Publications by authors named "Christine Kim Garcia"

49 Publications

Rare and Common Variants in Contribute to Genetic Risk of Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2022 Apr 13. Epub 2022 Apr 13.

Columbia University Irving Medical Center, 21611, Medicine, New York, New York, United States;

Rationale: Genetic studies of Idiopathic Pulmonary Fibrosis (IPF) have improved our understanding of this disease, but not all causal loci have been identified.

Objective: To identify genes enriched with rare deleterious variants in IPF and familial pulmonary fibrosis.

Methods: We performed gene burden analysis of whole exome data, tested single variants for disease association, conducted KIF15 functional studies, and examined human lung single cell RNA sequencing data.

Measurement And Main Results: Gene burden analysis of 1,725 cases and 23,509 controls identified heterozygous rare deleterious variants in , a kinesin involved in spindle separation during mitosis, and three telomere-related genes (, , ). was implicated in autosomal dominant models of rare deleterious variants (OR 4.9 [95%CI 2.7, 8.8] P=2.55x10) and rare protein-truncating variants (OR 7.6 [3.3, 17.1], P=8.12x10). Meta-analysis of the discovery and replication cohorts, including 2,966 cases and 29,817 controls, confirm the involvement of , plus the three telomere-related genes. A common variant within a intron (rs74341405, OR 1.6 [1.4, 1.9], P=5.63x10) is associated with IPF risk, confirming a prior report. Lymphoblastoid cells from individuals heterozygous for the common variant have decreased KIF15 and reduced rates of cell growth. Cell proliferation is dependent on KIF15 in the presence of an inhibitor of Eg5/KIF11, which has partially redundant function. is expressed specifically in replicating human lung cells, and shows diminished expression in replicating epithelial cells of IPF patients.

Conclusions: Both rare deleterious variants and common variants in link a non-telomerase pathway of cell proliferation with IPF susceptibility.
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http://dx.doi.org/10.1164/rccm.202110-2439OCDOI Listing
April 2022

The Role of Genetic Testing in Pulmonary Fibrosis: A Perspective From the Pulmonary Fibrosis Foundation Genetic Testing Work Group.

Chest 2022 Mar 23. Epub 2022 Mar 23.

Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, TN. Electronic address:

Patients with familial pulmonary fibrosis represents a subset of patients with pulmonary fibrosis in whom inherited gene variation predisposes them to disease development. In the appropriate setting, genetic testing allows for personalized assessment of disease, recognition of clinically relevant extrapulmonary manifestations, and assessing susceptibility in unaffected relatives. However currently, the use of genetic testing is inconsistent, partly because of the lack of guidance regarding high-yield scenarios in which the results of genetic testing can inform clinical decision-making. To address this, the Pulmonary Fibrosis Foundation commissioned a genetic testing work group comprising pulmonologists, geneticists, and genetic counselors from the United States to provide guidance on genetic testing in patients with pulmonary fibrosis. This CHEST special feature presents a concise review of these proceedings and reviews pulmonary fibrosis susceptibility, clinically available genetic testing methods, and clinical scenarios in which genetic testing should be considered.
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http://dx.doi.org/10.1016/j.chest.2022.03.023DOI Listing
March 2022

Proteomic biomarkers of progressive fibrosing interstitial lung disease: a multicentre cohort analysis.

Lancet Respir Med 2022 Jan 18. Epub 2022 Jan 18.

Division of Pulmonary, Critical Care and Sleep Medicine, University of California Davis, Sacramento, CA, USA. Electronic address:

Background: Progressive fibrosing interstitial lung disease (ILD) is characterised by parenchymal scar formation, leading to high morbidity and mortality. The ability to predict this phenotype remains elusive. We conducted a proteomic analysis to identify novel plasma biomarkers of progressive fibrosing ILD and developed a proteomic signature to predict this phenotype.

Methods: Relative plasma concentrations for 368 biomarkers were determined with use of a semi-quantitative, targeted proteomic platform in patients with connective tissue disease-associated ILD, chronic hypersensitivity pneumonitis, or unclassifiable ILD who provided research blood draws at the University of California (discovery cohort) and the University of Texas (validation cohort). Univariable logistic regression was used to identify individual biomarkers associated with 1-year ILD progression, defined as death, lung transplant, or 10% or greater relative forced vital capacity (FVC) decline. A proteomic signature of progressive fibrosing ILD was then derived with use of machine learning in the University of California cohort and validated in the University of Texas cohort.

Findings: The discovery cohort comprised 385 patients (mean age 63·6 years, 59% female) and the validation cohort comprised 204 patients (mean age 60·7 years, 61% female). 31 biomarkers were associated with progressive fibrosing ILD in the discovery cohort, with 17 maintaining an association in the validation cohort. Validated biomarkers showed a consistent association with progressive fibrosing ILD irrespective of ILD clinical diagnosis. A proteomic signature comprising 12 biomarkers was derived by machine learning and validated in the University of Texas cohort, in which it had a sensitivity of 0·90 and corresponding negative predictive value of 0·91, suggesting that approximately 10% of patients with a low-risk proteomic signature would experience ILD progression in the year after blood draw. Those with a low-risk proteomic signature experienced an FVC change of +85·7 mL (95% CI 6·9 to 164·4) and those with a high-risk signature experienced an FVC change of -227·1 mL (-286·7 to -167·5). A theoretical clinical trial restricted to patients with a high-risk proteomic signature would require 80% fewer patients than one designed without regard to proteomic signature.

