IFNL3 genotype is associated with pulmonary fibrosis in patients with systemic sclerosis.
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ABSTRACT:
SUBMITTER: Metwally M
PROVIDER: S-EPMC6795812 | biostudies-literature | 2019 Oct
REPOSITORIES: biostudies-literature
Publications
IFNL3 genotype is associated with pulmonary fibrosis in patients with systemic sclerosis.
Metwally Mayada M Thabet Khaled K Bayoumi Ali A Nikpour Mandana M Stevens Wendy W Sahhar Joanne J Zochling Jane J Roddy Janet J Tymms Kathleen K Strickland Gemma G Lester Susan S Rischmueller Maureen M Ngian Gene-Siew GS Walker Jennifer J Hissaria Pravin P Shaker Olfat O Liddle Christopher C Manolios Nicholas N Beretta Lorenzo L Proudman Susanna S George Jacob J Eslam Mohammed M
Scientific reports 20191016 1
Fibrosis across different organs and tissues is likely to share common pathophysiological mechanisms and pathways. Recently, a polymorphism (rs12979860) near the interferon lambda gene (IFNL3) was shown to be associated with fibrosis in liver across multiple disease etiologies. We determined whether this variant is a risk factor for pulmonary fibrosis (PF) and worsening cutaneous fibrosis in systemic sclerosis (SSc). Caucasian patients with SSc (n = 733) were genotyped to test for association wi ...[more]
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Project description:Pulmonary arterial hypertension (PAH) is the leading cause of death in systemic sclerosis (SSc) and affects up to 12% of all patients with SSc, with a 50% mortality rate within 3 years of PAH diagnosis. Compared with the idiopathic form of PAH (IPAH), patients with SSc-associated PAH (SSc-PAH) have a threefold increased risk of death and may receive a diagnosis late in the course of disease because of insidious onset and the high prevalence of cardiac, musculoskeletal, and pulmonary parenchymal comorbidities. Treatment with conventional forms of PAH therapy often yield poor results compared with IPAH cohorts; unfortunately, the exact reasons behind this remain poorly understood but likely include variations in the pathologic mechanisms, differences in cardiovascular response to increasing afterload, and inadequate strategies to detect and treat SSc-PAH early in its course. Current methods for screening and longitudinal evaluation of SSc-PAH, such as the 6-min walk test, transthoracic echocardiography, and MRI, each have notable advantages and disadvantages. We provide an up-to-date, focused review of SSc-PAH and how it differs from IPAH, including pathogenesis, appropriate screening for disease onset, and new approaches to treatment and longitudinal assessment of this disease.
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Project description:Pulmonary arterial hypertension (PAH) is a devastating vascular complication of a number of connective tissue diseases, including systemic sclerosis (SSc), where it has a dramatic impact on the clinical course and overall survival and is the single most common cause of death in patients afflicted with this syndrome. Although remarkable advances have been achieved in elucidating the pathogenesis of PAH over the past 2 decades, leading to the development of disease-targeted therapies for the idiopathic form of this condition (IPAH), the response to therapy is suboptimal in SSc-related PAH (SSc-PAH), and survival remains very poor. Factors accounting for striking clinical and prognostic differences between these two syndromes are unclear but may include a more pronounced autoimmune, cellular, and inflammatory response, and a higher prevalence of comorbidities in SSc-PAH, including cardiac and pulmonary venous and parenchymal involvement. Furthermore, currently available markers of disease severity and clinical tools to assess response to therapy, which may be reliable in IPAH, are either limited or lacking in SSc-PAH. Thus, a more focused approach, including a better understanding of the pathogenesis and genetic factors underlying the development of SSc-PAH, a search for more specific and reliable tools to adequately assess functional impairment and monitor therapy, as well as the design of novel targeted therapies, are all urgently required to alter the dismal course of this syndrome.
