RPA3-UMAD1 rs12702634 and rheumatoid arthritis-associated interstitial lung disease in European ancestry.

Objective: Recently, a genome-wide association study identified an association between RA-associated interstitial lung disease (ILD) and RPA3-UMAD1 rs12702634 in the Japanese population, especially for patients with a usual interstitial pneumonia (UIP) pattern. We aimed to replicate this association in a European population and test for interaction with MUC5B rs35705950. Methods: In this genetic case-control association study, patients with RA and ILD and controls with RA and no ILD were included from France, the USA and the Netherlands. Only cases and controls from European genetic ancestries determined by principal components analysis were included in the analyses. RA was defined by the 1987 ACR or 2010 ACR/EULAR criteria and ILD by chest high-resolution CT scan, except in the control dataset from the Netherlands, where the absence of ILD was determined by chart review. Patients were genotyped for RPA3-UMAD1 rs12702634 and MUC5B rs35705950. Associations were tested using logistic regression adjusted for sex, age at RA onset, age at ILD onset or at certified absence of ILD, tobacco smoking status and country of origin. Results: Among the 883 patients included, 322 were RA-ILD cases (36.5%). MUC5B rs35705950 was strongly associated with RA-ILD in all datasets {combined adjusted odds ratio [OR] 2.9 [95% CI 2.1, 3.9], P = 1.1 × 10-11. No association between RPA3-UMAD1 rs12702634 and RA-ILD was observed [combined OR 1.2 (95% CI 0.8, 1.6), P = 0.31. No interaction was found between RPA3-UMAD1 rs12702634 and MUC5B rs35705950 (P = 0.70). Conclusion: Our findings did not support a contribution of RPA3-UMAD1 rs12702634 to the overall RA-ILD susceptibility in the European population.

A new variant in the ZCCHC8 gene: diverse clinical phenotypes and expression in the lung.

Introduction: Pulmonary fibrosis is a severe disease which can be familial. A genetic cause can only be found in ∼40% of families. Searching for shared novel genetic variants may aid the discovery of new genetic causes of disease. Methods: Whole-exome sequencing was performed in 152 unrelated patients with a suspected genetic cause of pulmonary fibrosis from the St Antonius interstitial lung disease biobank. Variants of interest were selected by filtering for novel, potentially deleterious variants that were present in at least three unrelated pulmonary fibrosis patients. Results: The novel c.586G>A p.(E196K) variant in the ZCCHC8 gene was observed in three unrelated patients: two familial patients and one sporadic patient, who was later genealogically linked to one of the families. The variant was identified in nine additional relatives with pulmonary fibrosis and other telomere-related phenotypes, such as pulmonary arterial venous malformations, emphysema, myelodysplastic syndrome, acute myeloid leukaemia and dyskeratosis congenita. One family showed incomplete segregation, with absence of the variant in one pulmonary fibrosis patient who carried a PARN variant. The majority of ZCCHC8 variant carriers showed short telomeres in blood. ZCCHC8 protein was located in different lung cell types, including alveolar type 2 (AT2) pneumocytes, the culprit cells in pulmonary fibrosis. AT2 cells showed telomere shortening and increased DNA damage, which was comparable to patients with sporadic pulmonary fibrosis and those with pulmonary fibrosis carrying a telomere-related gene variant, respectively. Discussion: The ZCCHC8 c.586G>A variant confirms the involvement of ZCCHC8 in pulmonary fibrosis and short-telomere syndromes and underlines the importance of including the ZCCHC8 gene in diagnostic gene panels for these diseases.

New Insights via RNA Profiling of Formalin-Fixed Paraffin-Embedded Lung Tissue of Pulmonary Fibrosis Patients.

