Chu Minjie, Ji Xiaoming, Chen Weihong, Zhang Ruyang, Sun Chongqi, Wang Ting, Luo Chen, Gong Jianhang, Zhu Meng, Fan Jingjing, Hou Zhiguo, Dai Juncheng, Jin Guangfu, Wu Tangchun, Chen Feng, Hu Zhibin, Ni Chunhui, Shen Hongbing
Department of Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, School of Public Health.
Department of Occupational Medicine and Environmental Health, School of Public Health.
Hum Mol Genet. 2014 Dec 1;23(23):6385-94. doi: 10.1093/hmg/ddu333. Epub 2014 Jul 1.
Pneumoconiosis is the most serious occupational disease in China and its leading cause is occupational silica exposure. Pneumoconiosis takes several years to develop depending on the exposure level of silica. However, individual variation in the susceptibility to pneumoconiosis has been observed among the subjects with similar exposure. We conducted a genome-wide screening with 710,999 single nucleotide polymorphisms (SNPs) in a cohort of 400 coal workers (202 cases and 198 exposed controls) for pneumoconiosis susceptible loci. Seven promising variants were evaluated in an independent cohort of 568 coal workers (323 cases and 245 exposed controls), followed by a second replication on 463 iron ore workers (167 cases and 296 exposed controls). By pooling all of the genome-wide association studies and replication stages together, we found a genome-wide significant (P < 5.0 × 10(-8)) association for rs73329476 (P = 1.74 × 10(-8), OR = 2.17, 95% CI = 1.66-2.85) and two additional replicated associations for rs4320486 (P < 0.05) and rs117626015 (P < 0.05) with combined P-values of 4.29 × 10(-6) and 5.05 × 10(-6), respectively. In addition, the risk allele T of rs73329476 was significantly associated with lower mRNA expression levels of carboxypeptidase M (CPM) in total cellular RNA from whole blood of 156 healthy individuals (P = 0.0252). The identified pneumoconiosis susceptibility loci may provide new insights into the pathogenesis of pneumoconiosis, and may also have some clinical utility for risk prediction for pneumoconiosis and high-risk population screening for workers with occupational silica exposure.
尘肺病是我国最严重的职业病，其主要病因是职业性接触二氧化硅。尘肺病的发病需要数年时间，具体取决于二氧化硅的接触水平。然而，在接触情况相似的人群中，已观察到尘肺病易感性存在个体差异。我们对400名煤矿工人（202例病例和198名接触对照）组成的队列进行了全基因组筛查，检测了710,999个单核苷酸多态性（SNP），以寻找尘肺病易感基因座。在一个由568名煤矿工人（323例病例和245名接触对照）组成的独立队列中对7个有前景的变异进行了评估，随后在463名铁矿石工人（167例病例和296名接触对照）中进行了第二次重复验证。通过将所有全基因组关联研究和重复验证阶段的数据汇总在一起，我们发现rs73329476存在全基因组显著关联（P < 5.0 × 10(-8)）（P = 1.74 × 10(-8)，OR = 2.17，95% CI = 1.66 - 2.85），另外还发现rs4320486（P < 0.05）和rs117626015（P < 0.05）存在两个重复关联，其合并P值分别为4.29 × 10(-6)和5.05 × 10(-6)。此外，rs73329476的风险等位基因T与156名健康个体全血总细胞RNA中羧肽酶M（CPM）的mRNA表达水平显著降低相关（P = 0.0252）。所确定的尘肺病易感基因座可能为尘肺病的发病机制提供新的见解，也可能对尘肺病的风险预测以及职业性接触二氧化硅工人的高危人群筛查具有一定的临床应用价值。
