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Genetics of neurosarcoidosis

  • Abigail Hardin
    Affiliations
    Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, 825 NE 13th, Research Tower, Suite 2202, Oklahoma City, OK 73104, USA
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  • Bryan Dawkins
    Affiliations
    Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, 825 NE 13th, Research Tower, Suite 2202, Oklahoma City, OK 73104, USA
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  • Nathan Pezant
    Affiliations
    Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, 825 NE 13th, Research Tower, Suite 2202, Oklahoma City, OK 73104, USA
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  • Astrid Rasmussen
    Affiliations
    Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, 825 NE 13th, Research Tower, Suite 2202, Oklahoma City, OK 73104, USA
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  • Courtney Montgomery
    Correspondence
    Corresponding author: Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, 825 NE 13th, Research Tower, Suite 2202, Oklahoma City, OK 73104, USA.
    Affiliations
    Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, 825 NE 13th, Research Tower, Suite 2202, Oklahoma City, OK 73104, USA
    Search for articles by this author

      Highlights

      • A summary of results of the existing neurosarcoidosis genetic studies.
      • Compares and contrasts neurosarcoidosis to other genetic findings in sarcoidosis.
      • Novel genome-wide association to 3 regions on chromosomes 1, 10, and 12.
      • Differential clustering of neurosarcoidosis with other organs by ancestry.
      • Obstacles in the field of neurosarcoidosis genetics and paths forward.

      Abstract

      Sarcoidosis is a systemic, inflammatory, granulomatous disease characterized by great variability in organ involvement, clinical course, and severity. While pulmonary manifestations are almost universal, the central and peripheral nervous systems can also be affected. Neurosarcoidosis occurs in ∼5–15% of cases and is among the manifestations with the highest morbidity and mortality. It is known that sarcoidosis has genetic underpinnings and while multiple studies aimed at identifying associations to sarcoidosis susceptibility and prognosis, very few studies have focused on neurosarcoidosis. This review summarizes the genetic studies to date, compares and contrasts those findings with other genetic effects in sarcoidosis, and offers ideas for moving the field forward.

      Keywords

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      References

        • Access Research Group
        Design of a case-control etiologic study of sarcoidosis (Access). Access Research Group.
        J. Clin. Epidemiol. 1999; 52: 1173-1186
        • Adrianto I.
        • Lin C.P.
        • Hale J.J.
        • Levin A.M.
        • Datta I.
        • Parker R.
        • Adler A.
        • Kelly J.A.
        • Kaufman K.M.
        • Lessard C.J.
        • Moser K.L.
        • Kimberly R.P.
        • Harley J.B.
        • Iannuzzi M.C.
        • Rybicki B.A.
        • Montgomery C.G.
        Genome-wide association study of African and European Americans implicates multiple shared and ethnic specific loci in sarcoidosis susceptibility.
        PLoS One. 2012; 7e43907
        • Baughman R.P.
        • Teirstein A.S.
        • Judson M.A.
        • Rossman M.D.
        • Yeager Jr., H.
        • Bresnitz E.A.
        • Depalo L.
        • Hunninghake G.
        • Iannuzzi M.C.
        • Johns C.J.
        • Mclennan G.
        • Moller D.R.
        • Newman L.S.
        • Rabin D.L.
        • Rose C.
        • Rybicki B.
        • Weinberger S.E.
        • Terrin M.L.
        • Knatterud G.L.
        • Cherniak R.
        • Case Control Etiologic Study Of Sarcoidosis Research, G
        Clinical characteristics of patients in a case control study of sarcoidosis.
        Am. J. Respir. Crit. Care Med. 2001; 164: 1885-1889
        • Baughman R.P.
        • Field S.
        • Costabel U.
        • Crystal R.G.
        • Culver D.A.
        • Drent M.
        • Judson M.A.
        • Wolff G.
        Sarcoidosis in America. Analysis based on health care use.
        Ann Am Thorac Soc. 2016; 13: 1244-1252
        • Ben-Omran T.
        • Fahiminiya S.
        • Sorfazlian N.
        • Almuriekhi M.
        • Nawaz Z.
        • Nadaf J.
        • Khadija K.A.
        • Zaineddin S.
        • Kamel H.
        • Majewski J.
        • Tropepe V.
        Nonsense mutation in the WDR73 gene is associated with Galloway-Mowat syndrome.
