Systemic Sclerosis (SSc)

Systemic sclerosis (SSc) is a rare, chronic, autoimmune-mediated disorder affecting the microvasculature and connective tissues. The disease is characterized by the widespread development of fibrosis and endothelial abnormalities in the vasculature. Fibrosis interferes with the normal functioning of multiple internal organs, especially the heart, lungs, kidneys, and esophagus, and causes a host of complications due to internal organ dysfunction.^1,2 

Causative Factors in the Development of Systemic Sclerosis

The etiology of SSc is unknown; however, researchers hypothesize that the combination of a genetic predisposition and environmental exposures contributes to its development.¹ Together, these factors promote an immune system dysregulation that affects the microvasculature and results in the production and accumulation of excess collagen throughout the tissues.^1-3

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Genetic Predispositions Affecting the Immune System Response

Researchers have conducted many genetic studies during the past several decades to identify genes associated with SSc. Genome-wide association studies (GWAS), family association studies, and candidate gene analyses have located many genetic variants associated with SSc in noncoding regions that influence gene expression.³ 

Most of the genes determined to increase the risk of SSc regulate innate and adaptive immune system responses to antigens along with cell death. Genetic studies identified only a few genes involved in fibrosis and vascular homeostasis with the development of SSc.³

Studies on the Genetic Contribution of SSc

In studies that analyzed genetic patterns in 703 families with a history of the disease, SSc in affected families was more prevalent than SSc in the general population (1.6% vs 0.026%). These studies also identified HLA class II gene haplotypes more often in families affected by SSc than would be expected by chance.^3,4 

Twin studies also confirmed that autoimmunity, evidenced by the presence of antinuclear antibodies (ANAs), was more frequent in monozygotic than in dizygotic twins (90% vs 40%); however, the overall concordance for SSc was low among twins (4.7%). These findings suggest that genes contribute to the development of autoimmunity, but that similar genetic backgrounds do not necessarily lead to the development of SSc due to inheritance.^3,5

Early GWAS in patients with SSc indicated that the strongest association between genes and SSc occurred in the HLA class II region on chromosome 6.^3,6 HLA-DPB1 and HLA–DPB2 were identified in people with SSc across Korean and Caucasian ethnicities as specific genetic loci for single-nucleotide polymorphisms (SNPs) associated with SSc.⁶

Non-HLA genes associated with increased susceptibility to SSc also alter both innate and adaptive immune system responses.³

Read more about SSc clinical trials

Innate Immune System Genes Associated With SSc

GWAS research discovered an increased susceptibility to SSc associated with interferon regulatory factor 5 (IRF5). This gene regulates the production of proinflammatory cytokines including interleukins 6, 12, and 23 and tumor necrosis factor alpha (TNF-α), as well as specific phenotypic traits of macrophages. The cytokines and macrophages promote type 1 interferon signaling, which is a critical part of the innate immune system general response to infection or other perceived threats.³ A specific IRF5 variant (IRF5 rs2004640 polymorphism) especially correlates with the anti-topo I-positive diffuse cutaneous form of SSc with interstitial lung disease.^3,7,8

Abnormalities in other genes that regulate the type 1 interferon signaling pathway were also found in individuals with SSc. According to a meta-GWAS, SNPs located on the INF7 gene correlated with the presence of SSc-related anticentromere antibodies (ACAs) in individuals with SSc across Europe and the United States.^3,9

GWAS analysis also identified an SSc-associated gene connected with the innate immune systemTNF-α-induced protein 3 (TNFAIP3). This gene inhibits the TNF-induced nuclear factor kappa B (NF-κB) signaling pathway by expressing A20 protein. Decreased A20 expression stimulates transforming growth factor beta (TGF-β), which in turn stimulates fibroblastic collagen production.^3,10

Read more about SSc pathophysiology

Adaptive Immune System Genes Associated With SSc

Unlike the innate immune system, which mounts a general immune response to antigens, the adaptive immune system targets specific antigens. In several GWAS, the following adaptive immune system genes were associated with an increased risk for SSc³: 

• Signal transducer activator transcriptional factor 4 (STAT4)
• TNF ligand superfamily member 4 (TNFSF4)
• Protein tyrosine phosphatase, non-receptor type 22 (PTPN22)
• C-Src kinase (CSK)
• B cell-specific scaffold protein with ankyrin 1 (BANK1)
• B lymphocyte kinase (BLK)
• B lymphocyte-induced maturation protein 1 (PRDM1)
• Genes involved in the interleukin-12 signaling pathway (IL-12A, IL-12RB, IL-12RB2)
• Tyrosine kinase 2 (TYK2)

STAT4 and TYK2 have also been implicated in autoimmune conditions other than SSc, including systemic lupus erythematosus and rheumatoid arthritis.^3,11,12

Read more about SSc comorbidities

Cell Death Genes Associated With SSc

GWAS identified variants in several genes associated with cellular apoptosis, pyroptosis, and autophagy that also appeared to increase SSc susceptibility³:

• Deoxyribonuclease 1-like 3 (DNASE1L3)
• Growth factor receptor-bound protein 10 (GRB10)
• Ras-related protein Rab-2A (RAB2A)
• Autophagy-related 5 (ATG5)
• Gasdermin A/B (GSDMA/B)
• Neurogenic locus notch homolog protein 4 (NOTCH4)

Read more about SSc prognosis

Fibrosis and Vascular Genes Associated With SSc

Most SSc-related genes detected in GWAS affected immune system responses and cell death pathways, but a few were found to be involved in fibrosis and vascular homeostasis.