In sporadic idiopathic pulmonary fibrosis (sIPF) and pulmonary fibrosis caused by a mutation in telomere (TRG-PF) or surfactant related genes (SRG-PF), there are a number of aberrant cellular processes known that can lead to fibrogenesis. We investigated whether RNA expression of genes involved in these processes differed between sIPF, TRG-PF, and SRG-PF and whether expression levels were associated with survival. RNA expression of 28 genes was measured in lung biopsies of 26 sIPF, 17 TRG-PF, and 6 SRG-PF patients. Significant differences in RNA expression of TGFBR2 (p = 0.02) and SFTPA2 (p = 0.02) were found between sIPF, TRG-PF, and SRG-PF. Patients with low (

Simultaneous Assessment of mTORC1, JAK/STAT, and NLRP3 Inflammasome Activation Pathways in Patients with Sarcoidosis.

The unknown etiology of sarcoidosis, along with the variability in organ involvement and disease course, complicates the effective treatment of this disease. Based on recent studies, the cellular inflammatory pathways involved in granuloma formation are of interest regarding possible new treatment options, such as the mechanistic (formerly mammalian) target of rapamycin complex 1 (mTORC1) pathway, the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, and the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome pathway. The aim of this study was to explore the potential coexpression of these three inflammatory pathways in patients with sarcoidosis and see whether possible differences were related to disease outcome. The tissue of 60 patients with sarcoidosis was used to determine the activity of these three signaling pathways using immunohistochemistry. The activation of NLRP3 was present in 85% of all patients, and the activation of mTORC1 and JAK/STAT was present in 49% and 50% of patients, respectively. Furthermore, the presence of NLRP3 activation at diagnosis was associated with a chronic disease course of sarcoidosis. Our finding of different new conceptual inflammatory tissue phenotypes in sarcoidosis could possibly guide future treatment studies using the available inhibitors of either NLRP3, JAK-STAT, and mTORC1 inhibitors in a more personalized medicine approach.

Improved Survival of IPF patients Treated With Antifibrotic Drugs Compared With Untreated Patients.

PURPOSE: Pirfenidone and nintedanib unequivocally inhibit FVC decline, but have been inconsistently linked to reduced mortality in phase III studies. On the contrary, real-world data show a survival benefit of antifibrotic drugs. However, it is unknown what this benefit is across different Gender, Age, and Physiology (GAP) stages. RESEARCH QUESTIONS: Is there a difference in transplant-free (TPF) survival of IPF patients receiving antifibrotic drugs (IPFAF) compared with an untreated cohort (IPFnon-AF)? Is this different for patients with GAP stage I, II, or III. METHODS: This is a single-center observational cohort study using prospectively included patients diagnosed with IPF between 2008-2018. Primary outcomes were TPF survival difference and 1-, 2-, and 3-year cumulative mortality for IPFAF and IPFnon-AF. This was repeated after stratification for GAP stage. RESULTS: In total, 457 patients were included. The median transplant-free survival was 3.4 years in IPFAF (n = 313) and 2.2 years in IPFnon-AF (n = 144, p = 0.005). For GAP stage II, a median survival of 3.1 and 1.7 years was noted for IPFAF (n = 143) and IPFnon-AF (n = 59, p < 0.001), respectively. A significantly lower 1-, 2-, and 3- year cumulative mortality was found for IPFAF with GAP stage II (1 yr: 7.0% vs 35.6%, 2 yr: 26.6% vs 55.9%, and 3 yr: 46.9% vs 69.5%). The 1-year cumulative mortality of IPFAF with GAP III was also significantly lower (19.0% vs 65.0%). CONCLUSION: This large real-world study showed a survival benefit in IPFAF compared with IPFnon-AF. This especially holds true for patients with GAP stage II and III.

Decreased Survival and Lung Function in Progressive Pulmonary Fibrosis.

