Maternal and newborn polymorphisms in phase I/II metabolic genes contribute to risk of adverse reproductive outcomes.

摘要

Maternal cigarette smoke exposure during pregnancy has been identified as a risk factor for adverse reproductive outcomes, a major public health concern. However, little is known about genetic susceptibility and possible interactions with environmental factors to increase risk of these events. This study was designed to investigate relative contributions of genetic and maternal environmental risk factor interactions to adverse reproductive outcomes. Maternal peripheral and umbilical cord blood samples from 1148 healthy mother/newborn pairs were genotyped for a panel of polymorphisms associated with the metabolic enzymes CYP1A1, CYP2E1, GSTM1, GSTT1 and NAT2* for several subgroups; low birthweight (2500g, n = 86), preterm delivery (37th gestational week, n = 93), premature birth (2500g & 37th gestational week, n = 53) and small for gestational age (SGA) at term (≥37th gestational week, n = 948) in comparison to the average for gestational age (AGA) group (n = 948).; Maternal cigarette smoking during the last trimester was significantly associated with birthweight reduction (mu = 101.4g, SE = 32, p = 0.002). Maternal GSTT1 null genotype was significantly associated with low birthweight (OR = 1.97, 95% CI: 1.24--3.12, p = 0.004), preterm delivery (OR = 1.91, 95% CI: 1.22--2.98, p = 0.004) and premature birth (OR = 2.42, 95% CI: 1.38--4.26, p = 0.002). The mean reduction of birthweight observed among the maternal GSM null genotype group was 89.6g (SE = 37, p = 0.018) and the mean reduction in gestational age was 0.25 weeks (SE = 0.1, p = 0.049). In addition, African American women were more likely to have a smaller baby; the mean reduction of birthweight was 230g (SE = 34.5, p 0.001) compared with Caucasians. An additive interaction between smoking, African American ethnicity and GSTT1 null genotype was observed (OR = 7.81, 95% CI: 2.49--24.43, p 0.001). The mean birthweight reduction observed in this group was 570.0g (SE = 117, p 0.001) and the mean gestational age reduction was 1.10 weeks (SE = 0.4, p = 0.007). A similar risk was observed for newborn GSTT1 null genotype in the presence of maternal smoking (426.7g, SE = 111, p 0.001) and (1.0 weeks, SE = 0.4, p = 0.012).; These results demonstrated a clear overrepresentation of maternal and newborn GSTT1 null genotype among adverse reproductive outcome cases. Furthermore, a gene-gene-environment interaction was observed where the combination of maternal and newborn GSTT1 null genotype in the presence of maternal cigarette smoke during pregnancy significantly increased risk of adverse reproductive outcomes.