Riassunto

Objectives To determine whether genetic polymorphisms in several candidate genes related to innate immunity and protease–antiprotease balance modify individual susceptibility to develop asbestos-related fibrotic pleuropulmonary changes.

Methods Sixteen polymorphisms from nine genes (NLRP3, CARD8, TNF, TGFB1, GC, MMP1, MMP9, MMP12 and TIMP2) were genotyped from 951 Finnish asbestos-exposed workers. The genotype/haplotype data were compared to signs of fibrosis and pleural thickenings using linear and logistic regression analysis adjusted for potential confounders.

Results A functional polymorphism (Q705K; rs35829419) in the NLRP3 gene was associated with interstitial lung fibrosis (p=0.013), and the TGFB1 rs2241718 SNP with visceral pleural fibrosis (VPF) (p=0.044). In stratified analysis, the carriage of at least one NLRP3 variant allele conferred a 2.5-fold increased risk for pathological interstitial lung fibrosis (OR 2.44, 95% CI 0.97 to 6.14). Conversely, the carriage of at least one TGFB1 rs2241718 variant allele protected against VPF (OR 0.62, 95% CI 0.39 to 0.98). The TIMP2 rs2277698 SNP and a haplotype consisting of the TGFB1 rs1800469 and rs1800470 SNPs were associated with the degree of pleural thickening calcification (p=0.037 and p=0.035), and the CARD8 rs2043211 SNP with the greatest thickness of pleural plaques (p=0.015).

Conclusions Our results support the hypothesis that the NLRP3 inflammasome is important in the development of fibrotic lung disease by associating the NLRP3 rs35829419 variant allele with increased risk of asbestos-related interstitial lung fibrosis, and the TGFB1 rs2241718 variant allele with decreased risk of asbestos-related VPF. Polymorphisms in CARD8 and TIMP2 are proposed to modify the development and/or calcification of pleural thickenings.

Commento

Nel panorama dei meccanismi patogenetici responsabili delle patologie polmonari da amianto, un ruolo di primaria importanza è svolto da una risposta infiammatoria cronica mediata da specie reattive dell'ossigeno, citochine, fattori di crescita, fattori pro-infiammatori e fattori proteolitici. I geni coinvolti in questi processi sono tutti potenziali responsabili delle variazioni della suscettibilità individuale allo sviluppo delle patologie polmonari amianto-correlate.

Vari studi sul tema hanno già dimostrato che alterazioni della risposta immunitaria che coinvolgano l’NLRP3, una proteina chiave per l’aggregazione degli inflammasomi, potrebbero rappresentare un importante fattore causale per lo sviluppo di patologie polmonari di natura fibrotica.

Al fine di comprendere il ruolo del gene di questa proteina nelle patologie polmonari fibrotiche da amianto, in questo recente studio, pubblicato da un gruppo di ricerca finlandese, sono stati testati gli effetti dei polimorfismi del gene dell’NLRP3 e di altri 8 geni chiave coinvolti nella risposta infiammatoria.

Keywords

Asbestos, fibrotic pleuropulmonary changes, genetic polymorphisms, individual susceptibility, Innate immunity

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