        J. Med. Genet. 2015; 52: 381-390
        • Burns T.M.
        Neurosarcoidosis.
        Arch. Neurol. 2003; 60: 1166-1168
        • Caillat-Zucman S.
        New insights into the understanding of Mhc associations with immune-mediated disorders.
        Hla. 2017; 89: 3-13
        • Calender A.
        • Weichhart T.
        • Valeyre D.
        • Pacheco Y.
        Current insights in genetics of sarcoidosis: functional and clinical impacts.
        J. Clin. Med. 2020; 9
        • Casas J.P.
        • Hingorani A.D.
        • Bautista L.E.
        • Sharma P.
        Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls.
        Arch. Neurol. 2004; 61: 1652-1661
        • Celada L.J.
        • Hawkins C.
        • Drake W.P.
        The etiologic role of infectious antigens in sarcoidosis pathogenesis.
        Clin. Chest Med. 2015; 36: 561-568
        • Chen Y.
        • Adrianto I.
        • Ianuzzi M.C.
        • Garman L.
        • Montgomery C.G.
        • Rybicki B.A.
        • Levin A.M.
        • Li J.
        Extended methods for gene-environment-wide interaction scans in studies of admixed individuals with varying degrees of relationships.
        Genet. Epidemiol. 2019; 43: 414-426
        • Clifford D.B.
        Nemesis of neglected neurosarcoidosis.
        Ann Clin Transl Neurol. 2015; 2: 947-948
        • Colin E.
        • Huynh Cong E.
        • Mollet G.
        • Guichet A.
        • Gribouval O.
        • Arrondel C.
        • Boyer O.
        • Daniel L.
        • Gubler M.C.
        • Ekinci Z.
        • Tsimaratos M.
        • Chabrol B.
        • Boddaert N.
        • Verloes A.
        • Chevrollier A.
        • Gueguen N.
        • Desquiret-Dumas V.
        • Ferre M.
        • Procaccio V.
        • Richard L.
        • Funalot B.
        • Moncla A.
        • Bonneau D.
        • Antignac C.
        Loss-of-function mutations in WDR73 are responsible for microcephaly and steroid-resistant nephrotic syndrome: Galloway-Mowat syndrome.
        Am. J. Hum. Genet. 2014; 95: 637-648
        • Colland F.
        • Jacq X.
        • Trouplin V.
        • Mougin C.
        • Groizeleau C.
        • Hamburger A.
        • Meil A.
        • Wojcik J.
        • Legrain P.
        • Gauthier J.M.
        Functional proteomics mapping of a human signaling pathway.
        Genome Res. 2004; 14: 1324-1332
        • Darlington P.
        • Tallstedt L.
        • Padyukov L.
        • Kockum I.
        • Cederlund K.
        • Eklund A.
        • Grunewald J.
        Hla-DRB1* alleles and symptoms associated with Heerfordt’s syndrome in sarcoidosis.
        Eur. Respir. J. 2011; 38: 1151-1157
        • Davis B.N.
        • Hilyard A.C.
        • Lagna G.
        • Hata A.
        Smad proteins control Drosha-mediated microrna maturation.
        Nature. 2008; 454: 56-61
        • Dawkins B.A.
        • Garman L.
        • Cejda N.
        • Pezant N.
        • Rasmussen A.
        • Rybicki B.A.
        • Levin A.M.
        • Benchek P.
        • Seshadri C.
        • Mayanja-Kizza H.
        • Iannuzzi M.C.
        • Stein C.M.
        • Montgomery C.G.
        Novel Hla associations with outcomes of Mycobacterium tuberculosis exposure and sarcoidosis in individuals of African ancestry using nearest-neighbor feature selection.
        Genet. Epidemiol. 2022; : 1-12https://doi.org/10.1002/gepi.22490
        • De Bakker P.I.
        • Mcvean G.
        • Sabeti P.C.
        • Miretti M.M.
        • Green T.
        • Marchini J.
        • Ke X.
        • Monsuur A.J.
        • Whittaker P.
        • Delgado M.
        • Morrison J.
        • Richardson A.
        • Walsh E.C.
        • Gao X.
        • Galver L.
        • Hart J.
        • Hafler D.A.
        • Pericak-Vance M.
        • Todd J.A.
        • Daly M.J.
        • Trowsdale J.
        • Wijmenga C.
        • Vyse T.J.
        • Beck S.
