Rare Protein-Altering Telomere-related Gene Variants in Patients with Chronic Hypersensitivity Pneumonitis

Abstract

Rationale: Rare genetic variants in telomere-related genes have been identified in familial, idiopathic, and rheumatoid arthritis-associated pulmonary fibrosis. Short peripheral blood leukocyte (PBL) telomere length predicts poor outcomes in chronic hypersensitivity pneumonitis (CHP).Objectives: Determine the prevalence and clinical relevance of rare protein-altering variants in telomere-related genes in patients with CHP.Methods: Next-generation sequences from two CHP cohorts were analyzed to identify variants in TERT (telomerase reverse transcriptase), TERC (telomerase RNA component), DKC1 (dyskerin pseudouridine synthase 1), RTEL1 (regulator of telomere elongation helicase 1), PARN (poly[A]-specific RNase), and TINF2 (TERF1interacting nuclear factor 2). To qualify, variants were required to have a minor allele frequency less than 0.005 and be predicted to be damaging to protein function. Variant status (binary variable) was used in statistical association tests, including Cox proportional hazard models for transplant-free survival. PBL telomere length was measured using quantitative PCR.Measurements and Main Results: Qualifying variants were identified in 16 of 144 patients (11.1%; 95% confidence interval [CI], 6.5-17.4) in the discovery cohort and 17 of 209 patients (8.1%; 95% CI, 4.8-12.7) in the replication cohort. Age-and ancestry-adjusted PBL telomere length was significantly shorter in the presence of a variant in both cohorts (discovery: 2561 bp; 95% CI, 2933 to 2190; P = 0.003; replication: 2612 bp; 95% CI, 2870 to 2354; P = 5.30 3 10 26 ). Variant status was significantly associated with transplant-free survival in both cohorts (discovery: age-, sex-, and ancestry-adjusted hazard ratio, 3.73; 95% CI, 1.92-7.28; P = 0.0001; replication: hazard ratio, 2.72; 95% CI, 1.26-5.88; P = 0.011).Conclusions: A substantial proportion of patients diagnosed with CHP have rare, protein-altering variants in telomere-related genes, which are associated with short peripheral blood telomere length and significantly reduced transplant-free survival.

Histopathology and genetic susceptibility in COVID‐19 pneumonia

“…Other entry mechanisms may also play a role, such as transmembrane protease serine 2 (TMPRSS2), and TMPRSS2 variants and expression have indeed been linked to differences in COVID-19 severity 26 . Susceptibility to the development of post-COVID-19 pulmonary fibrosis could also have a genetic component, as variants in numerous genes or their promotors (such as MUC5B and TERT) have been found to predispose to lung fibrosis, both in the context of idiopathic pulmonary fibrosis and in interstitial fibrosis related to hypersensitivity pneumonitis and collagen vascular disease [27][28][29][30] .…”

Using Genome-Wide Association Study to Identify Genes and Pathways associated with Hypersensitivity Pneumonitis

“…The advantage of SKAT analysis is that it overcomes the traditional GWAS’s problem of having low power for rare variants 26 . Rare genetic variants may play key roles in HP development 10 .…”

“…After QC, there were 2,353,579 SNPs left. We didn’t exclude rare variants in this study because rare variants were found to be associated with HP significantly 10 .…”

“…Recent review by Kiszałkiewicz et al suggested several signaling pathways (e.g., TNF-α/NFκβ, TGF-β/SMAD, Wnt-β-catenin) are activated in idiopathic pulmonary fibrosis (IPF) and HP 9 . Ley et al (2019) found that rare variants in telomere-related genes are significantly associated with HP and reduced transplant-free survival in HP patients 10 . However, all previous HP genetic studies have concentrated on pre-selected genes, and thus have a limited ability to comprehensively identify genetic factors associated with HP.…”

Clinical Decision-Making in Hypersensitivity Pneumonitis: Diagnosis and Management

“…43,44 Sixth, genomic factors such as the MUC5B promoter variant rs35705950 and mutations in the telomerase pathway are associated with an increased risk of the development of pulmonary fibrosis and shortened survival in HP. 6,[45][46][47] Lastly, serum biomarkers are being investigated in CHP, and it is possible that in the future, these will have a role in prognostication. 48 In susceptible subjects, the IA may be causal but not necessarily a risk factor for disease progression.…”