Maternal Caffeine Intake, Selected Metabolic Gene Variants, and Neural Tube Defects (NTDs)

Purpose Using data from the National Birth Defects Prevention Study, we examined associations between NTDs and maternal caffeine intake, gene variants for caffeine metabolism, and their joint effects. Methods Total average caffeine per day was summed from maternal interview reports of coffee, tea, soda, and chocolate intake. Buccal swab samples from infants and birth parents were genotyped for CYP1A2∗ 1F , NAT2 C481T and G590A , NAT1 C1095A and rs13278990. CYP1A2∗ 1F was classified by oxidation status (fast vs. slow) and NAT2 variants were categorized by acetylation status (rapid vs. slow). Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for total caffeine, each caffeine source, and maternal and infant gene variants. We also conducted family-based and hybrid log-linear analyses to examine the association of each gene variant with NTDs, and used case-control, case-only, and family-based methods to assess interaction effects between caffeine intake and each gene variant. Results We found an association between maternal caffeine intake and spina bifida (SB), which varied by caffeine source across multiple and isolated case status. Mothers who consumed caffeine and were CYP1A2∗ 1F fast oxidizers and NAT2 slow acetylators had the greatest estimated risk for an NTD-affected pregnancy, although interaction effects were significant only for infant CYP1A2∗ 1F fast oxidizer status. There was a significant association of maternal CYP1A2∗ 1F fast oxidation status with NTDs that was stronger for isolated cases, non-Hispanic White mothers, and mothers of CYP1A2∗ 1F fast oxidizing infants. Infant slow NAT2 acetylator status was significantly associated with an increased NTD risk in the family-based analyses. There was not strong evidence for an increased risk of NTDs associated with infant NAT1 C1095A. Conclusion Maternal caffeine and its metabolites may be associated with increased risk for a NTD-affected pregnancy in certain subgroups. There is an association of maternal CYP1A2∗ 1F fast oxidation status with NTDs that should be examined further in the context of its other substrates.