Interpretation: 17 plasma biomarkers of progressive fibrosing ILD were identified and showed consistent associations across ILD subtypes. A proteomic signature of progressive fibrosing ILD could enrich clinical trial cohorts and avoid the need for antecedent progression when defining progressive fibrosing ILD for clinical trial enrolment.

Funding: National Heart Lung and Blood Institute.
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http://dx.doi.org/10.1016/S2213-2600(21)00503-8DOI Listing
January 2022

COVID-19-induced pulmonary sarcoid: A case report and review of the literature.

Clin Imaging 2022 Mar 13;83:152-158. Epub 2022 Jan 13.

Division of Cardiothoracic Imaging, Department of Radiology, Columbia University Irving Medical Center, New York, NY, United States of America.

Background: The COVID-19 pandemic has resulted in dramatic loss of life worldwide, but as the large number of acutely ill patients subsides, the emerging group of "COVID-19 long-haulers" present a clinical challenge. Studies have shown that many of these patients suffer long-term pulmonary disease related to residual fibrosis. Prior studies have shown that while many patients have non-specific findings of fibrotic-like changes, others develop specific patterns of interstitial lung disease.

Case Report: Here, we present the first case of a patient developing pulmonary sarcoidosis one year after critical illness from COVID-19. He developed numerous non-necrotizing and well-formed granulomas in mediastinal lymph nodes and pulmonary nodules, compatible radiographically and pathologically with sarcoid.

Conclusions: While the pathophysiology of sarcoid is incompletely understood, inflammation is mediated through the dysregulation of a number of different cytokines (IFNγ, IL-2, IL-12, IL-17, IL-22). This case provides valuable clues for better understanding of the shared pathophysiology of cytokine dysregulation seen in COVID-19 and other interstitial lung diseases such as sarcoidosis.
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http://dx.doi.org/10.1016/j.clinimag.2021.12.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755635PMC
March 2022

Associations of Monocyte Count and Other Immune Cell Types with Interstitial Lung Abnormalities.

Am J Respir Crit Care Med 2022 04;205(7):795-805

Department of Medicine, Columbia University, New York, New York.

Higher blood monocyte counts are associated with worse survival in adults with clinically diagnosed pulmonary fibrosis. Their association with the development and progression of interstitial lung abnormalities (ILA) in humans is unknown. We evaluated the associations of blood monocyte count, and other immune cell types, with ILA, high-attenuation areas, and FVC in four independent cohorts. We included participants with measured monocyte counts and computed tomographic (CT) imaging enrolled in MESA (Multi-Ethnic Study of Atherosclerosis,  = 484), AGES-Reykjavik (Age/Gene Environment Susceptibility Study,  = 3,547), COPDGene (Genetic Epidemiology of COPD,  = 2,719), and the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points,  = 646). After adjustment for covariates, a 1-SD increment in blood monocyte count was associated with ILA in MESA (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.0-1.8), AGES-Reykjavik (OR, 1.2; 95% CI, 1.1-1.3), COPDGene (OR, 1.3; 95% CI, 1.2-1.4), and ECLIPSE (OR, 1.2; 95% CI, 1.0-1.4). A higher monocyte count was associated with ILA progression over 5 years in AGES-Reykjavik (OR, 1.2; 95% CI, 1.0-1.3). Compared with participants without ILA, there was a higher percentage of activated monocytes among those with ILA in MESA. Higher monocyte count was associated with greater high-attenuation areas in MESA and lower FVC in MESA and COPDGene. Associations of other immune cell types were less consistent. Higher blood monocyte counts were associated with the presence and progression of interstitial lung abnormalities and lower FVC.
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http://dx.doi.org/10.1164/rccm.202108-1967OCDOI Listing
April 2022

Pulmonary fibrosis 4 months after COVID-19 is associated with severity of illness and blood leucocyte telomere length.

Thorax 2021 12 29;76(12):1242-1245. Epub 2021 Apr 29.

Medicine/PACC, Columbia University Irving Medical Center, New York, New York, USA

The risk factors for development of fibrotic-like radiographic abnormalities after severe COVID-19 are incompletely described and the extent to which CT findings correlate with symptoms and physical function after hospitalisation remains unclear. At 4 months after hospitalisation, fibrotic-like patterns were more common in those who underwent mechanical ventilation (72%) than in those who did not (20%). We demonstrate that severity of initial illness, duration of mechanical ventilation, lactate dehydrogenase on admission and leucocyte telomere length are independent risk factors for fibrotic-like radiographic abnormalities. These fibrotic-like changes correlate with lung function, cough and measures of frailty, but not with dyspnoea.
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http://dx.doi.org/10.1136/thoraxjnl-2021-217031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103561PMC
December 2021

Post-acute COVID-19 syndrome.