        • Murray S.S.
        • Carrington M.
        • Gregory S.
        • Deloukas P.
        • Rioux J.D.
        A high-resolution Hla and Snp haplotype map for disease association studies in the extended human Mhc.
        Nat. Genet. 2006; 38: 1166-1172
        • Dendrou C.A.
        • Petersen J.
        • Rossjohn J.
        • Fugger L.
        Hla variation and disease.
        Nat. Rev. Immunol. 2018; 18: 325-339
        • Drake K.M.
        • Zygmunt D.
        • Mavrakis L.
        • Harbor P.
        • Wang L.
        • Comhair S.A.
        • Erzurum S.C.
        • Aldred M.A.
        Altered Microrna processing in heritable pulmonary arterial hypertension: an important role for Smad-8.
        Am. J. Respir. Crit. Care Med. 2011; 184: 1400-1408
        • Esteller M.
        Non-coding RNAs in human disease.
        Nat. Rev. Genet. 2011; 12: 861-874
        • Esteves T.
        • Aparicio G.
        • Garcia-Patos V.
        Is there any association between Sarcoidosis and infectious agents?: a systematic review and meta-analysis.
        Bmc Pulm Med. 2016; 16: 165
        • Fingerlin T.E.
        • Hamzeh N.
        • Maier L.A.
        Genetics of sarcoidosis.
        Clin. Chest Med. 2015; 36: 569-584
        • Foreman M.G.
        • Mannino D.M.
        • Kamugisha L.
        • Westney G.E.
        Hospitalization for patients with sarcoidosis: 1979-2000.
        Sarcoidosis Vasc Diffuse Lung Dis. 2006; 23: 124-129
        • Fritz D.
        • Ferwerda B.
        • Brouwer M.C.
        • Van De Beek D.
        Whole genome sequencing identifies variants associated with sarcoidosis in a family with a high prevalence of sarcoidosis.
        Clin. Rheumatol. 2021; 40: 3735-3743
        • Garman L.
        • Montgomery C.G.
        • Rivera N.V.
        Recent advances in sarcoidosis genomics: epigenetics, gene expression, and gene by environment (G x E) interaction studies.
        Curr. Opin. Pulm. Med. 2020; 26: 544-553
        • Garman L.
        • Pezant N.
        • Pastori A.
        • Savoy K.A.
        • Li C.
        • Levin A.M.
        • Iannuzzi M.C.
        • Rybicki B.A.
        • Adrianto I.
        • Montgomery C.G.
        Genome-wide association study of ocular sarcoidosis confirms hla associations and implicates barrier function and autoimmunity in African Americans.
        Ocul. Immunol. Inflamm. 2020; : 1-6
        • Goodin D.S.
        • Khankhanian P.
        • Gourraud P.A.
        • Vince N.
        Highly conserved extended haplotypes of the major histocompatibility complex and their relationship to multiple sclerosis susceptibility.
        PLoS One. 2018; 13e0190043
        • Grunewald J.
        • Eklund A.
        Lofgren’s syndrome: human leukocyte antigen strongly influences the disease course.
        Am. J. Respir. Crit. Care Med. 2009; 179: 307-312
        • Grunewald J.
        • Brynedal B.
        • Darlington P.
        • Nisell M.
        • Cederlund K.
        • Hillert J.
        • Eklund A.
        Different Hla-DRB1 allele distributions in distinct clinical subgroups of sarcoidosis patients.
        Respir. Res. 2010; 11: 25
        • Hills S.E.
        • Parkes S.A.
        • Baker S.B.
        Epidemiology of sarcoidosis in the Isle of Man--2: Evidence for space-time clustering.
        Thorax. 1987; 42: 427-430
        • Hofmann S.
        • Franke A.
        • Fischer A.
        • Jacobs G.
        • Nothnagel M.
        • Gaede K.I.
        • Schurmann M.
        • Muller-Quernheim J.
        • Krawczak M.
        • Rosenstiel P.
        • Schreiber S.
        Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis.
        Nat. Genet. 2008; 40: 1103-1106
        • Hofmann S.
        • Fischer A.
        • Till A.
        • Muller-Quernheim J.
        • Hasler R.
        • Franke A.
        • Gade K.I.
        • Schaarschmidt H.
        • Rosenstiel P.
        • Nebel A.
        • Schurmann M.
        • Nothnagel M.
