Abstract：
BACKGROUND: Epigenetic changes leading to improper methylation of the pericentromeric region of chromosome 21 may contribute to the nondisjunction of this chromosome. Polymorphisms in the DNA Methyltransferase 3B (DNMT3B) gene, one of the crucial gene of the folate metabolism, affects the activity of the enzyme and increases the susceptibility of nondisjunction in mothers of Down syndrome children (MDS).
METHODS: Considering this hypothesis we investigated the association of single nucleotide polymorphisms in the promoter region of the DNMT3B gene (rs1569686 -579G>T; rs2424913 -149C>T) with a predisposition of mothers to deliver a Down syndrome (DS) child. The study was performed on DNA samples from 150 MDS and 172 control mothers. Transmission disequilibrium tests were performed on 103 DS trio families. Genotyping was done using a polymerase chain reaction-restriction fragment length polymorphism method.
RESULTS: With respect to the single nucleotide polymorphisms studied, no significant difference was observed in the genotypes and alleles frequency distributions between MDS and control mothers. The frequency of the DNMT3B-579G allele was, respectively, 0.34 in MDS and 0.33 in control mothers whereas the frequency of the DNMT3B-149C allele was respectively 0.31 in MDS and 0.26 in control mothers. No significant deviation in genotypic combinations as well as in transmission disequilibrium tests analysis was observed. However, a strong linkage disequilibrium was observed with significant differences in the distribution of G-T and G-C haplotypes among case and control mothers.
CONCLUSIONS: Although the above studied polymorphisms of DNMT3B may not be an independent risk factor it might be possible that certain allelic combinations (G-T) are. This finding suggests that DNMT3B might be a maternal risk factor for DS in our Indian cohort. Replication studies are required to confirm these findings.
METHODS: Considering this hypothesis we investigated the association of single nucleotide polymorphisms in the promoter region of the DNMT3B gene (rs1569686 -579G>T; rs2424913 -149C>T) with a predisposition of mothers to deliver a Down syndrome (DS) child. The study was performed on DNA samples from 150 MDS and 172 control mothers. Transmission disequilibrium tests were performed on 103 DS trio families. Genotyping was done using a polymerase chain reaction-restriction fragment length polymorphism method.
RESULTS: With respect to the single nucleotide polymorphisms studied, no significant difference was observed in the genotypes and alleles frequency distributions between MDS and control mothers. The frequency of the DNMT3B-579G allele was, respectively, 0.34 in MDS and 0.33 in control mothers whereas the frequency of the DNMT3B-149C allele was respectively 0.31 in MDS and 0.26 in control mothers. No significant deviation in genotypic combinations as well as in transmission disequilibrium tests analysis was observed. However, a strong linkage disequilibrium was observed with significant differences in the distribution of G-T and G-C haplotypes among case and control mothers.
CONCLUSIONS: Although the above studied polymorphisms of DNMT3B may not be an independent risk factor it might be possible that certain allelic combinations (G-T) are. This finding suggests that DNMT3B might be a maternal risk factor for DS in our Indian cohort. Replication studies are required to confirm these findings.
摘要：
背景：导致21号染色体着丝粒周区不正确甲基化的表观遗传变化可能导致该染色体不分离。DNA甲基转移酶3B（DNMT3B）基因的多态性，叶酸代谢的关键基因之一，影响酶的活性并增加唐氏综合征儿童（MDS）母亲的非分离易感性。
方法：考虑到这一假设，我们研究了DNMT3B基因启动子区域的单核苷酸多态性（rs1569686-579G>T；rs2424913-149C>T）与母亲分娩唐氏综合症（DS）儿童的易感性的关联。这项研究是对150名MDS母亲和172名对照母亲的DNA样本进行的。对103个DS三重奏家族进行了传输不平衡测试。使用聚合酶链反应-限制性片段长度多态性方法进行基因分型。
结果：关于所研究的单核苷酸多态性，MDS和对照母亲之间的基因型和等位基因频率分布没有显着差异。DNMT3B-579G等位基因的频率为,分别,MDS中的0.34和对照母亲中的0.33，而DNMT3B-149C等位基因的频率分别为MDS中的0.31和对照母亲中的0.26。在基因型组合和传播不平衡测试分析中未观察到显着偏差。然而,观察到强烈的连锁不平衡，病例母亲和对照母亲之间的G-T和G-C单倍型分布存在显着差异。
结论：尽管上述研究的DNMT3B多态性可能不是独立的危险因素，但某些等位基因组合（G-T）可能是独立的危险因素。这一发现表明DNMT3B可能是我们印度队列中DS的孕产妇危险因素。需要复制研究来证实这些发现。
方法：考虑到这一假设，我们研究了DNMT3B基因启动子区域的单核苷酸多态性（rs1569686-579G>T；rs2424913-149C>T）与母亲分娩唐氏综合症（DS）儿童的易感性的关联。这项研究是对150名MDS母亲和172名对照母亲的DNA样本进行的。对103个DS三重奏家族进行了传输不平衡测试。使用聚合酶链反应-限制性片段长度多态性方法进行基因分型。
结果：关于所研究的单核苷酸多态性，MDS和对照母亲之间的基因型和等位基因频率分布没有显着差异。DNMT3B-579G等位基因的频率为,分别,MDS中的0.34和对照母亲中的0.33，而DNMT3B-149C等位基因的频率分别为MDS中的0.31和对照母亲中的0.26。在基因型组合和传播不平衡测试分析中未观察到显着偏差。然而,观察到强烈的连锁不平衡，病例母亲和对照母亲之间的G-T和G-C单倍型分布存在显着差异。
结论：尽管上述研究的DNMT3B多态性可能不是独立的危险因素，但某些等位基因组合（G-T）可能是独立的危险因素。这一发现表明DNMT3B可能是我们印度队列中DS的孕产妇危险因素。需要复制研究来证实这些发现。
