COMT、CYP1A1基因多态性与子宫肌瘤相关性研究
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摘要
子宫肌瘤是女性生殖器官中最常见的良性肿瘤,是导致子宫切除的主要原因。该病的发生是遗传因素和环境因素共同作用的结果。由于子宫肌瘤是复杂的多基因遗传性疾病,其易感基因的数量、各基因的致病风险度以及致病机制尚未被阐明。因此,确定子宫肌瘤易感基因和决定疾病易感性的SNPs,进一步揭示子宫肌瘤的遗传背景及其发病机制,在基因水平上预防和治疗该病具有重要意义。
本研究采用病例-对照研究方法以中国汉族30岁～50岁子宫肌瘤患者和排除子宫肌瘤及其他雌激素依赖性疾病的健康女性为研究对象,应用生物信息学和分子生物学方法,检测分别位于22q11.2和15q22-24染色体区域的2个候选基因COMT和CYP1A1上的SNPs,筛检与子宫肌瘤相关联的基因位点。在2个候选基因上共选择4个SNPs作为遗传标记,利用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)分析方法确定个体基因型。应用SPSS12.0和UNPHASED 3.0.12统计软件分析处理数据。
结果显示COMT基因rs165774和rs3087869位点的基因多态性与中国汉族人群子宫肌瘤的发病无关联,COMT基因rs165599位点和CYP1A1基因的rs4646903位点的基因多态性可能与中国汉族人群子宫肌瘤的发病相关联。rs165599位点可能是中国汉族人群子宫肌瘤的易感位点,携带A/G基因型的女性可能是子宫肌瘤的易感人群。
本实验结果将有助于阐明子宫肌瘤的分子遗传学机制,为在基因水平上预测个体发病风险,有效防治子宫肌瘤,提高妇女生殖健康水平奠定重要的实验基础。
Uterine leiomyoma is not only the most common benign tumor in female organ, but also the one of the most common benign tumors in human body. Its etiopathogenisis probably is the hyperplasia of uterine smooth muscle cells. The morbidity rate in women with reproductive age is 20.0 % to 25.0 %. And the patients during 40 to 50 years old have the maximum morbidity rate which is about 52.2 % to 60.0 %. In fact, the quantity of the susceptibility genes, the pathopoiesis risk of candidate genes and its pathogenic mechanism remain unknown, because the uterine leiomyoma is also a representative complex disorder with typical heterogeneity. Since the investigations of the molecular genetics for uterine leiomyoma become noticeable generally, the more and more pathogenic mechanisms and predisposing factors of uterine leiomyoma have been demonstrated.
Objective:
To investigate the association between catechol-o-methyl transferase (COMT), cytochrome P4501A1 (CYP1A1) genes polymorphism and uterine leiomyoma in ordert to determine the predisposing genes and single nucleotide polymorphisms (SNPs) for uterine leiomyoma.
Methods:
A case-control study was established in this research. 170 healthy women had been chosen as the control group and 156 women with uterine leiomyoma from NO.1 Hospital of Jilin University had been chosen as the case group. The uterine leiomyoma patients had been diagnosed exactly with imageology and pathology in department of gynaecology and obstetrics, the control subjects were recruited from the same areas and had been considered as healthy individuals. These participants were all Chinese of Han origin, aged 30 to 50 years. All of them did not have a history of other gynecological tumors, diseases related with estrogen, usage of estrogenic drugs, induced abortion and breast-feed. About 5 ml of venous blood sample was drawn from each participant for extraction of genomic DNA. The COMT and CYP1A1 genes were chosen as candidate genes for uterine leiomyoma predisposing genes, and the single nucleotide polymorphisms (SNPs) had been determined as genetic markers.
Four SNPs present in COMT and CYP1A1 genes were chosen by accessing the databases at http://www.ncbi.nlm.nih.gov/, http://www.ncbi.nlm.nih.gov/ SNP and http://snp.cshl.org/ web sites. The candidate SNPs included rs3087869, rs165774 and rs165599 present in the COMT locus, and rs4646903 in the CYP1A1 locus, respectively. The genotyping of four SNPs were conducted by PCR-based restriction fragment length polymorphism (RFLP) analysis.
The goodness-of-fit test showed that if the genotypic distributions of all SNPs were deviated from the Hardy-Weinberg equilibrium. The statistical software SPSS12.0 program was applied to test allelic association for a single locus. The conditional test was performed with the UNPHASED3.0.12 software and used to test the combined effect of distinct loci on the disease by conditioning on allele (COA) or by conditioning on genotype (COG). Results:
(1) The Hardy-Weinberg equilibrium
The goodness-of-fit test showed that the genotypic distributions of all SNPs were not deviated from the H-W equilibrium (P>0.05), and thus this sample pool was suitable for the genetic analysis.
(2)Analysis of the effect of single locus
The frequencies of alleles and genotypes of the genes were statistically computed with the UNPHASED3.0.12 software. There were no significant differences of the allelic frequencies and genotypes in the rs3087869, rs165774 between the case and control group(sP>0.05).There were significant differences of the allelic frequencies and genotype in the rs165599 locus of COMT gene between the case and control groups (P=0.029 and P=0.016). The frequency distributions of genotypes had no markedly differences between the patients and the controls in the rs4646903 locus of CYP1A1 gene (P=0.110), but there were significant differences of the allelic frequencies (P=0.043).
(3) The association analysis of multi-loci
It was shown that there were no significant differences of association between the interaction of muti-loci and uterine leiomyoma.