        • Schreiber S.
        • Genphenresa C.
        A genome-wide association study reveals evidence of association with sarcoidosis at 6p12.1.
        Eur. Respir. J. 2011; 38: 1127-1135
        • Hunter D.J.
        Gene-environment interactions in human diseases.
        Nat. Rev. Genet. 2005; 6: 287-298
        • Iannuzzi M.C.
        • Iyengar S.K.
        • Gray-Mcguire C.
        • Elston R.C.
        • Baughman R.P.
        • Donohue J.F.
        • Hirst K.
        • Judson M.A.
        • Kavuru M.S.
        • Maliarik M.J.
        • Moller D.R.
        • Newman L.S.
        • Rabin D.L.
        • Rose C.S.
        • Rossman M.D.
        • Teirstein A.S.
        • Rybicki B.A.
        Genome-wide search for sarcoidosis susceptibility genes in African Americans.
        Genes Immun. 2005; 6: 509-518
        • Iannuzzi M.C.
        • Rybicki B.A.
        • Teirstein A.S.
        Sarcoidosis.
        N. Engl. J. Med. 2007; 357: 2153-2165
        • Jajosky P.
        Sarcoidosis diagnoses among U.S. military personnel: trends and ship assignment associations.
        Am. J. Prev. Med. 1998; 14: 176-183
        • Jinks R.N.
        • Puffenberger E.G.
        • Baple E.
        • Harding B.
        • Crino P.
        • Fogo A.B.
        • Wenger O.
        • Xin B.
        • Koehler A.E.
        • Mcglincy M.H.
        • Provencher M.M.
        • Smith J.D.
        • Tran L.
        • Al Turki S.
        • Chioza B.A.
        • Cross H.
        • Harlalka G.V.
        • Hurles M.E.
        • Maroofian R.
        • Heaps A.D.
        • Morton M.C.
        • Stempak L.
        • Hildebrandt F.
        • Sadowski C.E.
        • Zaritsky J.
        • Campellone K.
        • Morton D.H.
        • Wang H.
        • Crosby A.
        • Strauss K.A.
        Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73.
        Brain. 2015; 138: 2173-2190
        • Judson M.A.
        • Baughman R.P.
        • Thompson B.W.
        • Teirstein A.S.
        • Terrin M.L.
        • Rossman M.D.
        • Yeager Jr., H.
        • Mclennan G.
        • Bresnitz E.A.
        • Depalo L.
        • Hunninghake G.
        • Iannuzzi M.C.
        • Johns C.J.
        • Moller D.R.
        • Newman L.S.
        • Rabin D.L.
        • Rose C.
        • Rybicki B.A.
        • Weinberger S.E.
        • Knatterud G.L.
        • Cherniak R.
        • Group, A. R
        Two year prognosis of sarcoidosis: the Access experience.
        Sarcoidosis Vasc Diffuse Lung Dis. 2003; 20: 204-211
        • Judson M.A.
        • Boan A.D.
        • Lackland D.T.
        The clinical course of sarcoidosis: presentation, diagnosis, and treatment in a large white and black cohort in the United States.
        Sarcoidosis Vasc Diffuse Lung Dis. 2012; 29: 119-127
        • Khoury M.J.
        • Wacholder S.
        Invited commentary: from genome-wide association studies to gene-environment-wide interaction studies--challenges and opportunities.
        Am. J. Epidemiol. 2009; 169 (discussion 234-5): 227-230
        • Lareau C.A.
        • Adrianto I.
        • Levin A.M.
        • Iannuzzi M.C.
        • Rybicki B.A.
        • Montgomery C.G.
        Fine mapping of chromosome 15q25 implicates ZNF592 in neurosarcoidosis patients.
        Ann Clin Transl Neurol. 2015; 2: 972-977
        • Le S.
        • Josse J.
        • Husson F.
        FactoMineR: a package for multivariate analysis.
        J. Stat. Softw. 2008; 25: 1-18
        • Levin A.M.
        • Adrianto I.
        • Datta I.
        • Iannuzzi M.C.
        • Trudeau S.
        • Li J.
        • Drake W.P.
        • Montgomery C.G.
        • Rybicki B.A.
        Association of Hla-DRB1 with sarcoidosis susceptibility and progression in African Americans.
        Am. J. Respir. Cell Mol. Biol. 2015; 53: 206-216
        • Li J.
        • Yang J.