Nat Med 2021 04 22;27(4):601-615. Epub 2021 Mar 22.

Department of Neurology, Vagelos College of Physicians and Surgeons, New York-Presbyterian/Columbia University Irving Medical Center, New York, New York, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.
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http://dx.doi.org/10.1038/s41591-021-01283-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8893149PMC
April 2021

Family History of Pulmonary Fibrosis Predicts Worse Survival in Patients With Interstitial Lung Disease.

Chest 2021 05 21;159(5):1913-1921. Epub 2021 Jan 21.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.

Background: A number of genetic markers linked to familial pulmonary fibrosis predict differential survival in interstitial lung disease (ILD) patients. Although genetic testing is not performed routinely for ILD, family history commonly is obtained and may inform outcome risk.

Research Question: Does survival vary between patients with and without self-reported familial pulmonary fibrosis?

Methods: Family history was acquired systematically for consecutive ILD patients who consented to clinical registry enrollment at the University of Texas Southwestern and the University of California at Davis. Patients were stratified by idiopathic pulmonary fibrosis (IPF) and non-IPF ILD diagnosis and were substratified by presence or absence of familial pulmonary fibrosis, defined as one or more additional affected family members. Transplant-free survival was compared using multilevel, mixed-effects Cox proportional hazards regression.

Results: Of the 1,262 patients included, 534 (42%) had IPF ILD and 728 (58%) had non-IPF ILD. Of those with non-IPF ILD, 18.5% had connective tissue disease, 15.6% had chronic hypersensitivity pneumonitis, and 23.5% had unclassifiable ILD. Familial pulmonary fibrosis was reported in 134 IPF ILD patients (25.1%) and 90 non-IPF ILD patients (12.4%). Those with familial IPF showed an 80% increased risk of death or transplantation compared with those with sporadic IPF (hazard ratio [HR], 1.8; 95% CI, 1.37-2.37; P < .001), whereas those with familial non-IPF ILD showed a twofold increased risk compared with their counterparts with sporadic disease (HR, 2.08; 95% CI, 1.46-2.96; P < .001). Outcome risk among those with familial non-IPF ILD was no different than for those with sporadic IPF ILD (HR, 1.27; 95% CI, 0.89-1.84; P = .19).

Interpretation: Patient-reported familial pulmonary fibrosis is predictive of reduced transplant-free survival in IPF and non-IPF ILD patients. Because survival among patients with familial non-IPF ILD approximates that of sporadic IPF ILD, early intervention should be considered for such patients. Until clinical genetic testing is widely available and provides actionable results, family history should be ascertained and considered in risk stratification.
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http://dx.doi.org/10.1016/j.chest.2021.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173755PMC
May 2021

Leukocyte telomere length and mycophenolate therapy in chronic hypersensitivity pneumonitis.

Eur Respir J 2021 03 4;57(3). Epub 2021 Mar 4.

Section of Pulmonary and Critical Care Medicine, Dept of Medicine, University of California San Francisco, San Francisco, CA, USA.

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http://dx.doi.org/10.1183/13993003.02872-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104021PMC
March 2021

Myositis-specific Antibodies Identify A Distinct Interstitial Pneumonia with Autoimmune Features Phenotype.

Eur Respir J 2020 Jul 16. Epub 2020 Jul 16.

Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of California at Davis

Interstitial pneumonia with autoimmune features (IPAF) characterises individuals with interstitial lung disease (ILD) and features of connective tissue disease (CTD) who fail to satisfy CTD criteria. Inclusion of myositis-specific antibodies (MSAs) in the IPAF criteria has generated controversy, as these patients also meet proposed criteria for an anti-synthetase syndrome. Whether MSAs and myositis associated antibodies (MAA) identify phenotypically distinct IPAF subgroups remains unclear.A multi-center, retrospective investigation was conducted to assess clinical features and outcomes in patients meeting IPAF criteria stratified by the presence of MSAs and MAAs. IPAF subgroups were compared to cohorts of patients with idiopathic inflammatory myopathy-ILD (IIM-ILD), idiopathic pulmonary fibrosis (IPF) and non-IIM CTD-ILDs. The primary endpoint assessed was three-year transplant-free survival. Two hundred sixty-nine patients met IPAF criteria, including 35 (13%) with MSAs and 65 (24.2%) with MAAs. Survival was highest among patients with IPAF-MSA and closely approximated those with IIM-ILD. Survival did not differ between IPAF-MAA and IPAF without MSA/MAA cohorts. Usual interstitial pneumonia (UIP) morphology was associated with differential outcome risk, with IPAF patients with non-UIP morphology approximating survival observed in non-IIM CTD-ILDs. MSAs, but not MAAs identified a unique IPAF phenotype characterised by clinical features and outcomes similar to IIM-ILD. UIP morphology was a strong predictor of outcome in others meeting IPAF criteria. Because IPAF is a research classification without clear treatment approach, these findings suggest MSAs should be removed from the IPAF criteria and such patients should be managed as an IIM-ILD.
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http://dx.doi.org/10.1183/13993003.01205-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943372PMC
July 2020

Prevalence of pectus excavatum in an adult population-based cohort estimated from radiographic indices of chest wall shape.

