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Distinct pathways associated with chromosomal aberration frequency in a cohort exposed to genotoxic compounds compared to general population.
Mutagenesis ( IF 2.5 ) Pub Date : 2019-12-19 , DOI: 10.1093/mutage/gez024
Yasmeen Niazi 1, 2 , Hauke Thomsen 1 , Bozena Smolkova 3 , Ludmila Vodickova 4, 5, 6 , Soňa Vodenkova 4, 5, 7 , Michal Kroupa 4, 6 , Veronika Vymetalkova 4, 5 , Alena Kazimirova 8 , Magdalena Barancokova 8 , Katarina Volkovova 8 , Marta Staruchova 8 , Per Hoffmann 9, 10 , Markus M Nöthen 9, 11 , Maria Dusinska 12 , Ludovit Musak 13 , Pavel Vodicka 4, 5, 6 , Kari Hemminki 1 , Asta Försti 1
Affiliation  

Non-specific structural chromosomal aberrations (CAs) observed in peripheral blood lymphocytes of healthy individuals can be either chromosome-type aberrations (CSAs) or chromatid-type aberrations (CTAs) depending on the stage of cell division they are induced in and mechanism of formation. It is important to study the genetic basis of chromosomal instability as it is a marker of genotoxic exposure and a predictor of cancer risk. For that purpose, we conducted two genome-wide association studies (GWASs) on healthy individuals in the presence and absence of apparent genotoxic exposure from the Czech Republic and Slovakia. The pre-GWAS cytogenetic analysis reported the frequencies of CSA, CTA and total CA (CAtot). We performed both linear and binary logistic regression analysis with an arbitrary cut-off point of 2% for CAtot and 1% for CSA and CTA. Using the statistical threshold of 1.0 × 10-5, we identified five loci with in silico predicted functionality in the reference group and four loci in the exposed group, with no overlap between the associated regions. A meta-analysis on the two GWASs identified further four loci with moderate associations in each of the studies. From the reference group mainly loci within genes related to DNA damage response/repair were identified. Other loci identified from both the reference and exposed groups were found to be involved in the segregation of chromosomes and chromatin modification. Some of the discovered regions in each group were implicated in tumourigenesis and autism.

中文翻译:

与普通人群相比,暴露于遗传毒性化合物的队列中与染色体畸变频率相关的不同途径。

在健康个体的外周血淋巴细胞中观察到的非特异性结构性染色体畸变(CAs)可以是染色体型畸变(CSA)或染色单体型畸变(CTA),具体取决于它们诱导的细胞分裂阶段和形成机理。研究染色体不稳定性的遗传基础非常重要,因为它是遗传毒性暴露的标志物和癌症风险的预测指标。为此,我们在存在和不存在来自捷克共和国和斯洛伐克的明显遗传毒性的情况下,对健康个体进行了两项全基因组关联研究(GWAS)。GWAS之前的细胞遗传学分析报告了CSA,CTA和总CA(CAtot)的频率。我们执行了线性和二进制逻辑回归分析,其中CAtot的任意临界点为2%,CSA和CTA的临界点为1%。使用1.0×10-5的统计阈值,我们在参考组中确定了五个具有计算机预测功能的基因座,在暴露组中确定了四个基因座,相关区域之间没有重叠。对这两个GWAS的荟萃分析在每项研究中均确定了另外四个具有中等关联的基因座。从参考组中,主要鉴定了与DNA损伤应答/修复相关的基因内的基因座。从参考组和暴露组中都鉴定出的其他基因座被发现与染色体分离和染色质修饰有关。每组中一些发现的区域与肿瘤形成和自闭症有关。在相关区域之间没有重叠。对这两个GWAS的荟萃分析在每项研究中均确定了另外四个具有中等关联的基因座。从参考组中,主要鉴定了与DNA损伤应答/修复相关的基因内的基因座。从参考组和暴露组中都鉴定出的其他基因座被发现与染色体分离和染色质修饰有关。每组中一些发现的区域与肿瘤形成和自闭症有关。在相关区域之间没有重叠。对这两个GWAS的荟萃分析在每项研究中均确定了另外四个具有中等关联的基因座。从参考组中,主要鉴定了与DNA损伤应答/修复相关的基因内的基因座。从参考组和暴露组中都鉴定出的其他基因座被发现与染色体分离和染色质修饰有关。每组中一些发现的区域与肿瘤形成和自闭症有关。从参考组和暴露组中都鉴定出的其他基因座被发现与染色体分离和染色质修饰有关。每组中一些发现的区域与肿瘤形成和自闭症有关。从参考组和暴露组中都鉴定出的其他基因座被发现与染色体分离和染色质修饰有关。每组中一些发现的区域与肿瘤形成和自闭症有关。
更新日期:2019-11-01
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