Conclusions:
There were no significant differences of the allelic frequencies and genotypes in the rs3087869 and rs165774 loci of COMT gene between the case and control groups. The rs165599 of COMT gene may be associated with uterine leiomyoma. The frequency distributions of genotypes had no markedly differences between the patients and the controls in the rs4646903 locus of CYP1A1 gene, but the allelic frequencies may be associated with uterine leiomyoma. There were no association between the interaction of muti-loci and uterine leiomyoma. Further replication with more sample collection is needed to draw a firm conclusion.
本研究采用病例-对照研究方法以中国汉族30岁～50岁子宫肌瘤患者和排除子宫肌瘤及其他雌激素依赖性疾病的健康女性为研究对象,应用生物信息学和分子生物学方法,检测分别位于22q11.2和15q22-24染色体区域的2个候选基因COMT和CYP1A1上的SNPs,筛检与子宫肌瘤相关联的基因位点。在2个候选基因上共选择4个SNPs作为遗传标记,利用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)分析方法确定个体基因型。应用SPSS12.0和UNPHASED 3.0.12统计软件分析处理数据。
结果显示COMT基因rs165774和rs3087869位点的基因多态性与中国汉族人群子宫肌瘤的发病无关联,COMT基因rs165599位点和CYP1A1基因的rs4646903位点的基因多态性可能与中国汉族人群子宫肌瘤的发病相关联。rs165599位点可能是中国汉族人群子宫肌瘤的易感位点,携带A/G基因型的女性可能是子宫肌瘤的易感人群。
本实验结果将有助于阐明子宫肌瘤的分子遗传学机制,为在基因水平上预测个体发病风险,有效防治子宫肌瘤,提高妇女生殖健康水平奠定重要的实验基础。
Uterine leiomyoma is not only the most common benign tumor in female organ, but also the one of the most common benign tumors in human body. Its etiopathogenisis probably is the hyperplasia of uterine smooth muscle cells. The morbidity rate in women with reproductive age is 20.0 % to 25.0 %. And the patients during 40 to 50 years old have the maximum morbidity rate which is about 52.2 % to 60.0 %. In fact, the quantity of the susceptibility genes, the pathopoiesis risk of candidate genes and its pathogenic mechanism remain unknown, because the uterine leiomyoma is also a representative complex disorder with typical heterogeneity. Since the investigations of the molecular genetics for uterine leiomyoma become noticeable generally, the more and more pathogenic mechanisms and predisposing factors of uterine leiomyoma have been demonstrated.
Objective:
To investigate the association between catechol-o-methyl transferase (COMT), cytochrome P4501A1 (CYP1A1) genes polymorphism and uterine leiomyoma in ordert to determine the predisposing genes and single nucleotide polymorphisms (SNPs) for uterine leiomyoma.
Methods:
A case-control study was established in this research. 170 healthy women had been chosen as the control group and 156 women with uterine leiomyoma from NO.1 Hospital of Jilin University had been chosen as the case group. The uterine leiomyoma patients had been diagnosed exactly with imageology and pathology in department of gynaecology and obstetrics, the control subjects were recruited from the same areas and had been considered as healthy individuals. These participants were all Chinese of Han origin, aged 30 to 50 years. All of them did not have a history of other gynecological tumors, diseases related with estrogen, usage of estrogenic drugs, induced abortion and breast-feed. About 5 ml of venous blood sample was drawn from each participant for extraction of genomic DNA. The COMT and CYP1A1 genes were chosen as candidate genes for uterine leiomyoma predisposing genes, and the single nucleotide polymorphisms (SNPs) had been determined as genetic markers.
Four SNPs present in COMT and CYP1A1 genes were chosen by accessing the databases at http://www.ncbi.nlm.nih.gov/, http://www.ncbi.nlm.nih.gov/ SNP and http://snp.cshl.org/ web sites. The candidate SNPs included rs3087869, rs165774 and rs165599 present in the COMT locus, and rs4646903 in the CYP1A1 locus, respectively. The genotyping of four SNPs were conducted by PCR-based restriction fragment length polymorphism (RFLP) analysis.
The goodness-of-fit test showed that if the genotypic distributions of all SNPs were deviated from the Hardy-Weinberg equilibrium. The statistical software SPSS12.0 program was applied to test allelic association for a single locus. The conditional test was performed with the UNPHASED3.0.12 software and used to test the combined effect of distinct loci on the disease by conditioning on allele (COA) or by conditioning on genotype (COG). Results:
(1) The Hardy-Weinberg equilibrium
The goodness-of-fit test showed that the genotypic distributions of all SNPs were not deviated from the H-W equilibrium (P>0.05), and thus this sample pool was suitable for the genetic analysis.
(2)Analysis of the effect of single locus
The frequencies of alleles and genotypes of the genes were statistically computed with the UNPHASED3.0.12 software. There were no significant differences of the allelic frequencies and genotypes in the rs3087869, rs165774 between the case and control group(sP>0.05).There were significant differences of the allelic frequencies and genotype in the rs165599 locus of COMT gene between the case and control groups (P=0.029 and P=0.016). The frequency distributions of genotypes had no markedly differences between the patients and the controls in the rs4646903 locus of CYP1A1 gene (P=0.110), but there were significant differences of the allelic frequencies (P=0.043).
(3) The association analysis of multi-loci
It was shown that there were no significant differences of association between the interaction of muti-loci and uterine leiomyoma.
Conclusions:
There were no significant differences of the allelic frequencies and genotypes in the rs3087869 and rs165774 loci of COMT gene between the case and control groups. The rs165599 of COMT gene may be associated with uterine leiomyoma. The frequency distributions of genotypes had no markedly differences between the patients and the controls in the rs4646903 locus of CYP1A1 gene, but the allelic frequencies may be associated with uterine leiomyoma. There were no association between the interaction of muti-loci and uterine leiomyoma. Further replication with more sample collection is needed to draw a firm conclusion.
引文
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