PLoS One 2020 7;15(5):e0232575. Epub 2020 May 7.

Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, United States of America.

Background: Pectus excavatum is the most common chest wall skeletal deformity. Although commonly evaluated in adolescence, its prevalence in adults is unknown.

Methods And Findings: Radiographic indices of chest wall shape were analyzed for participants of the first (n = 2687) and second (n = 1780) phases of the population-based Dallas Heart Study and compared to clinical cases of pectus (n = 297). Thoracic computed tomography imaging studies were examined to calculate the Haller index, a measure of thoracic axial shape, and the Correction index, which quantitates the posterior displacement of the sternum relative to the ribs. At the level of the superior xiphoid, 0.5%, 5% and 0.4% of adult Dallas Heart Study subjects have evidence of pectus excavatum using thresholds of Haller index >3.25, Correction index >10%, or both, respectively. Radiographic measures of pectus are more common in females than males and there is a greater prevalence of pectus in women than men. In the general population, the Haller and Correction indices are associated with height and weight, independent of age, gender, and ethnicity. Repeat imaging of a subset of subjects (n = 992) demonstrated decreases in the mean Haller and Correction indices over seven years, suggesting change to a more circular axial thorax, with less sternal depression, over time.

Conclusions: To our knowledge, this is the first study estimating the prevalence of pectus in an unselected adult population. Despite the higher reported prevalence of pectus cases in adolescent boys, this study demonstrates a higher prevalence of radiographic indices of pectus in adult females.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232575PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205298PMC
September 2020

Telomere length and genetic variant associations with interstitial lung disease progression and survival.

Eur Respir J 2019 04 11;53(4). Epub 2019 Apr 11.

Dept of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Leukocyte telomere length (LTL), rs35705950 and rs5743890 have been associated with idiopathic pulmonary fibrosis (IPF).In this observational cohort study, we assessed the associations between these genomic markers and outcomes of survival and rate of disease progression in patients with interstitial pneumonia with autoimmune features (IPAF, n=250) and connective tissue disease-associated interstitial lung disease (CTD-ILD, n=248). IPF (n=499) was used as a comparator.The LTL of IPAF and CTD-ILD patients (mean age-adjusted log-transformed T/S of -0.05±0.29 and -0.04±0.25, respectively) is longer than that of IPF patients (-0.17±0.32). For IPAF patients, LTL <10th percentile is associated with faster lung function decline compared to LTL ≥10th percentile (-6.43% per year -0.86% per year; p<0.0001) and worse transplant-free survival (hazard ratio 2.97, 95% CI 1.70-5.20; p=0.00014). The rs35705950 minor allele frequency (MAF) is greater for IPAF patients (23.2, 95% CI 18.8-28.2; p<0.0001) than controls and is associated with worse transplant-free IPAF survival (hazard ratio 1.92, 95% CI 1.18-3.13; p=0.0091). Rheumatoid arthritis (RA)-associated ILD (RA-ILD) has a shorter LTL than non-RA CTD-ILD (-0.14±0.27 -0.01±0.23; p=0.00055) and higher MAF (34.6, 95% CI 24.4-46.3 14.1, 95% CI 9.8-20.0; p=0.00025). Neither LTL nor are associated with transplant-free CTD-ILD survival.LTL and MAF have different associations with lung function progression and survival for IPAF and CTD-ILD.
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http://dx.doi.org/10.1183/13993003.01641-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612265PMC
April 2019

Telomere Length and Use of Immunosuppressive Medications in Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2019 08;200(3):336-347

1Department of Medicine and.

Immunosuppression was associated with adverse events for patients with idiopathic pulmonary fibrosis (IPF) in the PANTHER-IPF (Evaluating the Effectiveness of Prednisone, Azathioprine and -Acetylcysteine in Patients with IPF) clinical trial. The reason why some patients with IPF experience harm is unknown. To determine whether age-adjusted leukocyte telomere length (LTL) was associated with the harmful effect of immunosuppression in patients with IPF. LTL was measured from available DNA samples from PANTHER-IPF (interim analysis,  = 79; final analysis,  = 118). Replication cohorts included ACE-IPF (Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis) ( = 101) and an independent observational cohort (University of Texas Southwestern Medical Center-IPF,  = 170). LTL-stratified and medication-stratified survival analyses were performed using multivariable Cox regression models for composite endpoint-free survival. Of the subjects enrolled in the PANTHER-IPF and ACE-IPF, 62% (49/79) and 56% (28/50) had an LTL less than the 10th percentile of normal, respectively. In PANTHER-IPF, exposure to prednisone/azathioprine/-acetylcysteine was associated with a higher composite endpoint of death, lung transplantation, hospitalization, or FVC decline for those with an LTL less than the 10th percentile (hazard ratio, 2.84; 95% confidence interval, 1.02-7.87;  = 0.045). This finding was replicated in the placebo arm of ACE-IPF for those exposed to immunosuppression (hazard ratio, 7.18; 95% confidence interval, 1.52-33.84;  = 0.013). A propensity-matched University of Texas Southwestern Medical Center IPF cohort showed a similar association between immunosuppression and composite endpoints (death, lung transplantation, or FVC decline) for those with an LTL less than the 10th percentile (hazard ratio, 3.79; 95% confidence interval, 1.73-8.30;  = 0.00085). An interaction was found between immunosuppression and LTL for the combined PANTHER-IPF and ACE-IPF clinical trials ( = 0.048), and the University of Texas Southwestern Medical Center IPF cohort ( = 0.00049). LTL is a biomarker that may identify patients with IPF at risk for poor outcomes when exposed to immunosuppression.
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http://dx.doi.org/10.1164/rccm.201809-1646OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680304PMC
August 2019