        • Levin A.M.
        • Montgomery C.G.
        • Datta I.
        • Trudeau S.
        • Adrianto I.
        • Mckeigue P.
        • Iannuzzi M.C.
        • Rybicki B.A.
        Efficient generalized least squares method for mixed population and family-based samples in genome-wide association studies.
        Genet. Epidemiol. 2014; 38: 430-438
        • Lokki M.L.
        • Paakkanen R.
        The complexity and diversity of major histocompatibility complex challenge disease association studies.
        Hla. 2019; 93: 3-15
        • Malkova A.
        • Starshinova A.
        • Zinchenko Y.
        • Basantsova N.
        • Mayevskaya V.
        • Yablonskiy P.
        • Shoenfeld Y.
        The opposite effect of human leukocyte antigen genotypes in sarcoidosis and tuberculosis: a narrative review of the literature.
        Erj Open Res. 2020; 6
        • Malovannaya A.
        • Li Y.
        • Bulynko Y.
        • Jung S.Y.
        • Wang Y.
        • Lanz R.B.
        • O’malley B.W.
        • Qin J.
        Streamlined analysis schema for high-throughput identification of endogenous protein complexes.
        Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 2431-2436
        • Massaous J.
        • Hata A.
        Tgf-beta signalling through the Smad pathway.
        Trends Cell Biol. 1997; 7: 187-192
        • Mcgrath D.S.
        • Daniil Z.
        • Foley P.
        • Du Bois J.L.
        • Lympany P.A.
        • Cullinan P.
        • Du Bois R.M.
        Epidemiology of familial sarcoidosis in the UK.
        Thorax. 2000; 55: 751-754
        • Mignot E.
        • Lin L.
        • Rogers W.
        • Honda Y.
        • Qiu X.
        • Lin X.
        • Okun M.
        • Hohjoh H.
        • Miki T.
        • Hsu S.
        • Leffell M.
        • Grumet F.
        • Fernandez-Vina M.
        • Honda M.
        • Risch N.
        Complex Hla-Dr and -Dq interactions confer risk of narcolepsy-cataplexy in three ethnic groups.
        Am. J. Hum. Genet. 2001; 68: 686-699
        • Mirsaeidi M.
        • Machado R.F.
        • Schraufnagel D.
        • Sweiss N.J.
        • Baughman R.P.
        Racial difference in sarcoidosis mortality in the United States.
        Chest. 2015; 147: 438-449
        • Muhlethaler-Mottet A.
        • Di Berardino W.
        • Otten L.A.
        • Mach B.
        Activation of the Mhc class Ii transactivator Ciita by interferon-gamma requires cooperative interaction between Stat1 and Usf-1.
        Immunity. 1998; 8: 157-166
        • Muñiz-Castrillo S.
        • Vogrig A.
        • Honnorat J.
        Associations between Hla and autoimmune neurological diseases with autoantibodies.
        Auto Immun. Highl. 2020; 11: 2
        • Nakamura Y.
        • Matsushita T.
        • Sato S.
        • Niino M.
        • Fukazawa T.
        • Yoshimura S.
        • Hisahara S.
        • Isobe N.
        • Shimohama S.
        • Watanabe M.
        • Yoshida K.
        • Houzen H.
        • Miyazaki Y.
        • Yamasaki R.
        • Kikuchi S.
        • Kira J.
        • Japan Multiple Sclerosis Genetics C
        Latitude and Hla-DRB1*04:05 independently influence disease severity in Japanese multiple sclerosis: a cross-sectional study.
        J. Neuroinflammation. 2016; 13: 239
        • Newman K.L.
        • Newman L.S.
        Occupational causes of sarcoidosis.
        Curr. Opin. Allergy Clin. Immunol. 2012; 12: 145-150
        • Newman L.S.
        • Rose C.S.
        • Bresnitz E.A.
        • Rossman M.D.
        • Barnard J.
        • Frederick M.
        • Terrin M.L.
        • Weinberger S.E.
        • Moller D.R.
        • Mclennan G.
        • Hunninghake G.
        • Depalo L.
        • Baughman R.P.
        • Iannuzzi M.C.
        • Judson M.A.
        • Knatterud G.L.
        • Thompson B.W.
        • Teirstein A.S.
        • Yeager Jr., H.
        • Johns C.J.
        • Rabin D.L.
        • Rybicki B.A.