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| S-EPMC4821403 | biostudies-literature
Project description:Pulmonary complications, including pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH), are the leading cause of mortality in patients with systemic sclerosis (SSc). The aim of this study was to compare the molecular fingerprint of lung tissue and matching primary fibroblasts from patients with SSc with that of lung tissue and fibroblasts from normal donors, patients with idiopathic pulmonary fibrosis (IPF), and patients with idiopathic pulmonary arterial hypertension (IPAH).Lung tissue samples were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, and patients with IPAH. Microarray data were analyzed using efficiency analysis for determination of the optimal data-processing methods. Real-time polymerase chain reaction and immunohistochemistry were used to confirm differential levels of messenger RNA and protein, respectively.Consensus efficiency analysis identified 242 and 335 genes that were differentially expressed in lungs and primary fibroblasts, respectively. SSc-PF and IPF lungs shared enriched functional groups in genes implicated in fibrosis, insulin-like growth factor signaling, and caveolin-mediated endocytosis. Gene functional groups shared by SSc-PAH and IPAH lungs included those involved in antigen presentation, chemokine activity, and interleukin-17 signaling.Using microarray analysis on carefully phenotyped SSc and comparator lung tissues, we demonstrated distinct molecular profiles in tissues and fibroblasts from patients with SSc-associated lung disease compared to idiopathic forms of lung disease. Unique molecular signatures were generated that are disease specific (SSc) and phenotype specific (PF versus PAH). These signatures provide new insights into the pathogenesis and potential therapeutic targets of SSc-related lung disease.
| S-EPMC3139818 | biostudies-literature
Project description:Objective: Pulmonary complications in systemic sclerosis (SSc), including pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH), are the leading cause of mortality. We compared the molecular fingerprint of SSc lung tissues and matching primary lung fibroblasts to those of normal donors, and patients with idiopathic pulmonary fibrosis (IPF) and idiopathic pulmonary arterial hypertension (IPAH). Methods: Lung tissues were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, or IPAH. Microarray data was analyzed using Efficiency Analysis for determination of optimal data processing methods. Real time PCR and immunohistochemistry were used to confirm differential levels of mRNA and protein, respectively. Results: We identified a consensus of 242 and 335 genes that were differentially expressed in lungs and primary fibroblasts, respectively. Enriched function groups in SSc-PF and IPF lungs included fibrosis, insulin-like growth factor signaling and caveolin-mediated endocytosis. Functional groups shared by SSc-PAH and IPAH lungs included antigen presentation, chemokine activity, and IL-17 signaling. Conclusion: Using microarray analysis on carefully phenotyped SSc and comparator lung tissues, we demonstrated distinct molecular profiles in tissues and fibroblasts of patients with SSc-associated lung disease compared to idiopathic forms of lung disease. Unique molecular signatures were generated that are disease- (SSc) and phenotype- (PF vs PAH) specific. These signatures provide new insights into pathogenesis and potential therapeutic targets for SSc lung disease. Lung tissues were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, or IPAH. Microarray data was analyzed using Efficiency Analysis for determination of optimal data processing methods. Real time PCR and immunohistochemistry were used to confirm differential levels of mRNA and protein, respectively.
2013-06-21 | E-GEOD-48149 | biostudies-arrayexpress
Project description:More than 80% of patients with systemic sclerosis (SSc) develop lung involvement, most commonly interstitial pneumonia (IP). We recently identified a common variant in the promoter region of MUC5B (rs35705950) that has a significant effect on the risk of developing both familial and sporadic forms of IP. We hypothesized that this MUC5B promoter polymorphism is also associated with IP in subjects with SSc.We examined the minor allele frequency of the MUC5B polymorphism among 231 subjects with SSc, 109 with IP, and 122 without IP. IP diagnosis was confirmed by HRCT imaging and defined as the presence of reticular infiltrates and/or honeycomb cysts. FVC and diffusing capacity of the lung for carbon monoxide (Dlco) were also assessed.We found no association between IP and the MUC5B polymorphism among subjects with SSc (OR = 1.1, P = .80). The frequencies of the MUC5B polymorphism among subjects with SSc with IP (10.6%) and without IP (9.4%) were similar to the frequency observed in a population of unaffected control subjects (9.0%). In secondary analyses, we found the MUC5B polymorphism was not significantly associated with either FVC (P = .42) or Dlco (P = .06). No association with SSc-associated IP was found even when we used a more conservative definition of IP (FVC ? 70% and evidence of reticulations or honeycombing vs SSc FVC > 70% and no evidence of reticulation or honeycombing).Although SSc-associated IP is clinically, radiologically, and histologically similar to other forms of IP, it appears to have distinct genetic risk factors. This study highlights the genetic and phenotypic heterogeneity of IP in general.