Insights from human genetic studies of lung and organ fibrosis.

J Clin Invest 2018 01 2;128(1):36-44. Epub 2018 Jan 2.

Genetic investigations of fibrotic diseases, including those of late onset, often yield unanticipated insights into disease pathogenesis. This Review focuses on pathways underlying lung fibrosis that are generalizable to other organs. Herein, we discuss genetic variants subdivided into those that shorten telomeres, activate the DNA damage response, change resident protein expression or function, or affect organelle activity. Genetic studies provide a window into the downstream cascade of maladaptive responses and pathways that lead to tissue fibrosis. In addition, these studies reveal interactions between genetic variants, environmental factors, and age that influence the phenotypic spectrum of disease. The discovery of forces counterbalancing inherited risk alleles identifies potential therapeutic targets, thus providing hope for future prevention or reversal of fibrosis.
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http://dx.doi.org/10.1172/JCI93556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749497PMC
January 2018

Whole-Exome Sequencing Insights into Adult Pulmonary Fibrosis. Repeating the Telomere Theme.

Am J Respir Crit Care Med 2017 07;196(1):7-9

1 McDermott Center for Human Growth and Development and.

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http://dx.doi.org/10.1164/rccm.201701-0194EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519965PMC
July 2017

The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study.

Lancet Respir Med 2017 08 22;5(8):639-647. Epub 2017 Jun 22.

Department of Medicine, University of California San Francisco, San Francisco, CA, USA.

Background: Patients with hypersensitivity pneumonitis are at risk of developing pulmonary fibrosis, which is associated with reduced survival. In families with multiple affected members, individuals might be diagnosed as having idiopathic pulmonary fibrosis (IPF) or chronic (fibrotic) hypersensitivity pneumonitis, which suggests these disorders share risk factors. We aimed to test whether the genomic risk factors associated with the development and progression of IPF are also associated with the development of fibrosis and reduced survival in people with chronic hypersensitivity pneumonitis.

Methods: We did an observational study of two independent cohorts of patients with chronic hypersensitivity pneumonitis, one from the University of California San Francisco, CA, USA (UCSF), and one from the University of Texas Southwestern, TX, USA (UTSW). We measured two common single-nucleotide polymorphisms associated with IPF (MUC5B rs35705950 and TOLLIP rs5743890) and telomere length in peripheral blood leucocytes, and assessed their associations with chronic hypersensitivity pneumonitis risk, survival, and clinical, radiographic, and pathological features. We compared findings with those in patients with IPF from the UCSF and UTSW cohorts, and healthy controls from the European population of the 1000 Genomes Project Phase 3, version 1.

Findings: The cohorts included 145 patients from UCSF and 72 from UTSW. The minor allele frequency (MAF) was greater for MUC5B rs35705950 in patients with chronic hypersensitivity pneumonitis than in healthy controls (24·4% in UCSF and 32·3% in UTSW vs 10·7%, both p<0·0001), but not for TOLLIP rs5743890. The MAFs were similar to those for IPF (UCSF 33·3%, p=0·09; UTSW 32·0%, p=0·95). In the combined UCSF and UTSW chronic hypersensitivity pneumonitis cohort, we saw associations between extent of radiographic fibrosis and MUC5B rs35705950 minor alleles (adjusted odds ratio [OR] 1·91, 95% CI 1·02-3·59, p=0·045) and short telomere length (adjusted OR per unit change in mean natural logarithm-transformed ratio of telomere repeat copy number to single gene copy number 0·23, 0·09-0·59, p=0·002). Telomere length less than the tenth percentile for age was also significantly associated with reduced survival (log-rank p=0·006).

Interpretation: The associations between MUC5B rs35705950 and short telomere length with extent of fibrosis, histopathological features of usual interstitial pneumonia, and reduced survival in patients with chronic hypersensitivity pneumonitis suggest shared pathobiology with IPF, and might help to stratify risk.

Funding: National Institutes of Health and Nina Ireland Program for Lung Health.
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http://dx.doi.org/10.1016/S2213-2600(17)30216-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555581PMC
August 2017

Pleuroparenchymal fibroelastosis associated with telomerase reverse transcriptase mutations.

Eur Respir J 2017 05 11;49(5). Epub 2017 May 11.

