Wang Jing, Sun Dejun, Lu Wenju, Zhang Zili, Zhang Chenting, Hu Ke
Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
Department of Rehabilitation Medicine, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, China.
Exp Physiol. 2020 Nov;105(11):1950-1959. doi: 10.1113/EP088210. Epub 2020 Sep 24.
What is the central question of this study? What is the role of breast cancer type 1 interacting protein C-terminal helicase 1 (BRIP1) polymorphism in chronic obstructive pulmonary disease (COPD)? What is the main finding and its importance? Variant rs10744996C>A of BRIP1 increases the susceptibility of the Mongolian population to COPD. The expression of BRIP1 was significantly reduced in cigarette smoke extract-treated airway epithelial cells.
Cigarette smoke is a major environmental pollutant that can induce DNA damage in humans. The development and progression of chronic obstructive pulmonary disease (COPD) are known to be related to the impairment of DNA repair. Breast cancer type 1 interacting protein C-terminal helicase 1 (BRIP1) plays an important role in DNA interstrand crosslink repair and double-strand break repair. However, the role of BRIP1 polymorphisms in COPD has not been previously described. In this study, whole genome sequencing was used to identify mutations, and single nucleotide polymorphism (SNP) genotyping was used to verify the selected SNPs. In addition the BRIP1 expression levels in 16HBE and A549 airway epithelial cells treated with or without cigarette smoke extract (CSE) were measured using western blotting and RT-qPCR. Rs10744996C>A in the 3'-untranslated region (3'UTR) of BRIP1 was then genotyped in 1296 COPD cases and 988 healthy control subjects from a Mongolian population in northern China. Significant differences in the distribution of rs10744996C>A variants between COPD and control groups (P = 0.001) were identified. Rs10744996C>A was found to be associated with significantly increased COPD risk (adjusted odds ratio = 1.60, 95% CI = 1.30-1.98, P < 0.0001). Additionally, rs10744996A genotype was found to interact with a family history of cancer and a history of x-ray exposure (P = 0.028 and 0.009, respectively). BRIP1 expression levels in 16HBE and A549 cells treated with CSE were significantly lower compared to the control treated cells. The rs10744996C>A variant of BRIP1 increased the COPD susceptibility of the Mongolian population cohort. BRIP1 mRNA and protein expression levels were significantly reduced in conjunction with CSE-induced DNA damage in 16HBE and A549 cells.
本研究的核心问题是什么？乳腺癌1型相互作用蛋白C末端解旋酶1（BRIP1）多态性在慢性阻塞性肺疾病（COPD）中起什么作用？主要发现及其重要性是什么？BRIP1的rs10744996C>A变异增加了蒙古族人群患COPD的易感性。在香烟烟雾提取物处理的气道上皮细胞中，BRIP1的表达显著降低。
香烟烟雾是一种主要的环境污染物，可导致人类DNA损伤。已知慢性阻塞性肺疾病（COPD）的发生和发展与DNA修复功能受损有关。乳腺癌1型相互作用蛋白C末端解旋酶1（BRIP1）在DNA链间交联修复和双链断裂修复中起重要作用。然而，此前尚未描述BRIP1多态性在COPD中的作用。在本研究中，使用全基因组测序来识别突变，并使用单核苷酸多态性（SNP）基因分型来验证所选的SNP。此外，使用蛋白质免疫印迹法和逆转录定量聚合酶链反应（RT-qPCR）测量了在有或无香烟烟雾提取物（CSE）处理的16HBE和A549气道上皮细胞中BRIP1的表达水平。然后，对来自中国北方蒙古族人群的1296例COPD病例和988例健康对照者进行了BRIP1 3'-非翻译区（3'UTR）中rs10744996C>A的基因分型。确定了COPD组和对照组之间rs10744996C>A变异分布的显著差异（P = 0.001）。发现rs10744996C>A与COPD风险显著增加相关（调整后的优势比 = 1.60，95%可信区间 = 1.30 - 1.98，P < 0.0001）。此外，发现rs10744996A基因型与癌症家族史和X射线暴露史存在相互作用（分别为P = 0.028和0.009）。与对照处理的细胞相比，CSE处理的16HBE和A549细胞中BRIP1的表达水平显著降低。BRIP1的rs10744996C>A变异增加了蒙古族人群队列患COPD的易感性。在16HBE和A549细胞中，BRIP1的mRNA和蛋白质表达水平随着CSE诱导的DNA损伤而显著降低。
