Current Insights in Genetics of Sarcoidosis: Functional and Clinical Impacts

Sarcoidosis is a complex disease that belongs to the vast group of autoinflammatory disorders, but the etiological mechanisms of which are not known. At the crosstalk of environmental, infectious, and genetic factors, sarcoidosis is a multifactorial disease that requires a multidisciplinary approach for which genetic research, in particular, next generation sequencing (NGS) tools, has made it possible to identify new pathways and propose mechanistic hypotheses. Codified treatments for the disease cannot always respond to the most progressive forms and the identification of new genetic and metabolic tracks is a challenge for the future management of the most severe patients. Here, we review the current knowledge regarding the genes identified by both genome wide association studies (GWAS) and whole exome sequencing (WES), as well the connection of these pathways with the current research on sarcoidosis immune-related disorders.

[1]  D. Bouros,et al.  Association of TGF-β3 and ANXA11 with pulmonary sarcoidosis in Greek population , 2020, Expert review of respiratory medicine.

[2]  X. Y. Yang,et al.  [Whole exome sequencing and analysis of a Chinese family with familial pulmonary sarcoidosis]. , 2020, Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases.

[3]  Xin Li,et al.  Arsenic induces mTOR-dependent autophagy, whereas it impairs the autophagy-lysosome pathway and the potential role of TFEB in cultured dendritic cells. , 2020, Metallomics : integrated biometal science.

[4]  R. Guleria,et al.  MicroRNAs in pulmonary sarcoidosis: A systematic review. , 2020, Respiratory investigation.

[5]  V. Cottin,et al.  [Diagnostic difficulties of chronic pulmonary berylliosis in France]. , 2020, Revue des maladies respiratoires.

[6]  S. Atif,et al.  Adaptive Immunity in Pulmonary Sarcoidosis and Chronic Beryllium Disease , 2020, Frontiers in Immunology.

[7]  M. Iannuzzi,et al.  Genome-Wide Association Study of Ocular Sarcoidosis Confirms HLA Associations and Implicates Barrier Function and Autoimmunity in African Americans , 2020, Ocular immunology and inflammation.

[8]  T. Weichhart,et al.  Sarcoidosis and the mTOR, Rac1, and Autophagy Triad. , 2020, Trends in immunology.

[9]  Rajeev K. Varshney,et al.  Fine mapping and gene cloning in the post-NGS era: advances and prospects , 2020, Theoretical and Applied Genetics.

[10]  P. Manque,et al.  Implications of Selective Autophagy Dysfunction for ALS Pathology , 2020, Cells.

[11]  L. Churilov,et al.  Sarcoidosis as an Autoimmune Disease , 2020, Frontiers in Immunology.

[12]  I. Jonkers,et al.  A practical view of fine-mapping and gene prioritization in the post-genome-wide association era , 2020, Open Biology.

[13]  M. Lokki,et al.  Exome Sequencing Identifies Susceptibility Loci for Sarcoidosis Prognosis , 2019, Frontiers in Immunology.

[14]  L. Alfredsson,et al.  A Gene–Environment Interaction Between Smoking and Gene polymorphisms Provides a High Risk of Two Subgroups of Sarcoidosis , 2019, Scientific Reports.

[15]  B. Kostov,et al.  Geoepidemiological big data approach to sarcoidosis: geographical and ethnic determinants. , 2019, Clinical and experimental rheumatology.

[16]  S. Pinson,et al.  Exome sequencing and pathogenicity-network analysis of five French families implicate mTOR signalling and autophagy in familial sarcoidosis , 2019, European Respiratory Journal.

[17]  N. Barnich,et al.  New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD , 2019, Autophagy.

[18]  J. Grunewald,et al.  Sarcoidosis , 2019, Nature Reviews Disease Primers.

[19]  S. Akira,et al.  Phosphorylation-dependent Regnase-1 release from endoplasmic reticulum is critical in IL-17 response , 2019, The Journal of experimental medicine.