Eugene McDermott Centre for Human Growth and Development, University of Texas Southwestern Medical Centre, Dallas, TX, USA

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http://dx.doi.org/10.1183/13993003.00696-2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833293PMC
May 2017

Telomere length in patients with pulmonary fibrosis associated with chronic lung allograft dysfunction and post-lung transplantation survival.

J Heart Lung Transplant 2017 Aug 4;36(8):845-853. Epub 2017 Feb 4.

Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address:

Background: Prior studies have shown that patients with pulmonary fibrosis with mutations in the telomerase genes have a high rate of certain complications after lung transplantation. However, few studies have investigated clinical outcomes based on leukocyte telomere length.

Methods: We conducted an observational cohort study of all patients with pulmonary fibrosis who underwent lung transplantation at a single center between January 1, 2007, and December 31, 2014. Leukocyte telomere length was measured from a blood sample collected before lung transplantation, and subjects were stratified into 2 groups (telomere length <10th percentile vs ≥10th percentile). Primary outcome was post-lung transplant survival. Secondary outcomes included incidence of allograft dysfunction, non-pulmonary organ dysfunction, and infection.

Results: Approximately 32% of subjects had a telomere length <10th percentile. Telomere length <10th percentile was independently associated with worse survival (hazard ratio 10.9, 95% confidence interval 2.7-44.8, p = 0.001). Telomere length <10th percentile was also independently associated with a shorter time to onset of chronic lung allograft dysfunction (hazard ratio 6.3, 95% confidence interval 2.0-20.0, p = 0.002). Grade 3 primary graft dysfunction occurred more frequently in the <10th percentile group compared with the ≥10th percentile group (28% vs 7%; p = 0.034). There was no difference between the 2 groups in incidence of acute cellular rejection, cytopenias, infection, or renal dysfunction.

Conclusions: Telomere length <10th percentile was associated with worse survival and shorter time to onset of chronic lung allograft dysfunction and thus represents a biomarker that may aid in risk stratification of patients with pulmonary fibrosis before lung transplantation.
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http://dx.doi.org/10.1016/j.healun.2017.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515686PMC
August 2017

Somatic mutations in telomerase promoter counterbalance germline loss-of-function mutations.

J Clin Invest 2017 Mar 13;127(3):982-986. Epub 2017 Feb 13.

Germline coding mutations in different telomere-related genes have been linked to autosomal-dominant familial pulmonary fibrosis. Individuals with these inherited mutations demonstrate incomplete penetrance of clinical phenotypes affecting the lung, blood, liver, skin, and other organs. Here, we describe the somatic acquisition of promoter mutations in telomerase reverse transcriptase (TERT) in blood leukocytes of approximately 5% of individuals with inherited loss-of-function coding mutations in TERT or poly(A)-specific ribonuclease (PARN), another gene linked to telomerase function. While these promoter mutations were initially identified as oncogenic drivers of cancer, individuals expressing the mutations have no history of cancer. Neither promoter mutation was found in population-based cohorts of similar or advanced age. The TERT promoter mutations were found more frequently in cis with the WT allele than the TERT coding sequence mutation. EBV-transformed lymphoblastoid B cell lines (LCLs) derived from subjects with TERT promoter mutations showed increased telomerase expression and activity compared with cell lines from family members with identical coding mutations. TERT promoter mutations resulted in an increased proliferation of LCLs and demonstrated positive selection over time. The persistence and recurrence of noncoding gain-of-function mutations in these cases suggests that telomerase activation is not only safely tolerated but also advantageous for clonal expansion.
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http://dx.doi.org/10.1172/JCI91161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330735PMC
March 2017

Pulmonary fibrosis in the era of stratified medicine.

Thorax 2016 12 31;71(12):1154-1160. Epub 2016 Oct 31.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Both common and rare variants contribute to the genetic architecture of pulmonary fibrosis. Genome-wide association studies have identified common variants, or those with a minor allele frequency of >5%, that are linked to pulmonary fibrosis. The most widely replicated variant (rs35705950) is located in the promoter region of the gene and has been strongly associated with idiopathic pulmonary fibrosis (IPF) and familial interstitial pneumonia (FIP) across multiple different cohorts. However, many more common variants have been identified with disease risk and in aggregate account for approximately one-third of the risk of IPF. Moreover, several of these common variants appear to have prognostic potential. Next generation sequencing technologies have facilitated the identification of rare variants. Recent whole exome sequencing studies have linked pathogenic rare variants in multiple new genes to FIP. Compared with common variants, rare variants have lower population allele frequencies and higher effect sizes. Pulmonary fibrosis rare variants genes can be subdivided into two pathways: telomere maintenance and surfactant metabolism. Heterozygous rare variants in telomere-related genes co-segregate with adult-onset pulmonary fibrosis with incomplete penetrance, lead to reduced protein function, and are associated with short telomere lengths. Despite poor genotype-phenotype correlations, lung fibrosis associated with pathogenic rare variants in different telomere genes is progressive and displays similar survival characteristics. In contrast, many of the heterozygous rare variants in the surfactant genes predict a gain of toxic function from protein misfolding and increased endoplasmic reticulum (ER) stress. Evidence of both telomere shortening and increased ER stress have been found in sporadic IPF patients, suggesting that the mechanisms identified from rare variant genetic studies in unique individuals and families are applicable to a wider spectrum of patients. The ability to sequence large cohorts of individuals rapidly has the potential to further our understanding of the relative contributions of common and rare variants in the pathogenesis of pulmonary fibrosis. The UK 100,000 Genomes Project will provide opportunities to interrogate both common and rare variants and to investigate how these biological signals provide diagnostic and prognostic information in the era of stratified medicine.
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http://dx.doi.org/10.1136/thoraxjnl-2016-209172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450041PMC
December 2016

Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive.