Background and Objectives: Progressive pulmonary fibrosis (PPF) is a recently described term reserved for patients with fibrotic ILD other than idiopathic pulmonary fibrosis (IPF) with fast clinical deterioration. Here, survival and prognostic biomarkers at the time of diagnosis for PPF are investigated in a fibrotic ILD other than IPF cohort (non-IPF). Materials and Methods: Patients diagnosed during the period of 2012-2018 at the ILD Center of Excellence (St. Antonius Hospital, Nieuwegein, The Netherlands) with a fibrotic ILD were included in this study. The presence of PPF was investigated using the criteria from the updated IPF/PPF guideline during the first year after diagnosis. Logistic regression analysis was used to determine risk factors for PPF. A Kaplan-Meier survival analysis with log-rank test was conducted to analyze survival in patients with and without PPF. Results: This study included 304 non-IPF patients and, for comparison, 379 IPF patients. In non-IPF patients, 146 (46%) fulfilled ≥2 criteria for PPF. These patients had a median transplant-free survival rate of 2.9 ± 0.4 years, which was worse than non-IPF patients without PPF (10.1 ± 1.8 years, p < 0.001). The risk for PPF was increased in patients with FVC < 50% (odds ratio (OR) of 2.50, 95% CI = 1.01-6.17, p = 0.047) or DLCOc ≤ 35% (OR = 2.57, 95% CI = 1.24-5.35, p = 0.011). In the first 3 years after diagnosis, survival in PPF and IPF is the same, while in the following years IPF has a significantly worse survival. Conclusions: The non-IPF cohort with PPF had a significantly worse transplant-free survival compared with the non-IPF cohort without PPF. Independent risk factors for PPF in non-IPF were FVC < 50% and DLCOc ≤ 35%.

MUC5B rs35705950 minor allele associates with older age and better survival in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: The minor T-allele of the MUC5B promoter polymorphism rs35705950 is strongly associated with idiopathic pulmonary fibrosis (IPF). However, conflicting results have been reported on the relationship between the MUC5B minor allele and survival and it is unknown whether a specific subgroup of IPF patients might benefit from MUC5B minor allele carriage. We investigated the association between MUC5B rs35705950, survival and patient characteristics in a real-world population of European IPF patients. METHODS: In this retrospective study, 1751 patients with IPF from 8 European centres were included. MUC5B rs35705950 genotype, demographics, clinical characteristics at diagnosis and survival data were analysed. RESULTS: In a multi-variate Cox proportional hazard model the MUC5B minor allele was a significant independent predictor of survival when adjusted for age, sex, high resolution computed tomography pattern, smoking behaviour and pulmonary function tests in IPF. MUC5B minor allele carriers were significantly older at diagnosis (p = 0.001). The percentage of MUC5B minor allele carriers increased significantly with age from 44% in patients aged <56 year, to 63% in patients aged >75. In IPF patients aged <56, the MUC5B minor allele was not associated with survival. In IPF patients aged ≥56, survival was significantly better for MUC5B minor allele carriers (45 months [CI: 42-49]) compared to non-carriers (29 months [CI: 26-33]; p = 4 × 10-12 ). CONCLUSION: MUC5B minor allele carriage associates with a better median transplant-free survival of 16 months in the European IPF population aged over 56 years. MUC5B genotype status might aid disease prognostication in clinical management of IPF patients.

Progressive Disease With Low Survival in Adult Patients With Pulmonary Fibrosis Carrying Surfactant-Related Gene Mutations: An Observational Study.

BACKGROUND: In some patients with progressive fibrosing interstitial lung disease (ILD), disease is caused by carriage of a mutation in a surfactant-related gene (SRG) such as SFTPC, SFTPA2, or ABCA3. However, no aggregated data on disease evolution and treatment outcome have been presented for these patients. RESEARCH QUESTION: In adult patients with ILD with an SRG mutation, what is the course of lung function after diagnosis and during treatment and the survival in comparison with patients with sporadic idiopathic pulmonary fibrosis (sIPF) and familial pulmonary fibrosis (FPF)? STUDY DESIGN AND METHODS: We retrospectively examined the clinical course of a cohort of adults with an SRG mutation by screening 48 patients from 20 families with an SRG mutation for availability of clinical follow-up data. For comparison, 248 patients with FPF and 575 patients with sIPF were included. RESULTS: Twenty-three patients with ILD (median age: 45 years; 11 men) with an SRG mutation fulfilled criteria. At diagnosis, patients with an SRG mutation were younger and less often male, but had lower FVC (72% predicted) and diffusing capacity of the lungs for carbon monoxide (46% predicted) compared with patients with FPF or sIPF. In the SRG mutation group, median FVC decline 6 months after diagnosis was -40 mL and median transplant-free survival was 44 months and not different from patients with FPF or sIPF. FVC course was not different among the three cohorts; however, a significantly larger decrease in FVC was found while patients received immunomodulatory or antifibrotic treatment compared with those receiving no treatment. Subsequent analysis in the SRG group showed that patients with a surfactant mutation (n = 7) treated for 6 months with antifibrotic drugs showed stable lung function with a median change in FVC of +40 mL (interquartile range, -40 to 90 mL), whereas patients with an SRG mutation treated with immunomodulatory drugs showed a variable response dependent on the gene involved. INTERPRETATION: This study showed that patients with ILD carrying an SRG mutation experience progressive loss of lung function with severely reduced survival despite possible beneficial effects of treatment.