[20]  Kenny Q. Ye,et al.  Genetic Variants Associated with FDNY WTC-Related Sarcoidosis , 2019, International journal of environmental research and public health.

[21]  J. Taunton,et al.  MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis. , 2019, JCI insight.

[22]  L. Grossman,et al.  HIF-1α regulates IL-1β and IL-17 in sarcoidosis , 2019, eLife.

[23]  M. Rosenbach,et al.  Resolution of cutaneous sarcoidosis after Janus kinase inhibitor therapy for concomitant polycythemia vera , 2019, JAAD case reports.

[24]  D. Maucort-Boulch,et al.  BTNL2 gene polymorphism and sarcoid uveitis , 2019, British Journal of Ophthalmology.

[25]  C. van Moorsel,et al.  Clinical epidemiology of familial sarcoidosis: A systematic literature review. , 2019, Respiratory medicine.

[26]  B. King,et al.  Tofacitinib Treatment and Molecular Analysis of Cutaneous Sarcoidosis , 2018, The New England journal of medicine.

[27]  Hara Kang,et al.  Hypoxia‐induced regulation of mTOR signaling by miR‐7 targeting REDD1 , 2018, Journal of cellular biochemistry.

[28]  S. Akira,et al.  Regnase-1 controls colon epithelial regeneration via regulation of mTOR and purine metabolism , 2018, Proceedings of the National Academy of Sciences.

[29]  A. Franke,et al.  Whole-exome sequencing identifies rare genetic variations in German families with pulmonary sarcoidosis , 2018, Human Genetics.

[30]  S. Chi,et al.  XAF1 forms a positive feedback loop with IRF-1 to drive apoptotic stress response and suppress tumorigenesis , 2018, Cell Death & Disease.

[31]  J. Grunewald,et al.  Familial aggregation and heritability of sarcoidosis: a Swedish nested case−control study , 2018, European Respiratory Journal.

[32]  J. Todd,et al.  Approaches and advances in the genetic causes of autoimmune disease and their implications , 2018, Nature Immunology.

[33]  A. Alcamí,et al.  Chemokines cooperate with TNF to provide protective anti-viral immunity and to enhance inflammation , 2018, Nature Communications.

[34]  A. Fontenot Immunologic Effects of Beryllium Exposure , 2018, Annals of the American Thoracic Society.

[35]  V. Besnard,et al.  G908R NOD2 variant in a family with sarcoidosis , 2018, Respiratory Research.

[36]  J. Bernaudin,et al.  Whole exome sequencing in three families segregating a pediatric case of sarcoidosis , 2018, BMC Medical Genomics.

[37]  Greg M. Delgoffe,et al.  IL-23 and IL-1β Drive Human Th17 Cell Differentiation and Metabolic Reprogramming in Absence of CD28 Costimulation. , 2018, Cell reports.

[38]  P. Mota,et al.  Associations between sarcoidosis clinical course and ANXA11 rs1049550 C/T, BTNL2 rs2076530 G/A, and HLA class I and II alleles , 2018, The clinical respiratory journal.

[39]  A. Choi,et al.  Autophagy and inflammation in chronic respiratory disease , 2018, Autophagy.

[40]  S. Davoudi,et al.  Association of genetic variants in RAB23 and ANXA11 with uveitis in sarcoidosis , 2018, Molecular vision.

[41]  Iannis E. Adamopoulos,et al.  Structural Activation of Pro‐inflammatory Human Cytokine IL‐23 by Cognate IL‐23 Receptor Enables Recruitment of the Shared Receptor IL‐12R&bgr;1 , 2018, Immunity.

[42]  W. Drake,et al.  Genetic, Immunologic, and Environmental Basis of Sarcoidosis. , 2017, Annals of the American Thoracic Society.

[43]  David C. Thomas,et al.  The phagocyte respiratory burst: Historical perspectives and recent advances. , 2017, Immunology letters.

[44]  E. Louis,et al.  CCDC88B is required for pathogenesis of inflammatory bowel disease , 2017, Nature Communications.

