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.
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.
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).
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.