ANXA11 rs1049550 Associates with Löfgren's Syndrome and Chronic Sarcoidosis Patients.

Sarcoidosis is an immune mediated granulomatous disease commonly affecting the lungs. Genome wide association studies identified many genomic regions that are shared among multiple immune mediated diseases. However, ANXA11 gene polymorphism rs1049550 is exclusively associated with sarcoidosis, making it a key gene of interest for sarcoidosis disease pathogenesis. However, sarcoidosis is a heterogeneous disease and contradictory findings for ANXA11 have been reported for disease phenotypes. We performed a case-control association study to investigate if ANXA11 associates with benign (Löfgren's syndrome (LS)) or chronic sarcoidosis and performed a meta-analysis on previously reported findings. A total of 262 sarcoidosis patients, of which 149 had LS and 113 chronic sarcoidosis, and 363 controls were genotyped for rs1049550. Meta-analysis included allele findings for rs1049550 from 6 additional studies. We found a significantly lower T allele frequency in sarcoidosis patients than in healthy controls (0.30 vs. 0.41, respectively, odds ratio (OR) 0.61, 95% confidence interval (CI) 0.48-0.77, p = 3 × 10-5). In LS the T allele frequency of 0.33, and in chronic sarcoidosis the T allele frequency of 0.26 were significantly lower than in healthy controls (OR 0.69, 95% CI 0.52-0.92, p = 0.01 and OR 0.51, 95% CI 0.36-0.70, p = 4 × 10-5, respectively). Meta-analysis including previously published European, African American and Asian cohorts confirmed the association of rs1049550 with sarcoidosis and resulted in a pooled OR of 0.70 (CI 0.66-0.75, p = 3.58 × 10-29). Presence of the T allele of rs1049550 in ANXA11 is protective for sarcoidosis, including benign and chronic phenotypes of the disease.

Extrapulmonary manifestations of a telomere syndrome in patients with idiopathic pulmonary fibrosis are associated with decreased survival.

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a heterogenous disease with a median survival of 3-4 years. Patients with mutations in telomere-related genes exhibit extrapulmonary signs and symptoms. These patients represent a distinct phenotype of IPF with worse survival. As genetic analyses are not available for most patients with IPF, we sought to determine the predictive value of extrapulmonary signs and symptoms of a telomere syndrome in patients with IPF. METHODS: We retrospectively studied 409 patients with IPF. Clinical characteristics, laboratory results and family history suggestive of a telomere syndrome were related to leukocyte telomere length measured by quantitative PCR and patient outcomes. RESULTS: The cohort included 293 patients with sporadic IPF and 116 patients with a background of familial pulmonary fibrosis. Any or a combination of a clinical history (haematological disease, liver disease, early greying of hair, nail dystrophy, skin abnormalities), a family history or haematological laboratory abnormalities (macrocytosis, anaemia, thrombopenia or leukopenia) suggestive of a telomere syndrome was present in 27% of IPF patients and associated with shorter leukocyte telomere length and shorter survival (p = 0.002 in a multivariate model). In sporadic IPF, having either a clinical history, family history or haematological laboratory abnormalities was not significantly associated with decreased survival (p = 0.07 in a multivariate model). CONCLUSION: Taking a careful clinical and family history focused on extrapulmonary manifestations of a telomere syndrome can provide important prognostic information in patients with IPF, as this is associated with shorter survival.

