Sata Fumihiro, Yamada Hideto, Suzuki Kana, Saijo Yasuaki, Yamada Takashi, Minakami Hisanori, Kishi Reiko
Department of Public Health, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Pharmacogenet Genomics. 2006 Nov;16(11):775-81. doi: 10.1097/01.fpc.0000230116.49452.c0.
The pathophysiologic processes that occur at the cellular and molecular levels in intrauterine fetal growth restriction are largely unknown. Catechol-O-methyltransferase (COMT) is a phase II enzyme that inactivates catechol estrogens by transfer of a methyl group. A functional Val158Met polymorphism in the COMT gene has been known as a susceptible marker for breast cancer. The aim of this study was to examine the association between this polymorphism and fetal growth.
A consecutive series of 412 women who experienced singleton deliveries was assessed in the birth cohort study. Genotyping of COMT and CYP17A1 polymorphisms was determined by allelic discrimination using fluorogenic probes and the 5'nuclease assay.
The adjusted odds ratio for the risk of low birth weight (<2.500 g) in women with homozygous low-activity (COMT-L) alleles was 2.98 (95% confidence interval, 1.10-8.11). The mean birth weight of infants whose mothers were homozygous for COMT-L was less than that of infants whose mothers had at least one high-activity (COMT-H) allele (2.610 versus 2.800 g, P=0.07). The odds ratio for the risk of intrauterine fetal growth restriction, defined as birth weight <10th percentile or <mean-1.5 SD, in women homozygous for COMT-L alleles was 2.63/2.57 (95% confidence interval, 1.14-6.05/0.96-6.88). In the recessive genotype model, the odds ratios for the risk of low birth weight and intrauterine fetal growth restriction in women homozygous for COMT-L were 3.36 (95% confidence interval, 1.30-8.65) and 2.89/2.65 (95% confidence interval, 1.31-6.34/1.06-6.65), respectively. A positive association exists between birth weight and the homozygous CYP17A1 A2 genotype (P<0.01). When both COMT and CYP17A1 genotypes were considered, the highest risk of low birth weight/intrauterine fetal growth restriction was found among women with the homozygous COMT-L and CYP17A1 A1 genotype. The odds ratio for the risk of intrauterine fetal growth restriction (<10th percentile) in those women was 5.35 (95% confidence interval, 1.15-25.0).
Our findings suggest that the allele encoding low-activity COMT may be a susceptible marker for intrauterine fetal growth restriction.
宫内胎儿生长受限在细胞和分子水平上发生的病理生理过程很大程度上尚不清楚。儿茶酚-O-甲基转移酶（COMT）是一种II期酶，通过甲基转移使儿茶酚雌激素失活。COMT基因中的功能性Val158Met多态性已被认为是乳腺癌的易感标志物。本研究的目的是检查这种多态性与胎儿生长之间的关联。
在出生队列研究中对连续412名单胎分娩的女性进行了评估。使用荧光探针和5'核酸酶测定法通过等位基因鉴别确定COMT和CYP17A1多态性的基因分型。
纯合低活性（COMT-L）等位基因女性低出生体重（<2500 g）风险的校正比值比为2.98（95%置信区间，1.10-8.11）。母亲为COMT-L纯合子的婴儿的平均出生体重低于母亲至少有一个高活性（COMT-H）等位基因的婴儿（2.610对2.800 g，P = 0.07）。COMT-L等位基因纯合的女性中，定义为出生体重<第10百分位数或<均值-1.5标准差的宫内胎儿生长受限风险的比值比为2.63/2.57（95%置信区间，1.14-6.05/0.96-6.88）。在隐性基因型模型中，COMT-L纯合女性低出生体重和宫内胎儿生长受限风险的比值比分别为3.36（95%置信区间，1.30-8.65）和2.89/2.65（95%置信区间，1.31-6.34/1.06-6.65）。出生体重与CYP17A1 A2纯合基因型之间存在正相关（P<0.01）。当同时考虑COMT和CYP17A1基因型时，则COMT-L纯合和CYP17A1 A1基因型的女性中低出生体重/宫内胎儿生长受限的风险最高。这些女性中宫内胎儿生长受限（<第10百分位数）风险的比值比为5.35（95%置信区间，1.15-25.0）。
我们的研究结果表明，编码低活性COMT的等位基因可能是宫内胎儿生长受限的易感标志物。