        • Cherniack R.
        • Group, A. R
        A case control etiologic study of sarcoidosis: environmental and occupational risk factors.
        Am. J. Respir. Crit. Care Med. 2004; 170: 1324-1330
        • Nicolas E.
        • Poitelon Y.
        • Chouery E.
        • Salem N.
        • Levy N.
        • Megarbane A.
        • Delague V.
        Camos, a nonprogressive, autosomal recessive, congenital cerebellar ataxia, is caused by a mutant zinc-finger protein, ZNF592.
        Eur. J. Hum. Genet. 2010; 18: 1107-1113
        • Oksenberg J.R.
        • Panzara M.A.
        • Begovich A.B.
        • Mitchell D.
        • Erlich H.A.
        • Murray R.S.
        • Shimonkevitz R.
        • Sherritt M.
        • Rothbard J.
        • Bernard C.C.
        • Steinman L.
        Selection for T-cell receptor V beta-D beta-J beta gene rearrangements with specificity for a myelin basic protein peptide in brain lesions of multiple sclerosis.
        Nature. 1993; 362: 68-70
        • Parkes S.A.
        • Baker S.B.
        • Bourdillon R.E.
        • Murray C.R.
        • Rakshit M.
        • Sarkies J.W.
        • Travers J.P.
        • Williams E.W.
        Incidence of sarcoidosis in the Isle of Man.
        Thorax. 1985; 40: 284-287
        • Pastori C.
        • Wahlestedt C.
        Involvement of long noncoding RNAs in diseases affecting the central nervous system.
        RNA Biol. 2012; 9: 860-870
        • Perez-Alvarez R.
        • Brito-Zeron P.
        • Kostov B.
        • Feijoo-Masso C.
        • Fraile G.
        • Gomez-De-La-Torre R.
        • De-Escalante B.
        • Lopez-Dupla M.
        • Alguacil A.
        • Chara-Cervantes J.
        • Perez-Conesa M.
        • Rascon J.
        • Garcia-Morillo J.S.
        • Perez-Guerrero P.
        • Fonseca-Aizpuru E.
        • Akasbi M.
        • Bonet M.
        • Callejas J.L.
        • Pallares L.
        • Ramos-Casals M.
        • Sarco G.-S.R.
        Systemic phenotype of sarcoidosis associated with radiological stages. Analysis of 1230 patients.
        Eur J Intern Med. 2019; 69: 77-85
        • Petersdorf E.W.
        • O’huigin, C.
        The Mhc in the era of next-generation sequencing: Implications for bridging structure with function.
        Hum. Immunol. 2019; 80: 67-78
        • R Core Team
        R: A language and environment for statistical computing.
        R Foundation for Statistical Computing, Vienna, Austria2020
        • Rivera N.V.
        • Patasova K.
        • Kullberg S.
        • Diaz-Gallo L.M.
        • Iseda T.
        • Bengtsson C.
        • Alfredsson L.
        • Eklund A.
        • Kockum I.
        • Grunewald J.
        • Padyukov L.
        A gene-environment interaction between smoking and gene polymorphisms provides a high risk of two subgroups of sarcoidosis.
        Sci. Rep. 2019; 9: 18633
        • Ronsmans S.
        • De Ridder J.
        • Vandebroek E.
        • Keirsbilck S.
        • Nemery B.
        • Hoet P.H.M.
        • Vanderschueren S.
        • Wuyts W.A.
        • Yserbyt J.
        Associations between occupational and environmental exposures and organ involvement in sarcoidosis: a retrospective case-case analysis.
        Respir. Res. 2021; 22: 224
        • Rybicki B.A.
        • Major M.
        • Popovich Jr., J.
        • Maliarik M.J.
        • Iannuzzi M.C.
        Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization.
        Am. J. Epidemiol. 1997; 145: 234-241
        • Rybicki B.A.
        • Iannuzzi M.C.
        • Frederick M.M.
        • Thompson B.W.
        • Rossman M.D.
        • Bresnitz E.A.
        • Terrin M.L.
        • Moller D.R.
        • Barnard J.
        • Baughman R.P.
        • Depalo L.
        • Hunninghake G.
        • Johns C.
        • Judson M.A.
        • Knatterud G.L.
        • Mclennan G.
        • Newman L.S.
        • Rabin D.L.
        • Rose C.
        • Teirstein A.S.
