.
Results
NTDs were independently associated with infant slow NAT2 acetylator status (RR: 2.00, 95% CI: 1.10–3.64) and maternal CYP1A2*1F fast oxidation status (OR: 1.49 95% CI: 1.10–2.03). Caffeine-consuming mothers who were CYP1A2*1F fast oxidizers and NAT2 slow acetylators had non-significantly elevated estimated risk for an NTD-affected pregnancy (OR: 3.10 95% CI: 0.86–11.21). Multiplicative interaction effects were observed between maternal caffeine and infant CYP1A2*1F fast oxidizer status (pinteraction = 0.03).
Conclusions
The association identified between maternal CYP1A2*1F fast oxidation status and NTDs should be examined further in the context of CYP1A2’s other substrates. Maternal caffeine and its metabolites may be associated with increased risk for NTD-affected pregnancies in genetically susceptible subgroups.
doi:10.1002/bdra.20681
PMCID: PMC2917796  PMID: 20641098
Caffeine; Gene-environment Interaction, Effect Modification; Cytochrome P450 CYP1A2; N-Acetyltransferase NAT2; Embryo, Mammalian; Metabolism; Maternal Exposure/*adverse effects; Neural Tube Defects; Spinal Dysraphism; Encephalocele
6.  Watercraft-related drownings among New York State residents, 1988-1994. 
Public Health Reports  2003;118(5):459-463.
OBJECTIVE: To describe environmental and personal risk factors associated with watercraft-related drownings. This information may be useful in developing boating safety programs, regulations, and enforcement priorities. METHODS: A companion article in this issue (Unintentional Drownings Among New York State Residents, page 448) summarizes an investigation of 883 non-bathtub drownings among New York State residents for the years 1988 to 1994 using medical examiner, coroner, police, and hospital records in addition to death certificate data. This report details the environmental and personal risk factors associated with 216 watercraft-related drownings. RESULTS: Ninety-three percent of watercraft-related drowning victims were male, with the highest rate of drowning observed among males ages 15-44 years. Most commonly, the victim entered the water when the watercraft capsized (36%), the victim fell overboard (24%), or the victim intended to swim (11%). Personal flotation devices (PFDs) were known to be worn by only 9% of drowning victims, and in these cases other risks overwhelmed the effectiveness of the PFD. Of 73 individuals 15 years of age or older for whom adequate blood alcohol concentration analyses were provided, 44% were positive for blood alcohol. CONCLUSIONS: Based on this study, increased use of PFDs, avoidance of dangerous currents, and less alcohol use by operators and passengers of all types of watercraft would result in a reduction in watercraft-related drownings. In addition to continued education efforts, boating safety measures that deserve consideration include enforcement of current PFD and boating while intoxicated (BWI) regulations and expansion of BWI laws to apply to all boaters.
PMCID: PMC1497574  PMID: 12941858
7.  Unintentional drownings among New York State residents, 1988-1994. 
Public Health Reports  2003;118(5):448-458.
OBJECTIVE: This study examines situations in which drownings occur (environmental risk factors) and the victims' personal risk factors (age, gender, use of personal flotation device, medical condition, alcohol or drug use) to provide guidance for future drowning prevention efforts. METHODS: The authors investigated 883 non-bathtub drownings among New York State residents for the years 1988 to 1994 using medical examiner, coroner, police, and/or hospital records in addition to death certificate data. RESULTS: Males, children ages 0-4 years, and African American males ages 5-14 years residing in New York State outside New York City experienced the highest rates of drowning. The majority of drownings occurred in a natural body of water for all age groups, with the exception of children ages 0-4 years. Most drownings among children ages 0-4 years occurred in residential swimming pools. The child usually gained access to the pool via inadequate fencing, an open or ineffective gate, or a ladder (to an above-ground pool) left in the "down" position. Less than 10% of victims of watercraft-related drownings were wearing personal flotation devices. Blood alcohol concentration (BAC) tests were positive for 44% of 250 persons 15 years of age and older for whom valid toxicology results were provided; 30% had BACs of 100 mg/dl or more. CONCLUSIONS: Suggested prevention efforts include stricter enforcement of fencing requirements for residential swimming pools and drowning prevention education stressing personal flotation device use while boating and the danger of mixing alcohol and water-related activities.
PMCID: PMC1497570  PMID: 12941857

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