Eur Respir J 2016 12 18;48(6):1710-1720. Epub 2016 Aug 18.

Eugene McDermott Centre for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA

Heterozygous mutations in four telomere-related genes have been linked to pulmonary fibrosis, but little is known about similarities or differences of affected individuals.115 patients with mutations in telomerase reverse transcriptase (TERT) (n=75), telomerase RNA component (TERC) (n=7), regulator of telomere elongation helicase 1 (RTEL1) (n=14) and poly(A)-specific ribonuclease (PARN) (n=19) were identified and clinical data were analysed.Approximately one-half (46%) had a multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF); others had unclassifiable lung fibrosis (20%), chronic hypersensitivity pneumonitis (12%), pleuroparenchymal fibroelastosis (10%), interstitial pneumonia with autoimmune features (7%), an idiopathic interstitial pneumonia (4%) and connective tissue disease-related interstitial fibrosis (3%). Discordant interstitial lung disease diagnoses were found in affected individuals from 80% of families. Patients with TERC mutations were diagnosed at an earlier age than those with PARN mutations (51±11 years versus 64±8 years; p=0.03) and had a higher incidence of haematological comorbidities. The mean rate of forced vital capacity decline was 300 mL·year and the median time to death or transplant was 2.87 years. There was no significant difference in time to death or transplant for patients across gene mutation groups or for patients with a diagnosis of IPF versus a non-IPF diagnosis.Genetic mutations in telomere related genes lead to a variety of interstitial lung disease (ILD) diagnoses that are universally progressive.
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http://dx.doi.org/10.1183/13993003.00308-2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433348PMC
December 2016

Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia.

BMC Genet 2016 06 7;17(1):74. Epub 2016 Jun 7.

National Heart and Lung Institute, Imperial College, London, UK.

Background: Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci.

Results: We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P meta  = 3.7 × 10(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10(-7) and DQB1*06:02 P = 6.1 × 10(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10(-16)).

Conclusions: We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.
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http://dx.doi.org/10.1186/s12863-016-0377-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895966PMC
June 2016

Epigenetic inheritance of telomere length obscures identification of causative PARN locus.

J Med Genet 2016 05 23;53(5):356-8. Epub 2016 Feb 23.

Eugene McDermott Center for Human Growth and Development, Dallas, Texas, USA Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

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http://dx.doi.org/10.1136/jmedgenet-2015-103685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4875813PMC
May 2016

Running short on time: lung transplant evaluation for telomere-related pulmonary fibrosis.

Chest 2015 Jun;147(6):1450-1452

McDermott Center for Human Growth and Development and the Department of Internal Medicine, University of Texas Southwestern Medical Center. Dallas, TX. Electronic address:

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http://dx.doi.org/10.1378/chest.15-0077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395048PMC
June 2015

Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.

Nat Genet 2015 May 13;47(5):512-7. Epub 2015 Apr 13.

1] Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Idiopathic pulmonary fibrosis (IPF) is an age-related disease featuring progressive lung scarring. To elucidate the molecular basis of IPF, we performed exome sequencing of familial kindreds with pulmonary fibrosis. Gene burden analysis comparing 78 European cases and 2,816 controls implicated PARN, an exoribonuclease with no previous connection to telomere biology or disease, with five new heterozygous damaging mutations in unrelated cases and none in controls (P = 1.3 × 10(-8)); mutations were shared by all affected relatives (odds in favor of linkage = 4,096:1). RTEL1, an established locus for dyskeratosis congenita, harbored significantly more new damaging and missense variants at conserved residues in cases than in controls (P = 1.6 × 10(-6)). PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic inheritance of short telomeres in family members. Together, these genes explain ~7% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction.
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http://dx.doi.org/10.1038/ng.3278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414891PMC
May 2015

Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: an observational cohort study with independent validation.

Lancet Respir Med 2014 Jul 16;2(7):557-65. Epub 2014 Jun 16.

University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address:

Background: Short telomere lengths are found in a subset of patients with idiopathic pulmonary fibrosis, but their clinical significance is unknown. Our aim was to investigate whether patients with various blood leucocyte telomere lengths had different overall survival.

Methods: In this observational cohort study, we enrolled patients with interstitial lung disease from Dallas, TX (primary cohort), and from Chicago, IL, and San Francisco, CA (replication cohorts). We obtained genomic DNA samples from unrelated healthy controls in Dallas, TX, and spouses of patients were also enrolled as an independent control group. Telomere lengths were measured in genomic DNA samples isolated from peripheral blood obtained at the time of the initial enrolment assessment. The primary endpoint was transplant-free survival (ie, time to death or lung transplantation) in the Dallas cohort. Findings were validated in the two independent idiopathic pulmonary fibrosis cohorts (Chicago and San Francisco).