        • Weinberger S.E.
        • Yeager H.
        • Cherniack R.
        • Group, A. R
        Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (Access).
        Am. J. Respir. Crit. Care Med. 2001; 164: 2085-2091
        • Rybicki B.A.
        • Kirkey K.L.
        • Major M.
        • Maliarik M.J.
        • Popovich Jr., J.
        • Chase G.A.
        • Iannuzzi M.C.
        Familial risk ratio of sarcoidosis in African-American sibs and parents.
        Am. J. Epidemiol. 2001; 153: 188-193
        • Rybicki B.A.
        • Sinha R.
        • Iyengar S.
        • Gray-Mcguire C.
        • Elston R.C.
        • Iannuzzi M.C.
        • Consortium, S. S
        Genetic linkage analysis of sarcoidosis phenotypes: the sarcoidosis genetic analysis (Saga) study.
        Genes Immun. 2007; 8: 379-386
        • Safran M.
        • Rosen N.
        • Twik M.
        • Barshir R.
        • Stein T.I.
        • Dahary D.
        • Fishilevich S.
        • Lancet D.
        The GeneCards Suite.
        in: Abugessaisa I. Kasukawa T. Practical Guide to Life Science Databases. Singapore, Springer Nature Singapore2021
        • Sato H.
        • Nagai S.
        • Du Bois R.M.
        • Handa T.
        • Suginoshita Y.
        • Ohta K.
        • Welsh K.I.
        • Izumi T.
        Hla-DQB1 0602 allele is associated with splenomegaly in Japanese sarcoidosis.
        J. Intern. Med. 2007; 262: 449-457
        • Sato H.
        • Woodhead F.A.
        • Ahmad T.
        • Grutters J.C.
        • Spagnolo P.
        • Van Den Bosch J.M.
        • Maier L.A.
        • Newman L.S.
        • Nagai S.
        • Izumi T.
        • Wells A.U.
        • Du Bois R.M.
        • Welsh K.I.
        Sarcoidosis HLA class II genotyping distinguishes differences of clinical phenotype across ethnic groups.
        Hum. Mol. Genet. 2010; 19: 4100-4111
        • Schupp J.C.
        • Freitag-Wolf S.
        • Bargagli E.
        • Mihailovic-Vucinic V.
        • Rottoli P.
        • Grubanovic A.
        • Muller A.
        • Jochens A.
        • Tittmann L.
        • Schnerch J.
        • Olivieri C.
        • Fischer A.
        • Jovanovic D.
        • Filipovic S.
        • Videnovic-Ivanovic J.
        • Bresser P.
        • Jonkers R.
        • O’reilly K.
        • Ho L.P.
        • Gaede K.I.
        • Zabel P.
        • Dubaniewicz A.
        • Marshall B.
        • Kieszko R.
        • Milanowski J.
        • Gunther A.
        • Weihrich A.
        • Petrek M.
        • Kolek V.
        • Keane M.P.
        • O’beirne S.
        • Donnelly S.
        • Haraldsdottir S.O.
        • Jorundsdottir K.B.
        • Costabel U.
        • Bonella F.
        • Wallaert B.
        • Grah C.
        • Peros-Golubicic T.
        • Luisetti M.
        • Kadija Z.
        • Pabst S.
        • Grohe C.
        • Strausz J.
        • Vasakova M.
        • Sterclova M.
        • Millar A.
        • Homolka J.
        • Slovakova A.
        • Kendrick Y.
        • Crawshaw A.
        • Wuyts W.
        • Spencer L.
        • Pfeifer M.
        • Valeyre D.
        • Poletti V.
        • Wirtz H.
        • Prasse A.
        • Schreiber S.
        • Krawczak M.
        • Muller-Quernheim J.
        Phenotypes of organ involvement in sarcoidosis.
        Eur. Respir. J. 2018; 51
        • Sheedy F.J.
        Turning 21: induction of miR-21 as a key switch in the inflammatory response.
        Front. Immunol. 2015; 6: 19
        • Shintani M.
        • Yagi H.
        • Nakayama T.
        • Saji T.
        • Matsuoka R.
        A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension.
        J. Med. Genet. 2009; 46: 331-337
        • Smith B.
        • Wong C.A.
        • Smith T.C.
        • Boyko E.J.
        • Gackstetter G.D.
        • Ryan M.A.K.