[45]  Ming-Hsi Wang,et al.  Crohn's Disease: Genetics Update. , 2017, Gastroenterology clinics of North America.

[46]  A. Prasse,et al.  Transcriptome profiles in sarcoidosis and their potential role in disease prediction , 2017, Current opinion in pulmonary medicine.

[47]  P. Visscher,et al.  10 Years of GWAS Discovery: Biology, Function, and Translation. , 2017, American journal of human genetics.

[48]  R. Pique-Regi,et al.  RNA-sequencing Identifies Novel Pathways in Sarcoidosis Monocytes , 2017, Scientific Reports.

[49]  Robert H. Brown,et al.  Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis , 2017, Science Translational Medicine.

[50]  V. Anttila,et al.  SNP Variants in Major Histocompatibility Complex Are Associated with Sarcoidosis Susceptibility—A Joint Analysis in Four European Populations , 2017, Front. Immunol..

[51]  Jun Sun,et al.  Inhibition of p70 S6 kinase (S6K1) activity by A77 1726, the active metabolite of leflunomide, induces autophagy through TAK1-mediated AMPK and JNK activation , 2017, Oncotarget.

[52]  J. Hugot,et al.  Nod2: The intestinal gate keeper , 2017, PLoS pathogens.

[53]  M. V. van Vugt,et al.  PLK1 (polo like kinase 1) inhibits MTOR complex 1 and promotes autophagy , 2017, Autophagy.

[54]  Li-qiang Zheng,et al.  Rab23’s genetic structure, function and related diseases: a review , 2017, Bioscience reports.

[55]  J. Garcia,et al.  Annexin A11 is associated with pulmonary fibrosis in African American patients with sarcoidosis. , 2016, Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG.

[56]  Wolfram Weckwerth,et al.  Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression , 2016, Nature Immunology.

[57]  M. Elsensohn,et al.  Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort , 2016, Orphanet Journal of Rare Diseases.

[58]  T. Yoshimoto,et al.  Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family , 2016, Front. Immunol..

[59]  Chuan Wu,et al.  Tiam1/Rac1 complex controls Il17a transcription and autoimmunity , 2016, Nature Communications.

[60]  Ralf Herwig,et al.  Analyzing and interpreting genome data at the network level with ConsensusPathDB , 2016, Nature Protocols.

[61]  S. Vermeire,et al.  Sarcoidosis-Like Lesions: Another Paradoxical Reaction to Anti-TNF Therapy? , 2016, Journal of Crohn's & colitis.

[62]  M. Diao,et al.  The Association between ANXA11 Gene Polymorphisms and Sarcoidosis: a Meta-Analysis and systematic review. , 2016, Sarcoidosis Vasculities and Diffuse Lung Diseases.

[63]  H. Deng,et al.  In vitro and in vivo inhibition of mTOR by 1,25-dihydroxyvitamin D3 to improve early diabetic nephropathy via the DDIT4/TSC2/mTOR pathway , 2016, Endocrine.

[64]  H. Fan,et al.  The BTNL2 G16071A gene polymorphism increases granulomatous disease susceptibility , 2016, Medicine.

[65]  N. Prescott,et al.  Genetic Association Analysis Reveals Differences in the Contribution of NOD2 Variants to the Clinical Phenotypes of Orofacial Granulomatosis , 2016, Inflammatory bowel diseases.

[66]  Lishuang Shen,et al.  NOD2 genetic variants and sarcoidosis-associated uveitis☆ , 2016, American journal of ophthalmology case reports.

[67]  H. Jiao,et al.  Glucocorticoids Enhance Muscle Proteolysis through a Myostatin-Dependent Pathway at the Early Stage , 2016, PloS one.

[68]  Jin-young Shin,et al.  Thiopurine Prodrugs Mediate Immunosuppressive Effects by Interfering with Rac1 Protein Function* , 2016, The Journal of Biological Chemistry.

[69]  M. Mirsaeidi,et al.  Annexins family: insights into their functions and potential role in pathogenesis of sarcoidosis , 2016, Journal of Translational Medicine.

