title: A genome-wide association study identifies susceptibility loci of silica-related pneumoconiosis in Han Chinese.
abstract: 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.
authors.affiliation: Department of Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, School of Public Health.
authors.forename: Minjie
authors.initials: M
authors.lastname: Chu
authors.affiliation: Department of Occupational Medicine and Environmental Health, School of Public Health.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Ji
authors.affiliation: Ministry of Education Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Weihong
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, School of Public Health.
authors.forename: Ruyang
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, School of Public Health.
authors.forename: Chongqi
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Occupational Medicine and Environmental Health, School of Public Health.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Occupational Medicine and Environmental Health, School of Public Health.
authors.forename: Chen
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, School of Public Health.
authors.forename: Jianhang
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, School of Public Health.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Occupational Medicine and Environmental Health, School of Public Health.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Occupational Medicine and Environmental Health, School of Public Health.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Hou
authors.affiliation: Department of Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, School of Public Health, Section of Clinical Epidemiology, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center and.
authors.forename: Juncheng
authors.initials: J
authors.lastname: Dai
authors.affiliation: Department of Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, School of Public Health, Section of Clinical Epidemiology, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center and.
authors.forename: Guangfu
authors.initials: G
authors.lastname: Jin
authors.affiliation: Ministry of Education Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Tangchun
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, School of Public Health.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, School of Public Health, Section of Clinical Epidemiology, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China and.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Occupational Medicine and Environmental Health, School of Public Health.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Ni
authors.affiliation: Department of Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, School of Public Health, Section of Clinical Epidemiology, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China and hbshen@njmu.edu.cn.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Shen
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002681:China; D015331:Cohort Studies; D004198:Disease Susceptibility; D058851:GPI-Linked Proteins / Q000235:genetics; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics; D008906:Mining; D016273:Occupational Exposure / Q000009:adverse effects*; D011009:Pneumoconiosis / Q000209:etiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012822:Silicon Dioxide / Q000633:toxicity*; D055815:Young Adult
chemical_list: D058851:GPI-Linked Proteins; D012822:Silicon Dioxide; C058479:carboxypeptidase M; D008666:Metalloendopeptidases