Towards a Better Classification and Novel Therapies Based on the Genetics of Systemic Sclerosis

Overview

Journal Curr Rheumatol Rep

Publisher Current Science

Specialty Rheumatology

Date 2019 Jul 16

PMID 31304568

Citations 4

Authors

Marialbert Acosta-Herrera

Elena Lopez-Isac

Javier Martin

Affiliations

Soon will be listed here.

Abstract

Purpose Of The Review: Nowadays, important advances have occurred in our understanding of the pathogenesis of systemic sclerosis (SSc), which is a rare immune-mediated inflammatory disease (IMID) characterized by vascular damage, immune imbalance, and fibrosis. Its etiology remains unknown; nevertheless, both environmental and genetic factors play a major role in the disease. This review will focus on the main advances made in the field of genetics of SSc.

Recent Findings: The assessment of how interindividual genetic variability affects disease onset and progression has enhanced our knowledge of disease biology, and this will eventually translate in the development of new diagnostic and therapeutic tools, which is the final goal of personalized medicine. We will provide an overview of the most relevant achievements in the genetics of SSc, its shared genetics among IMIDs with special attention on drug repurposing, current challenges for the functional characterization of risk variants, and future directions.

Citing Articles

Curating Genetic Associations With Rheumatologic Autoimmune Diseases to Improve Patient Outcomes.

Bridges Jr S, Shapira R, Aksentijevich I, Mack S, Merriman T, Klein C Arthritis Rheumatol. 2024; 76(11):1577-1581.

PMID: 38965695 PMC: 11521766. DOI: 10.1002/art.42943.

Repolarization dispersion in patients with systemic sclerosis.

Nussinovitch U, Beeri G, Rubin S, Lidar M, Levi Y, Livneh A Eur J Rheumatol. 2020; 8(3):144-149.

PMID: 33372887 PMC: 9770413. DOI: 10.5152/eurjrheum.2020.19215.

Epigenomics and transcriptomics of systemic sclerosis CD4+ T cells reveal long-range dysregulation of key inflammatory pathways mediated by disease-associated susceptibility loci.

Li T, Ortiz-Fernandez L, Andres-Leon E, Ciudad L, Javierre B, Lopez-Isac E Genome Med. 2020; 12(1):81.

PMID: 32977850 PMC: 7519528. DOI: 10.1186/s13073-020-00779-6.

Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients.

Beretta L, Barturen G, Vigone B, Bellocchi C, Hunzelmann N, De Langhe E Ann Rheum Dis. 2020; 79(9):1218-1226.

PMID: 32561607 PMC: 7456554. DOI: 10.1136/annrheumdis-2020-217116.

References

Arnett F, Cho M, Chatterjee S, Aguilar M, Reveille J, Mayes M . Familial occurrence frequencies and relative risks for systemic sclerosis (scleroderma) in three United States cohorts. Arthritis Rheum. 2001; 44(6):1359-62. DOI: 10.1002/1529-0131(200106)44:6<1359::AID-ART228>3.0.CO;2-S. View

Feghali-Bostwick C, Medsger Jr T, Wright T . Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum. 2003; 48(7):1956-63. DOI: 10.1002/art.11173. View

Assassi S, Arnett F, Reveille J, Gourh P, Mayes M . Clinical, immunologic, and genetic features of familial systemic sclerosis. Arthritis Rheum. 2007; 56(6):2031-7. DOI: 10.1002/art.22647. View

Gabrielli A, Avvedimento E, Krieg T . Scleroderma. N Engl J Med. 2009; 360(19):1989-2003. DOI: 10.1056/NEJMra0806188. View

Arnett F, Gourh P, Shete S, Ahn C, Honey R, Agarwal S . Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls. Ann Rheum Dis. 2009; 69(5):822-7. PMC: 2916702. DOI: 10.1136/ard.2009.111906. View

Simeon C, Fonollosa V, Tolosa C, Palou E, Selva A, Solans R . Association of HLA class II genes with systemic sclerosis in Spanish patients. J Rheumatol. 2009; 36(12):2733-6. DOI: 10.3899/jrheum.090377. View

Zhou X, Lee J, Arnett F, Xiong M, Park M, Yoo Y . HLA-DPB1 and DPB2 are genetic loci for systemic sclerosis: a genome-wide association study in Koreans with replication in North Americans. Arthritis Rheum. 2009; 60(12):3807-14. PMC: 2829245. DOI: 10.1002/art.24982. View

Schoenfelder S, Clay I, Fraser P . The transcriptional interactome: gene expression in 3D. Curr Opin Genet Dev. 2010; 20(2):127-33. DOI: 10.1016/j.gde.2010.02.002. View

Radstake T, Gorlova O, Rueda B, Martin J, Alizadeh B, Palomino-Morales R . Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet. 2010; 42(5):426-9. PMC: 2861917. DOI: 10.1038/ng.565. View

10.

Katsumoto T, Whitfield M, Connolly M . The pathogenesis of systemic sclerosis. Annu Rev Pathol. 2010; 6:509-37. DOI: 10.1146/annurev-pathol-011110-130312. View

11.

Cortes A, Brown M . Promise and pitfalls of the Immunochip. Arthritis Res Ther. 2011; 13(1):101. PMC: 3157635. DOI: 10.1186/ar3204. View

12.

Dieude P, Boileau C, Guedj M, Avouac J, Ruiz B, Hachulla E . Independent replication establishes the CD247 gene as a genetic systemic sclerosis susceptibility factor. Ann Rheum Dis. 2011; 70(9):1695-6. DOI: 10.1136/ard.2010.147009. View

13.

Allanore Y, Saad M, Dieude P, Avouac J, Distler J, Amouyel P . Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS Genet. 2011; 7(7):e1002091. PMC: 3131285. DOI: 10.1371/journal.pgen.1002091. View

14.

Gorlova O, Martin J, Rueda B, Koeleman B, Ying J, Teruel M . Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy. PLoS Genet. 2011; 7(7):e1002178. PMC: 3136437. DOI: 10.1371/journal.pgen.1002178. View

15.

Bossini-Castillo L, Martin J, Broen J, Gorlova O, Simeon C, Beretta L . A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations. Hum Mol Genet. 2011; 21(4):926-33. PMC: 3298110. DOI: 10.1093/hmg/ddr522. View

16.

Beretta L, Rueda B, Marchini M, Santaniello A, Simeon C, Fonollosa V . Analysis of Class II human leucocyte antigens in Italian and Spanish systemic sclerosis. Rheumatology (Oxford). 2011; 51(1):52-9. PMC: 3276293. DOI: 10.1093/rheumatology/ker335. View

17.

Martin J, Broen J, Carmona F, Teruel M, Simeon C, Vonk M . Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up. Hum Mol Genet. 2012; 21(12):2825-35. PMC: 3368627. DOI: 10.1093/hmg/dds099. View

18.

Bossini-Castillo L, Martin J, Broen J, Simeon C, Beretta L, Gorlova O . Confirmation of TNIP1 but not RHOB and PSORS1C1 as systemic sclerosis risk factors in a large independent replication study. Ann Rheum Dis. 2012; 72(4):602-7. PMC: 3887516. DOI: 10.1136/annrheumdis-2012-201888. View

19.

Martin J, Assassi S, Diaz-Gallo L, Broen J, Simeon C, Castellvi I . A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci. Hum Mol Genet. 2013; 22(19):4021-9. PMC: 3766185. DOI: 10.1093/hmg/ddt248. View

20.

Parkes M, Cortes A, van Heel D, Brown M . Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet. 2013; 14(9):661-73. DOI: 10.1038/nrg3502. View