Telomere dysfunction implicates POT1 in patients with idiopathic pulmonary fibrosis.

Exonic sequencing identified a family with idiopathic pulmonary fibrosis (IPF) containing a previously unreported heterozygous mutation in POT1 p.(L259S). The family displays short telomeres and genetic anticipation. We found that POT1(L259S) is defective in binding the telomeric overhang, nuclear accumulation, negative regulation of telomerase, and lagging strand maintenance. Patient cells containing the mutation display telomere loss, lagging strand defects, telomere-induced DNA damage, and premature senescence with G1 arrest. Our data suggest POT1(L259S) is a pathogenic driver of IPF and provide insights into gene therapy options.

Evidence for shared genetic risk factors between lymphangioleiomyomatosis and pulmonary function.

INTRODUCTION: Lymphangioleiomyomatosis (LAM) is a rare low-grade metastasising disease characterised by cystic lung destruction. The genetic basis of LAM remains incompletely determined, and the disease cell-of-origin is uncertain. We analysed the possibility of a shared genetic basis between LAM and cancer, and LAM and pulmonary function. METHODS: The results of genome-wide association studies of LAM, 17 cancer types and spirometry measures (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC ratio and peak expiratory flow (PEF)) were analysed for genetic correlations, shared genetic variants and causality. Genomic and transcriptomic data were examined, and immunodetection assays were performed to evaluate pleiotropic genes. RESULTS: There were no significant overall genetic correlations between LAM and cancer, but LAM correlated negatively with FVC and PEF, and a trend in the same direction was observed for FEV1. 22 shared genetic variants were uncovered between LAM and pulmonary function, while seven shared variants were identified between LAM and cancer. The LAM-pulmonary function shared genetics identified four pleiotropic genes previously recognised in LAM single-cell transcriptomes: ADAM12, BNC2, NR2F2 and SP5. We had previously associated NR2F2 variants with LAM, and we identified its functional partner NR3C1 as another pleotropic factor. NR3C1 expression was confirmed in LAM lung lesions. Another candidate pleiotropic factor, CNTN2, was found more abundant in plasma of LAM patients than that of healthy women. CONCLUSIONS: This study suggests the existence of a common genetic aetiology between LAM and pulmonary function.

Connective Tissue Growth Factor Single Nucleotide Polymorphisms in (Familial) Pulmonary Fibrosis and Connective Tissue Disease Associated Interstitial Lung Disease.

PURPOSE: Connective tissue growth factor (CTGF) is an important mediator in fibrotic disease. Single nucleotide polymorphisms (SNPs) in CTGF have been found to be associated with different fibrotic diseases and CTGF protein was found to be upregulated in lung tissue, bronchoalveolar lavage cells, and plasma of idiopathic pulmonary fibrosis (IPF) patients. We investigated whether genetic variants predispose to sporadic IPF (spIPF), familial pulmonary fibrosis (FPF), and connective tissue disease associated ILD (CTD-ILD). METHODS: In total, 294 patients with spIPF and 294 healthy individuals were genotyped for CTGF rs12526196, rs9402373, rs6918698, and rs9399005. For replication of CTGF rs6918698 findings in pulmonary fibrosis, 128 patients with FPF, 125 with CTD-ILD, and an independent control cohort of 130 individuals were included. Lung tissue of 6 IPF patients was stained for CTGF to assess pulmonary localization. RESULTS: Of the four SNPs, only the minor allele frequency (MAF) of CTGF rs6918698 deviated between spIPF (MAF 0.41) and controls (MAF 0.47; OR 0.774 (0.615-0.975); p = 0.030). Further comparison of CTGF rs6918698G showed a difference between FPF (MAF 0.33) and controls (MAF 0.48; OR 0.545 (0.382-0.778); p = 0.001), but not with CTD-ILD. CTGF was localized in alveolar and bronchiolar epithelium, alveolar macrophages, myofibroblasts and endothelium and highly expressed in the basal cell layer of sandwich foci. CONCLUSION: CTGF rs6918698G associates with spIPF and with FPF, but not with CTD-ILD in a Dutch cohort. CTGF is localized in lung tissue involved in IPF pathogenesis. Further research into the role of this SNP on CTGF expression and fibrogenesis is warranted.

