Pharmacogenomics of maternal tobacco use: metabolic gene polymorphisms and risk of adverse pregnancy outcomes

Abstract

Objective: To assess whether functional maternal or fetal genotypes along well-characterized metabolic pathways (ie, CYP1A1, GSTT1, and CYP2A6) may account for varying associations with adverse outcomes among pregnant women who smoke.

Methods: DNA samples from 502 smokers and their conceptuses, alongside women in a control group, were genotyped for known functional allelic variants of CYP1A1 (Ile462Val AA>AG/GG), GSTT1(del), and CYP2A6 (Lys160His T>A). Modification of the association between smoking and outcome by genotype was evaluated. Outcomes included birth weight, pregnancy loss, preterm birth, small for gestational age, and a composite outcome composed of the latter four components plus abruption.

Results: No interaction between maternal or fetal genotype of any of the polymorphisms and smoking could be demonstrated. In contrast, the association of smoking with gestational age-adjusted birth weight (birth weight ratio) was modified by fetal GSTT1 genotype (P for interaction=.02). Fetuses with GSTT1(del) had a mean birth weight reduction among smokers of 262 g (P=.01), whereas in fetuses without the GSTT1(del) the effect of tobacco exposure was nonsignificant (mean reduction 87 g, P=.16). After adjusting for confounding, results were similar.

Conclusion: Fetal GSTT1 deletion significantly and specifically modifies the effect of smoking on gestational age-corrected birth weight.

Fig. 1

Odds ratio of smoking for small for gestational age (SGA) for fetal GSTT1(del) allelic combinations. Calculation of SGA was defined as birth weight less than the 10th percentile, derived from sex- and race-specific growth curves for gestational age for live births after 20 weeks of gestation with nonmissing birth weight.^– GSTT1, normal GSTT1 allele; GSTT1del, GSTT1 deletion; CYP1A1 AA, CYP1A1 AA genotype; CYP2A6 TT, CYP2A6 TT genotype.^–