Findings: 370 patients were enrolled into the Dallas cohort between June 17, 2003, and Aug 25, 2011. The 149 patients with idiopathic pulmonary fibrosis had shorter telomere lengths than did the 195 healthy controls (mean age-adjusted log-transformed ratio of telomere to single copy gene was -0.16 [SD 0.23] vs 0.00 [0.18]; p<0.0001); however, telomere lengths of the Dallas patients with idiopathic pulmonary fibrosis (1.33 [SD 0.25]) were similar to the 221 patients with other interstitial lung disease diagnoses (1.46 [0.24]) after adjusting for age, sex, and ethnicity (p=0.47). Telomere length was independently associated with transplant-free survival time for patients with idiopathic pulmonary fibrosis (HR 0.22 [95% CI 0.08-0.63]; p=0.0048), but not for patients with interstitial lung disease diagnoses other than idiopathic pulmonary fibrosis (HR 0.73 [0.16-3.41]; p=0.69). The association between telomere length and survival in patients with idiopathic pulmonary fibrosis was independent of age, sex, forced vital capacity, or diffusing capacity of carbon monoxide, and was replicated in the two independent idiopathic pulmonary fibrosis replication cohorts (Chicago cohort, HR 0.11 [0.03-0.39], p=0.00066; San Francisco cohort, HR 0.25 [0.07-0.87], p=0.029).

Interpretation: Shorter leucocyte telomere lengths are associated with worse survival in idiopathic pulmonary fibrosis. Additional studies will be needed to establish clinically relevant thresholds for telomere length and how this biomarker might affect risk stratification of patients with idiopathic pulmonary fibrosis.

Funding: US National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, Harroun Family Foundation, and Nina Ireland Lung Disease Program.
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http://dx.doi.org/10.1016/S2213-2600(14)70124-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136521PMC
July 2014

Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report.

Am J Respir Crit Care Med 2014 Jan;189(2):214-22

1 Vanderbilt University Medical Center, Nashville, Tennessee.

The median survival of patients with idiopathic pulmonary fibrosis (IPF) continues to be approximately 3 years from the time of diagnosis, underscoring the lack of effective medical therapies for this disease. In the United States alone, approximately 40,000 patients die of this disease annually. In November 2012, the NHLBI held a workshop aimed at coordinating research efforts and accelerating the development of IPF therapies. Basic, translational, and clinical researchers gathered with representatives from the NHLBI, patient advocacy groups, pharmaceutical companies, and the U.S. Food and Drug Administration to review the current state of IPF research and identify priority areas, opportunities for collaborations, and directions for future research. The workshop was organized into groups that were tasked with assessing and making recommendations to promote progress in one of the following six critical areas of research: (1) biology of alveolar epithelial injury and aberrant repair; (2) role of extracellular matrix; (3) preclinical modeling; (4) role of inflammation and immunity; (5) genetic, epigenetic, and environmental determinants; (6) translation of discoveries into diagnostics and therapeutics. The workshop recommendations provide a basis for directing future research and strategic planning by scientific, professional, and patient communities and the NHLBI.
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http://dx.doi.org/10.1164/rccm.201306-1141WSDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983890PMC
January 2014

Lung fibrosis-associated surfactant protein A1 and C variants induce latent transforming growth factor β1 secretion in lung epithelial cells.

J Biol Chem 2013 Sep 7;288(38):27159-27171. Epub 2013 Aug 7.

Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, Texas 75390; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390. Electronic address:

Missense mutations of surfactant proteins are recognized as important causes of inherited lung fibrosis. Here, we study rare and common surfactant protein (SP)-A1 and SP-C variants, either discovered in our familial pulmonary fibrosis cohort or described by others. We show that expression of two SP-A1 (R219W and R242*) and three SP-C (I73T, M71V, and L188Q) variant proteins lead to the secretion of the profibrotic latent transforming growth factor (TGF)-β1 in lung epithelial cell lines. The secreted TGF-β1 is capable of autocrine and paracrine signaling and is dependent upon expression of the latent TGF-β1 binding proteins. The dependence upon unfolded protein response (UPR) mediators for TGF-β1 induction differs for each variant. TGF-β1 secretion induced by the expression of the common SP-A1 R219W variant is nearly completely blocked by silencing the UPR transducers IRE-1α and ATF6. In contrast, the secretion of TGF-β1 induced by two rare SP-C mutant proteins (I73T and M71V), is largely unaffected by UPR silencing or by the addition of the small molecular chaperone 4-phenylbutyric acid, implicating a UPR-independent mechanism for these variants. Blocking TGF-β1 secretion reverses cell death of RLE-6TN cells expressing these SP-A1 and SP-C variants suggesting that anti-TGF-β therapeutics may be beneficial to this molecularly defined subgroup of pulmonary fibrosis patients.
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http://dx.doi.org/10.1074/jbc.M113.475335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779714PMC
September 2013
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