学位論文内容の要旨

博士の専攻分野の名称

博士（医 学） 氏 名

Titilola Serifat Braimoh

学 位 論 文 題 名

EFFECTS OF MATERNAL SECONDHAND SMOKE EXPOSURE AND GENEPOLYMORPHISMS OF CYP1A1, EPHX1 AND NAT2 ON INFANT BIRTH SIZE
（妊婦の受動喫煙曝露と CYP1A1, EPHX1 , NAT2 遺伝子多型が出生時体格に及ぼす影響）
BACKGROUND: The recent high prevalence of low birth weight (LBW, defined as
birth weight <2500g) in Japan compared to other developed countries is a major publichealth concern. Nonsmoking pregnant women are at risk of secondhand smoke (SHS)
exposure especially at home due to the high prevalence of smoking among Japanesemen. Results of the effects of secondhand smoke (SHS) exposure on infant birth weightobserved in previous studies are inconclusive. Also, not all mothers who were prenatally
exposed to SHS gave birth to LBW babies. This suggests that genetic susceptibility may
be playing a role.
OBJECTIVE: The main aim of this study was to investigate the moderating role ofmaternal genetic susceptibility in the association of secondhand smoke exposure with
infant birth size
METHODS: A prospective cohort study involving 1336 nonsmoking native Japanesepregnant women enrolled for antenatal care at hospitals within Hokkaido Prefecturefrom 2003 to 2007 was conducted. Self-administered questionnaires and birth records
were used for gathering information on maternal and infants’ characteristics andlifestyle behaviors. Cotinine measurements were carried out by analyzing biochemicallymaternal blood specimen using enzyme-linked immunosorbent assay (ELISA)
technique. Genetic analyses included extraction of genomic DNA from maternal blood
specimen collected at delivery and genotyping using real-time polymerase chain
reaction (PCR) technique. Descriptive statistics, analysis of variance (ANOVA), ROC
curve and multiple linear regression models were used for the statistical analyses. All
statistical analyses were performed using SPSS for Windows, version 16.0.
RESULTS: Exposure to SHS had a marginal association with reductions in the meanbirth weight (-32g, SE, 21; P = 0.07) and birth length (-0.4cm, SE, 0.2; P = 0.09) after
adjusting for the confounding variables. Independently, Tyr/His113 and His/His113

genotypes of EPHX1 Tyr113His had an adverse effect on the mean birth weight (-59g, P= 0.039 and 92g, P = 0.003 respectively). However, in the presence of SHS exposure,
CYP1A1*2C variant genotype conferred an adverse effect on the birth size of the infantsof the exposed mothers (mean birth weight reduction = -88g, SE, 37; P = 0.019 andbirth length reduction = -0.9cm, SE, 0.4; P = 0.025). The exposed women with EPHX1
Tyr113His homozygous recessive genotypes also had the lowest mean birth weight andbirth length (-154g, SE, 42; P < 0.001 and 1.1cm, SE, 0.4; P = 0.010) respectively. For
NAT2*7, the mean reduction in birth weight was 51g (SE, 24; P = 0.034) for theexposed slow acetylators.
EPHX1 Tyr113His and NAT2*7 had a combined effect on the birth weight, birth lengthand head circumference (145g, SE, 48; P = 0.003; 1.1cm, SE, 0.5; P = 0.003; 0.9cm, SE,0.5; P = 0.052 respectively) among the exposed EPHX1 homozygous recessive group
and NAT2*7 slow acetylation genotype. Also, SHS exposure with a combination ofEPHX1 His/His 113 and NAT2*7 fast acetylation genotype groups reduced birth weightby 180g (SE, 70; P = 0.010). Interaction of both genes with SHS exposure had astronger effect on birth weight. The unexposed showed no statistically significant
association between any of the genotypes and birth size reduction.
DISCUSSION: The consistent vulnerability of CYP1A1*2C variant genotypes (A/G+G/G), EPHX1 Tyr113His His/His113 and NAT2*7 slow alleles to the negative effectsof tobacco smoke implies a relationship between metabolic genes and SHS exposure.
CYP1A1 is a phase 1 gene whereas EPHX1 and NAT2 perform dual functions(activation and detoxification) in xenobiotic metabolism depending on the substrate.
The ability of an individual to convert the toxic metabolites of cigarette smoke into lessharmful compounds is crucial for reducing their adverse effects on birth outcomes. The
missense mutation which occurred in EPHX1 Tyr113His at codon 113 of exon 3,
however, may lead to a decrease in enzyme activity while that of CYP1A1*2C variantgenotypes may increase enzyme activity.
This is the first study to demonstrate a significant association between CYP1A1*2C,
EPHX1 Tyr113His and NAT2*7 mutant alleles and SHS exposure with infant birth sizein the Japanese population.
CONCLUSION: This study has demonstrated that maternal genetic factor (EPHX1
Tyr113His, NAT2*7 and CYP1A1*2C) play an important modifying role in theassociation between maternal exposure to SHS during pregnancy and birth size among
Japanese subjects.