[70]  U. Pleyer,et al.  Sirolimus for the treatment of noninfectious uveitis , 2016, Expert opinion on pharmacotherapy.

[71]  K. Amber,et al.  TNF‐α: a treatment target or cause of sarcoidosis? , 2015, Journal of the European Academy of Dermatology and Venereology : JEADV.

[72]  M. Iannuzzi,et al.  Role of NOD2 Pathway Genes in Sarcoidosis Cases with Clinical Characteristics of Blau Syndrome. , 2015, American journal of respiratory and critical care medicine.

[73]  C. Gieger,et al.  Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk. , 2015, American journal of respiratory and critical care medicine.

[74]  B. Rybicki,et al.  Granuloma genes in sarcoidosis: what is new? , 2015, Current opinion in pulmonary medicine.

[75]  M. Iannuzzi,et al.  Fine mapping of chromosome 15q25 implicates ZNF592 in neurosarcoidosis patients , 2015, Annals of clinical and translational neurology.

[76]  M. Suchánková,et al.  TREM-2 Receptor Expression Increases with 25(OH)D Vitamin Serum Levels in Patients with Pulmonary Sarcoidosis , 2015, Mediators of inflammation.

[77]  F. Song,et al.  Intracellular calcium signaling regulates autophagy via calcineurin-mediated TFEB dephosphorylation , 2015, Autophagy.

[78]  Q. Al-Awqati Kidney growth and hypertrophy: the role of mTOR and vesicle trafficking. , 2015, The Journal of clinical investigation.

[79]  A. Kijlstra,et al.  Genetic variations of IL17F and IL23A show associations with Behçet's disease and Vogt-Koyanagi-Harada syndrome. , 2015, Ophthalmology.

[80]  M. Iannuzzi,et al.  Association of HLA-DRB1 with Sarcoidosis Susceptibility and Progression in African Americans. , 2014, American journal of respiratory cell and molecular biology.

[81]  M. Lathrop,et al.  CCDC88B is a novel regulator of maturation and effector functions of T cells during pathological inflammation , 2014, The Journal of experimental medicine.

[82]  J. Ninomiya-Tsuji,et al.  Activated Macrophage Survival Is Coordinated by TAK1 Binding Proteins , 2014, PloS one.

[83]  N. Ruddle Lymphotoxin and TNF: how it all began-a tribute to the travelers. , 2014, Cytokine & growth factor reviews.

[84]  A. Gabrielsen,et al.  HLA-alleles associated with increased risk for extra-pulmonary involvement in sarcoidosis. , 2014, Tissue antigens.

[85]  M. Iannuzzi,et al.  Admixture Fine-Mapping in African Americans Implicates XAF1 as a Possible Sarcoidosis Risk Gene , 2014, PloS one.

[86]  E. Hoitsma,et al.  Association of the TNF-α G-308A polymorphism with TNF-inhibitor response in sarcoidosis , 2014, European Respiratory Journal.

[87]  Y. Wu,et al.  Regulation of autophagy by the Rab GTPase network , 2014, Cell Death and Differentiation.

[88]  I. Surakka,et al.  Major histocompatibility complex class II and BTNL2 associations in sarcoidosis , 2013, European Respiratory Journal.

[89]  R. Baughman,et al.  Calcium and vitamin D metabolism in sarcoidosis. , 2013, Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG.

[90]  Freddy Radtke,et al.  Regulation of innate and adaptive immunity by Notch , 2013, Nature Reviews Immunology.

[91]  Y. Iwakura,et al.  Negative feedback on IL-23 exerted by IL-17A during pulmonary inflammation , 2013, Innate immunity.

[92]  I. Adzhubei,et al.  Predicting Functional Effect of Human Missense Mutations Using PolyPhen‐2 , 2013, Current protocols in human genetics.

[93]  C. Gieger,et al.  A novel sarcoidosis risk locus for Europeans on chromosome 11q13.1. , 2012, American journal of respiratory and critical care medicine.