MUC5B promoter variant rs35705950 and rheumatoid arthritis associated interstitial lung disease survival and progression.

BACKGROUND: The major risk factor for idiopathic pulmonary fibrosis (IPF), MUC5B rs35705950, was found to be associated with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Whilst the MUC5B rs35705950 T risk allele has been associated with better survival in IPF, its impact on RA-ILD prognosis remains to be determined. Our objective was to explore the influence of MUC5B rs35705950 on survival and progression in RA-ILD. METHODS: Through an international retrospective observational study, patients with RA-ILD were genotyped for the MUC5B rs35705950 variant and consecutive pulmonary function tests (PFTs) findings were collected. Longitudinal data up to a 10-year follow-up were considered and analyzed using mixed regression models. Proportional hazards and joint proportional hazards models were used to analyze the association of baseline and longitudinal variables with lung transplant-free survival. Significant progression of RA-ILD was defined as at least an absolute or relative 10% decline of forced vital capacity at 2 years from baseline. RESULTS: Out of 321 registered patients, 261 were included in the study: 139 women (53.3%), median age at RA-ILD diagnosis 65 years (interquartile range [IQR] 57 to 71), 151 ever smokers (59.2%). Median follow-up was 3.5 years (IQR 1.3 to 6.6). Mortality rate was 32% (95%CI 19 to 42) at 10 years. The MUC5B rs35705950 variant did not impact lung transplant-free survival (HR for the T risk allele carriers=1.26; 95%CI 0.61 to 2.62; P=0.53). Decline in pulmonary function at 2 years was not influenced by MUC5B rs35705950 (OR=0.95; 95%CI 0.44 to 2.05; P=0.89), irrespective of the HRCT pattern. CONCLUSION: In this study, the MUC5B rs35705950 promoter variant did not influence transplant- free survival or decline in pulmonary function in patients with RA-ILD.

Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis.

Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, we propose monoamine-derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine-derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF-D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L-histidine analog, or a low L-histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.

Heterogeneity and Cancer-Related Features in Lymphangioleiomyomatosis Cells and Tissue.

Lymphangioleiomyomatosis (LAM) is a rare, low-grade metastasizing disease characterized by cystic lung destruction. LAM can exhibit extensive heterogeneity at the molecular, cellular, and tissue levels. However, the molecular similarities and differences among LAM cells and tissue, and their connection to cancer features are not fully understood. By integrating complementary gene and protein LAM signatures, and single-cell and bulk tissue transcriptome profiles, we show sources of disease heterogeneity, and how they correspond to cancer molecular portraits. Subsets of LAM diseased cells differ with respect to gene expression profiles related to hormones, metabolism, proliferation, and stemness. Phenotypic diseased cell differences are identified by evaluating lumican (LUM) proteoglycan and YB1 transcription factor expression in LAM lung lesions. The RUNX1 and IRF1 transcription factors are predicted to regulate LAM cell signatures, and both regulators are expressed in LAM lung lesions, with differences between spindle-like and epithelioid LAM cells. The cancer single-cell transcriptome profiles most similar to those of LAM cells include a breast cancer mesenchymal cell model and lines derived from pleural mesotheliomas. Heterogeneity is also found in LAM lung tissue, where it is mainly determined by immune system factors. Variable expression of the multifunctional innate immunity protein LCN2 is linked to disease heterogeneity. This protein is found to be more abundant in blood plasma from LAM patients than from healthy women. IMPLICATIONS: This study identifies LAM molecular and cellular features, master regulators, cancer similarities, and potential causes of disease heterogeneity.

Genetic disorders of the surfactant system: focus on adult disease.

