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.

miRNA sequencing reveals miRNA‐4508 from peripheral blood lymphocytes as potential diagnostic biomarker for silica‐related pulmonary fibrosis: A multistage study

“…This study has several merits. Previous studies have clearly shown that silica dust exposure is associated with SPF risk, and that silica dust exposure‐based matching can be effective in controlling for potential confounding effects when studying genetic susceptibility . In the current study, all cases and controls in each stage (except GSE80555) were matched by years of silica dust exposure, which may considerably increase the possibility of identifying potential biomarkers.…”

GITR promoter polymorphism contributes to risk of coal workers’ pneumoconiosis: A case–control study from China

“…Genetic factors can influence the susceptibility and/or severity of CWP. Indeed, a series of genetic factors have been documented in association with initiation and development of CWP, including genes modulating inflammatory and immune responses [6,8]. Interaction of GITR with GITRL could up-regulate conventional T cell responses and down-regulate T reg suppressor activity, thus upset the balance and result in a breakdown of autoimmune response and immunological tolerance [23,31].…”

“…prolonged lung inflammation and fibrotic nodular lesions that usually lead to progressive fibrosis [5]. Although silica dust exposure is recognized as the primary cause of pneumoconiosis, extensive researches indicate that genetic factors have played important roles in the development of pulmonary fibrosis [2,[6][7][8]. During the past four decades in China, CWP continues to occur even though work environment and prevention measures have been greatly improved [9], and still more than 23 million workers exposed to silica particles [10].…”

Coal mine dust lung disease in the modern era

“…No genomic markers, however, have been validated to date . This includes potential susceptibility loci from genome‐wide association studies (GWAS, rs73329476, rs4320486 and rs117626015), and the T1559C/rs5368 polymorphism . Regarding TNF‐α, the TNF‐α‐308A allele has been linked to ever having CWP especially with nodules as opposed to PMF, whereas TNF‐α promoter TNF2 polymorphism has been associated with the development of large opacities .…”