[94]  M. Iannuzzi,et al.  Association of ANXA11 genetic variation with sarcoidosis in African Americans and European Americans , 2012, Genes and Immunity.

[95]  Jessica J. Hale,et al.  Genome-Wide Association Study of African and European Americans Implicates Multiple Shared and Ethnic Specific Loci in Sarcoidosis Susceptibility , 2012, PloS one.

[96]  R. Tampé,et al.  Direct evidence that the N-terminal extensions of the TAP complex act as autonomous interaction scaffolds for the assembly of the MHC I peptide-loading complex , 2012, Cellular and Molecular Life Sciences.

[97]  B. Horwitz,et al.  Nfkb1 Inhibits LPS-Induced IFN-β and IL-12 p40 Production in Macrophages by Distinct Mechanisms , 2012, PloS one.

[98]  M. Qiao,et al.  The XAF1 tumor suppressor induces autophagic cell death via upregulation of Beclin-1 and inhibition of Akt pathway. , 2011, Cancer letters.

[99]  Prescott G Woodruff,et al.  Sarcoidosis blood transcriptome reflects lung inflammation and overlaps with tuberculosis. , 2011, American journal of respiratory and critical care medicine.

[100]  B. Charreau,et al.  The adaptor Lnk (SH2B3): an emerging regulator in vascular cells and a link between immune and inflammatory signaling. , 2011, Biochemical pharmacology.

[101]  Justine R. Smith,et al.  Association of Interleukin 23 Receptor Gene with Sarcoidosis , 2011, Disease markers.

[102]  Y. Zhang,et al.  Human leukocyte antigen-A, -B, and -DRB1 alleles and sarcoidosis in Chinese Han subjects. , 2011, Human immunology.

[103]  A. Schuldt Cell growth: RAC1 sizes up mTOR , 2011, Nature Reviews Molecular Cell Biology.

[104]  P. Rosenstiel,et al.  A genome-wide association study reveals evidence of association with sarcoidosis at 6p12.1 , 2011, European Respiratory Journal.

[105]  P. Spagnolo,et al.  Sarcoidosis HLA class II genotyping distinguishes differences of clinical phenotype across ethnic groups. , 2010, Human molecular genetics.

[106]  B. Ryffel,et al.  Limited Role for Lymphotoxin α in the Host Immune Response to Mycobacterium tuberculosis , 2010, The Journal of Immunology.

[107]  P. Spagnolo,et al.  CC chemokine receptor 5 gene polymorphisms in beryllium disease , 2010, European Respiratory Journal.

[108]  I. Kockum,et al.  Major histocompatibility complex class II transactivator gene polymorphism: associations with Löfgren's syndrome. , 2010, Tissue antigens.

[109]  J. Grunewald Review: role of genetics in susceptibility and outcome of sarcoidosis. , 2010, Seminars in respiratory and critical care medicine.

[110]  Nicolas Levy,et al.  CAMOS, a nonprogressive, autosomal recessive, congenital cerebellar ataxia, is caused by a mutant zinc-finger protein, ZNF592 , 2010, European Journal of Human Genetics.

[111]  S. Biswal,et al.  Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke – induced pulmonary injury and emphysema , 2010, Nature Medicine.

[112]  H. Rammensee,et al.  Autoimmune T cell responses to antigenic peptides presented by bronchoalveolar lavage cell HLA-DR molecules in sarcoidosis. , 2009, Clinical immunology.

[113]  D. Cutler,et al.  Variation in the lymphotoxin-alpha/tumor necrosis factor locus modifies risk of erythema nodosum in sarcoidosis. , 2009, The Journal of investigative dermatology.

[114]  R. Elashoff,et al.  Immune response CC chemokines CCL2 and CCL5 are associated with pulmonary sarcoidosis , 2009, Fibrogenesis & tissue repair.

[115]  G. McLennan,et al.  HLA and environmental interactions in sarcoidosis. , 2008, Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG.