        • Millenium Cohort Study Team
        Newly reported respiratory symptoms and conditions among military personnel deployed to Iraq and Afghanistan: a prospective population-based study.
        Am. J. Epidemiol. 2009; 170: 1433-1442
        • Spagnolo P.
        • Maier L.A.
        Genetics in sarcoidosis.
        Curr. Opin. Pulm. Med. 2021; 27: 423-429
        • Stern B.J.
        • Krumholz A.
        • Johns C.
        • Scott P.
        • Nissim J.
        Sarcoidosis and its neurological manifestations.
        Arch. Neurol. 1985; 42: 909-917
        • Stern B.J.
        • Royal 3rd, W.
        • Gelfand J.M.
        • Clifford D.B.
        • Tavee J.
        • Pawate S.
        • Berger J.R.
        • Aksamit A.J.
        • Krumholz A.
        • Pardo C.A.
        • Moller D.R.
        • Judson M.A.
        • Drent M.
        • Baughman R.P.
        Definition and consensus diagnostic criteria for neurosarcoidosis: from the neurosarcoidosis consortium consensus group.
        Jama Neurol. 2018; 75: 1546-1553
        • Street D.
        • Halfpenny C.A.
        • Galea I.
        Cns inflammation other than multiple sclerosis: how likely is diagnosis?.
        Neurology. 2014; 82: 1187-1189
        • Valeyre D.
        • Prasse A.
        • Nunes H.
        • Uzunhan Y.
        • Brillet P.Y.
        • Muller-Quernheim J.
        Sarcoidosis.
        Lancet. 2014; 383: 1155-1167
        • Vodopiutz J.
        • Seidl R.
        • Prayer D.
        • Khan M.I.
        • Mayr J.A.
        • Streubel B.
        • Steiss J.O.
        • Hahn A.
        • Csaicsich D.
        • Castro C.
        • Assoum M.
        • Muller T.
        • Wieczorek D.
        • Mancini G.M.
        • Sadowski C.E.
        • Levy N.
        • Megarbane A.
        • Godbole K.
        • Schanze D.
        • Hildebrandt F.
        • Delague V.
        • Janecke A.R.
        • Zenker M.
        WDR73 mutations cause infantile neurodegeneration and variable glomerular kidney disease.
        Hum. Mutat. 2015; 36: 1021-1028
        • Voorter C.E.
        • Drent M.
        • Hoitsma E.
        • Faber K.G.
        • Van Den Berg-Loonen E.M.
        Association of Hla DQB1 0602 in sarcoidosis patients with small fiber neuropathy.
        Sarcoidosis Vasc Diffuse Lung Dis. 2005; 22: 129-132
        • Wang P.
        • Sidney J.
        • Dow C.
        • Mothe B.
        • Sette A.
        • Peters B.
        A systematic assessment of Mhc class Ii peptide binding predictions and evaluation of a consensus approach.
        PLoS Comput. Biol. 2008; 4e1000048
        • Webber M.P.
        • Yip J.
        • Zeig-Owens R.
        • Moir W.
        • Ungprasert P.
        • Crowson C.S.
        • Hall C.B.
        • Jaber N.
        • Weiden M.D.
        • Matteson E.L.
        • Prezant D.J.
        Post-9/11 sarcoidosis in Wtc-exposed firefighters and emergency medical service workers.
        Respir. Med. 2017; 132: 232-237
        • Yazar S.
        • Mishra A.
        • Ang W.
        • Kearns L.S.
        • Mountain J.A.
        • Pennell C.
        • Montgomery G.W.
        • Young T.L.
        • Hammond C.J.
        • Macgregor S.
        • Mackey D.A.
        • Hewitt A.W.
        Interrogation of the platelet-derived growth factor receptor alpha locus and corneal astigmatism in Australians of Northern European ancestry: results of a genome-wide association study.
        Mol. Vis. 2013; 19: 1238-1246
        • Zivadinov R.
        • Uxa L.
        • Bratina A.
        • Bosco A.
        • Srinivasaraghavan B.
        • Minagar A.
        • Ukmar M.
        • Benedetto S.
        • Zorzon M.
        Hla-DRB1*1501, -DQB1*0301, -DQB1*0302, -DQB1*0602, and -DQB1*0603 alleles are associated with more severe disease outcome on MRI in patients with multiple sclerosis.
        Int. Rev. Neurobiol. 2007; 79: 521-535