Participation in the NBDPS for the period 1999–2007 was 74% among NTD case mothers, yielding 1,553 families available for analysis. Among those, 759 (49%) provided buccal swabs (1,787 individuals). Genotyping was performed on DNA samples derived from these 759 families. Based on quality control checks, 18 families (2% of families) were excluded for being inconsistent with Mendelian inheritance at more than 2 genotypes. Additionally, 47 subjects were excluded for failure at more than 11 genotypes (>50%), resulting in 4 more triads' being excluded and leaving a total of 737 case-parent triads (97% of the original sample). Of those, 317 were complete triads, 313 were dyads, and 107 were monads with only 1 person in the family. After these quality control measures were applied, at least 95% of the samples for each variant were available for analyses; therefore, the genotypes were considered of sufficiently high quality.
The distributions of key characteristics among NTD case-parent triads are presented in Table . Spina bifida was the most common phenotype among case subjects (n = 449; 60.9%). Furthermore, a majority of case mothers were non-Hispanic white (n = 439; 59.8%). Among case mothers, 176 were obese (25.4%), 13 had prepregnancy diabetes (1.8%), and 29 had gestational diabetes (4.2%). The only characteristics presented in Table that were significantly different between interviewed case mothers who provided buccal swabs and those who did not were race/ethnicity and education (data not shown).
Table shows estimated relative risks (heterozygote vs. common homozygote) and 95% confidence intervals for the association between offspring and maternal genotypes and NTDs, as well as the likelihood ratio test P values and false discovery rate Q values for the model comparisons for each variant. Offspring genotypes for ADRB3, ENPP1, FTO, LEP, PPARG, PPARGC1A, SLC2A2, or TCF7L2 were not associated with NTD risk. However, the offspring genotype for UCP2 rs660339 was associated with NTD risk (relative risk (RR) = 1.32, 95% confidence interval (CI): 1.06, 1.64).
Log-Linear Results for the Association Between Diabetes and Obesity-Related Genes and the Risk of Neural Tube Defects, National Birth Defects Prevention Study, 1999–2007
There was no statistical evidence of associations between maternal genotypes for ADRB3, ENPP1, PPARG, PPARGC1A, SLC2A2, or UCP2 and the risk of NTDs in offspring (Table ). However, the less common alleles of all FTO genotypes (rs1421085, rs8050136, rs9939609, and rs17817449) were negatively associated with NTD risk among mothers. In contrast, the less common alleles for LEP rs2071045 and TCF7L2 rs3814573 were associated with an elevated risk among mothers (RR = 1.31 (95% CI: 1.08, 1.60) and RR = 1.22 (95% CI: 1.04, 1.44), respectively). Results were similar (e.g., the estimated relative risks were similar) when analyses were restricted to 1) spina bifida cases only, 2) mothers without pregestational diabetes, 3) mothers without pregestational or gestational diabetes, and 4) non-Hispanic whites; therefore, only results for the full group are presented.
When analyses were stratified on the basis of maternal body mass index (Tables and ), the effect of TCF7L2 rs3814573 was stronger among obese women (RR = 1.64, 95% CI: 1.15, 2.33) than among nonobese women (RR = 1.11, 95% CI: 0.92, 1.35). Additionally, none of the FTO genotypes were significantly associated with NTD risk in obese women, whereas these variants were associated with NTD risk in nonobese women. Offspring genetic effects also appeared to differ by maternal prepregnancy obesity (Tables and ). For instance, the association between NTD risk and UCP2 rs660339 was stronger for the offspring of obese women (RR = 1.74, 95% CI: 1.14, 2.64) than for the offspring of nonobese women (RR = 1.19, 95% CI: 0.91, 1.55). The offspring genetic effect of LEP rs3828942 also differed on the basis of maternal prepregnancy obesity, whereby the less common allele was associated with a reduced risk in offspring of obese women (RR = 0.66, 95% CI: 0.44, 0.98) and an increased risk in offspring of nonobese women (RR = 1.31, 95% CI: 1.00, 1.72). This was also true for LEP rs12706831, whereby the less common allele was associated with a reduced risk in offspring of obese women (RR = 0.69, 95% CI: 0.45, 1.06) and an increased risk in offspring of nonobese women (RR = 1.31, 95% CI: 1.01, 1.69).
Log-Linear Results Among Obese Mothers for the Association Between Diabetes and Obesity-Related Genes and the Risk of Neural Tube Defects, National Birth Defects Prevention Study, 1999–2007
Log-Linear Results Among Nonobese Mothers for the Association Between Diabetes and Obesity-Related Genes and the Risk of Neural Tube Defects, National Birth Defects Prevention Study, 1999–2007
Because of the number of comparisons, we applied the false discovery rate in the full group. Although none of the offspring genetic effects remained statistically significant, 5 of the 6 significant maternal genetic effects in Table (the 4 FTO genotypes and LEP rs2071045) remained significant at P < 0.05.