Genes involved in the production of pulmonary surfactant are crucial for the development and maintenance of healthy lungs. Germline mutations in surfactant-related genes cause a spectrum of severe monogenic pulmonary diseases in patients of all ages. The majority of affected patients present at a very young age, however, a considerable portion of patients have adult-onset disease. Mutations in surfactant-related genes are present in up to 8% of adult patients with familial interstitial lung disease (ILD) and associate with the development of pulmonary fibrosis and lung cancer.High disease penetrance and variable expressivity underscore the potential value of genetic analysis for diagnostic purposes. However, scarce genotype-phenotype correlations and insufficient knowledge of mutation-specific pathogenic processes hamper the development of mutation-specific treatment options.This article describes the genetic origin of surfactant-related lung disease and presents spectra for gene, age, sex and pulmonary phenotype of adult carriers of germline mutations in surfactant-related genes.

Pulmonary Fibrosis and a TERT Founder Mutation With a Latency Period of 300 Years.

BACKGROUND: Germline mutations in the gene encoding TERT cause haploinsufficiency with subsequent telomere shortening. TERT mutations are associated with short telomere syndromes, such as pulmonary fibrosis (PF), which is often the first manifestation of a short telomere syndrome. Telomere length is heritable, and progeny of telomerase mutation carriers are known to have shorter telomeres. In families with TERT mutations, genetic anticipation, the earlier onset of symptoms with successive generation, is described. Little is known on the number of generations that may pass before disease occurs in families with a TERT mutation. RESEARCH QUESTION: The objective of this study was to determine classification and origin of the new TERT c.2005T mutation from population genetics and genealogic data and disease history of affected families. STUDY DESIGN AND METHODS: The TERT gene of 240 patients with familial PF was screened for mutations. Additionally, 1,015 patients with PF, 1,237 patients with an interstitial lung disease (ILD) without PF, and 529 healthy control subjects were genotyped for the TERT c.2005C>T mutation. Genealogic research was performed on all patients who carried the TERT c.2005T mutation. RESULTS: We detected the TERT c.2005T (p.Arg669Trp) mutation in 13 out of 1,255 patients with PF vs none of the patients with ILD without PF and the healthy control subjects. Genealogic research connected four of the TERT c.2005T mutation carriers to a common ancestor who lived seven generations back, spanning a period of 300 years. INTERPRETATION: The TERT c.2005T mutation is a pathogenic mutation and associates with PF. This study learns that a latency period of > 300 years may pass before the cumulative effect of telomere shortening eventually leads to PF. This finding underlines the complexity of the clinical interpretation of TERT mutations because, not the presence of the mutation, but the result of genetic anticipation, is associated with disease. Therefore, multidisciplinary discussion between pulmonary physicians, clinical geneticists, and genetic laboratory experts is recommended.

Pharmacogenetics of antitumor necrosis factor therapy in severe sarcoidosis.

PURPOSE OF REVIEW: Antitumor necrosis factor (TNF) treatment is an effective third-line treatment option in severe sarcoidosis. But not all patients respond to treatment. Pharmacogenetics studies the influence of genetic variations on treatment response. RECENT FINDINGS: In sarcoidosis, only one study reported on a relationship between genetic variation in TNF and response to anti-TNF therapy. In immune-mediated inflammatory diseases (IMIDs) other than sarcoidosis, several genetic variants were associated with response to anti-TNF therapy. Genes related to TNF, the target of this group of drugs, and the pathway by which TNF exerts its effect, TNF receptor, were studied most extensively. Recent findings related genetic variations in the human leukocyte antigen region to development of antidrug antibodies.We also included new original data on genetic variations and response to anti-TNF therapy in severe sarcoidosis. We found that TNFRSF1A rs1800693 AA genotype, TNFRSF1B 196T and absence of HLA-DRB103 associate with better response after infliximab treatment in severe sarcoidosis. SUMMARY: Data on pharmacogenetics of anti-TNF therapy in severe sarcoidosis are scarce. Findings in other IMIDs indicate there may be a role for pharmacogenetics in predicting response and adverse events in anti-TNF therapy, also in sarcoidosis. Future studies are needed to evaluate pharmacogenetics as a predicting marker in anti-TNF therapy in sarcoidosis.