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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  &lt; 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  &lt; 0.05) and rs117626015 ( P  &lt; 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.

A genome-wide association study identifies susceptibility loci of silica-related pneumoconiosis in Han Chinese