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Project description:INTRODUCTION: CD226 genetic variants have been associated with a number of autoimmune diseases and recently with systemic sclerosis (SSc). The aim of this study was to test the influence of CD226 loci in SSc susceptibility, clinical phenotypes and autoantibody status in a large multicenter European population. METHODS: A total of seven European populations of Caucasian ancestry were included, comprising 2,131 patients with SSc and 3,966 healthy controls. Three CD226 single nucleotide polymorphisms (SNPs), rs763361, rs3479968 and rs727088, were genotyped using Taqman 5'allelic discrimination assays. RESULTS: Pooled analyses showed no evidence of association of the three SNPs, neither with the global disease nor with the analyzed subphenotypes. However, haplotype block analysis revealed a significant association for the TCG haplotype (SNP order: rs763361, rs34794968, rs727088) with lung fibrosis positive patients (PBonf = 3.18E-02 OR 1.27 (1.05 to 1.54)). CONCLUSION: Our data suggest that the tested genetic variants do not individually influence SSc susceptibility but a CD226 three-variant haplotype is related with genetic predisposition to SSc-related pulmonary fibrosis.
| S-EPMC3446459 | biostudies-literature
Project description:Objective: Pulmonary complications in systemic sclerosis (SSc), including pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH), are the leading cause of mortality. We compared the molecular fingerprint of SSc lung tissues and matching primary lung fibroblasts to those of normal donors, and patients with idiopathic pulmonary fibrosis (IPF) and idiopathic pulmonary arterial hypertension (IPAH). Methods: Lung tissues were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, or IPAH. Microarray data was analyzed using Efficiency Analysis for determination of optimal data processing methods. Real time PCR and immunohistochemistry were used to confirm differential levels of mRNA and protein, respectively. Results: We identified a consensus of 242 and 335 genes that were differentially expressed in lungs and primary fibroblasts, respectively. Enriched function groups in SSc-PF and IPF lungs included fibrosis, insulin-like growth factor signaling and caveolin-mediated endocytosis. Functional groups shared by SSc-PAH and IPAH lungs included antigen presentation, chemokine activity, and IL-17 signaling. Conclusion: Using microarray analysis on carefully phenotyped SSc and comparator lung tissues, we demonstrated distinct molecular profiles in tissues and fibroblasts of patients with SSc-associated lung disease compared to idiopathic forms of lung disease. Unique molecular signatures were generated that are disease- (SSc) and phenotype- (PF vs PAH) specific. These signatures provide new insights into pathogenesis and potential therapeutic targets for SSc lung disease.
2013-06-21 | GSE48149 | GEO
Project description:Systemic sclerosis–associated pulmonary artery hypertension (SScPAH) has a worse prognosis compared with idiopathic pulmonary arterial hypertension (IPAH), with a median survival of 3 years after diagnosis often caused by right ventricular (RV) failure. We tested whether SScPAH or systemic sclerosis–related pulmonary hypertension with interstitial lung disease imposes a greater pulmonary vascular load than IPAH and leads to worse RV contractile function.We analyzed pulmonary artery pressures and mean flow in 282 patients with pulmonary hypertension (166 SScPAH, 49 systemic sclerosis–related pulmonary hypertension with interstitial lung disease, and 67 IPAH). An inverse relation between pulmonary resistance and compliance was similar for all 3 groups, with a near constant resistance×compliance product. RV pressure–volume loops were measured in a subset, IPAH (n=5) and SScPAH (n=7), as well as SSc without PH (n=7) to derive contractile indexes (end-systolic elastance [Ees] and preload recruitable stroke work [Msw]), measures of RV load (arterial elastance [Ea]), and RV pulmonary artery coupling (Ees/Ea). RV afterload was similar in SScPAH and IPAH (pulmonary vascular resistance=7.0±4.5 versus 7.9±4.3 Wood units; Ea=0.9±0.4 versus 1.2±0.5 mm Hg/mL; pulmonary arterial compliance=2.4±1.5 versus 1.7±1.1 mL/mm Hg; P>0.3 for each). Although SScPAH did not have greater vascular stiffening compared with IPAH, RV contractility was more depressed (Ees=0.8±0.3 versus 2.3±1.1, P<0.01; Msw=21±11 versus 45±16, P=0.01), with differential RV-PA uncoupling (Ees/Ea=1.0±0.5 versus 2.1±1.0; P=0.03). This ratio was higher in SSc without PH (Ees/Ea=2.3±1.2; P=0.02 versus SScPAH).RV dysfunction is worse in SScPAH compared with IPAH at similar afterload, and may be because of intrinsic systolic function rather than enhanced pulmonary vascular resistive and pulsatile loading.
| S-EPMC3815697 | biostudies-literature