[116]  A. Nebel,et al.  Genetics of Sarcoidosis , 2014, Seminars in Respiratory and Critical Care Medicine.

[117]  P. Rosenstiel,et al.  Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis , 2008, Nature Genetics.

[118]  V. Backer,et al.  Heredity in sarcoidosis: a registry-based twin study , 2008, Thorax.

[119]  B. Ghosh,et al.  Association of TNF polymorphisms with sarcoidosis, its prognosis and tumour necrosis factor (TNF)‐α levels in Asian Indians , 2007, Clinical and experimental immunology.

[120]  R. Elston,et al.  Genetic linkage analysis of sarcoidosis phenotypes: the sarcoidosis genetic analysis (SAGA) study , 2007, Genes and Immunity.

[121]  M. Iannuzzi,et al.  Epidemiology of Sarcoidosis: Recent Advances and Future Prospects , 2007, Seminars in respiratory and critical care medicine.

[122]  M. Judson,et al.  Racial and ethnic disparities in sarcoidosis: from genetics to socioeconomics. , 2006, Clinics in chest medicine.

[123]  P. Spagnolo,et al.  C-C chemokine receptor 5 gene variants in relation to lung disease in sarcoidosis. , 2005, American journal of respiratory and critical care medicine.

[124]  R. Elston,et al.  A sarcoidosis genetic linkage consortium: the sarcoidosis genetic analysis (SAGA) study. , 2005, Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG.

[125]  K. Huse,et al.  Sarcoidosis is associated with a truncating splice site mutation in BTNL2 , 2005, Nature Genetics.

[126]  E. Hafen,et al.  Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. , 2004, Genes & development.

[127]  M. Iannuzzi,et al.  HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites. , 2003, American journal of human genetics.

[128]  Steven Henikoff,et al.  SIFT: predicting amino acid changes that affect protein function , 2003, Nucleic Acids Res..

[129]  S. Meloche,et al.  Rho Family GTPases Are Required for Activation of Jak/STAT Signaling by G Protein-Coupled Receptors , 2003, Molecular and Cellular Biology.

[130]  G. Thomas,et al.  CARD15 mutations in Blau syndrome , 2001, Nature Genetics.

[131]  K. Welsh,et al.  Correspondence and requests for reprints should be addressed to Dr. Martin , 2022 .

[132]  H. Inoko,et al.  HLA-DQB1*0601 is primarily associated with the susceptibility to cardiac sarcoidosis. , 2000, Tissue antigens.

[133]  K. Welsh,et al.  Analysis of MHC encoded antigen-processing genes TAP1 and TAP2 polymorphisms in sarcoidosis. , 1999, American journal of respiratory and critical care medicine.

[134]  M. Iannuzzi Genetics of sarcoidosis. , 1998, Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace.

[135]  B. Veress,et al.  The distribution of S100 and lysozyme immunoreactive cells in the various phases of granuloma development in sarcoidosis. , 1987, Sarcoidosis.

[136]  M. Yáñez,et al.  An Update to Calcium Binding Proteins. , 2020, Advances in experimental medicine and biology.

[137]  A. Wells,et al.  Advanced sarcoidosis. , 2019, Current opinion in pulmonary medicine.

[138]  D. Gritz,et al.  Clinical Course of Sarcoidosis in World Trade Center‐Exposed Firefighters , 2018, Chest.

[139]  Abbas Dehghan,et al.  Genome-Wide Association Studies. , 2018, Methods in molecular biology.

[140]  P. Rutgeerts,et al.  Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease. , 2016, The New England journal of medicine.

[141]  Kumar Kshitij Patel,et al.  Human genome meeting 2016 , 2016, Human Genomics.

[142]  L. Platanias,et al.  Intersection of mTOR and STAT signaling in immunity. , 2015, Trends in immunology.

[143]  Y. Lee,et al.  Associations between TNF-α −308 A/G and lymphotoxin-α +252 A/G polymorphisms and susceptibility to sarcoidosis: a meta-analysis , 2013, Molecular Biology Reports.