Affected genes that suppress collagen synthesis or actively inhibit tissue fibrosis included peroxisome proliferator-activated receptor gamma (PPARG), caveolin 1 (CAV1), and the concurrent presence of a rare variant of the retinoid X receptor-beta (RXRB) and HLA-DPB1*13:01 in Japanese patients with SSc.^3,13-15

Other genes highlighted in GWAS of patients with SSc included DDX6, DGKQ, and NAB1, although the biomolecular function of these genes in relation to SSc is unknown. They may play a role in vasculopathy.^3,9

As the field of genetics, genomics, and epigenetics advances, additional genes that increase susceptibility to SSc continue to be identified. Variants of these genes promote changes in the innate or adaptive immune system, cell signaling processes, apoptosis, autophagy, DNA/RNA degradation, and extracellular matrix, which lead to the manifestations of various disease subphenotypes.¹⁶

Read more about SSc diagnosis

References

1. Systemic scleroderma. Medline Plus. Accessed April 15, 2023.
2. Pattanaik D, Brown M, Postlethwaite BC, Postlethwaite AE. Pathogenesis of systemic sclerosis. Front Immunol. 2015;6. doi:10.3389/fimmu.2015.00272  
3. Ota Y, Kuwana M. Updates on genetics in systemic sclerosis. Inflamm Regener. 2021;41(1):17. doi:10.1186/s41232-021-00167-6
4. Arnett FC, Cho M, Chatterjee S, Aguilar MB, Reveille JD, Mayes MD. Familial occurrence frequencies and relative risks for systemic sclerosis (scleroderma) in three United States cohorts. Arthritis Rheum. 2001;44(6):1359-1362. doi:10.1002/1529-0131(200106)44:6<1359::AID-ART228>3.0.CO;2-S
5. Feghali-Bostwick C, Medsger TA Jr, Wright TM. 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):1956-1963. doi:10.1002/art.11173
6. Zhou X, Lee JE, Arnett FC, et al. 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):3807-3814. doi:10.1002/art.24982
7. Dieudé P, Guedj M, Wipff J, et al. Association between the IRF5 rs2004640 functional polymorphism and systemic sclerosis: a new perspective for pulmonary fibrosis. Arthritis Rheum. 2009;60(1):225-233. doi:10.1002/art.24183
8. Xu Y, Wang W, Tian Y, Liu J, Yang R. Polymorphisms in STAT4 and IRF5 increase the risk of systemic sclerosis: a meta-analysis. Int J Dermatol. 2016;55(4):408-416. doi:10.1111/ijd.12839
9. López-Isac E, Acosta-Herrera M, Kerick M, et al. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways. Nat Commun. 2019;10:4955. doi:10.1038/s41467-019-12760-y
10. Dieudé P, Guedj M, Wipff J, et al. Association of the TNFAIP3 rs5029939 variant with systemic sclerosis in the European Caucasian population. Ann Rheum Dis. 2010;69(11):1958-1964. doi:10.1136/ard.2009.127928
11. Kunz M, Ibrahim SM. Non-major histocompatibility complex rheumatoid arthritis susceptibility genes. Crit Rev Immunol. 2011;31(2):99-114. doi:10.1615/critrevimmunol.v31.i2.20
12. Diogo D, Bastarache L, Liao KP, et al. TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits. PLoS One. 2015;10(4):e0122271. doi:10.1371/journal.pone.0122271
13. López-Isac E, Bossini-Castillo L, Simeon CP, et al. A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility. Arthritis Res Ther. 2014;16:R6. doi:10.1186/ar4432
14. Manetti M, Allanore Y, Saad M, et al. Evidence for caveolin-1 as a new susceptibility gene regulating tissue fibrosis in systemic sclerosis. Ann Rheum Dis. 2012;71(6):1034-1041. doi:10.1136/annrheumdis-2011-200986
15. Oka A, Asano Y, Hasegawa M, et al. RXRB is an MHC-encoded susceptibility gene associated with anti-topoisomerase I antibody-positive systemic sclerosis. J Invest Dermatol. 2017;137(9):1878-1886. doi:10.1016/j.jid.2017.04.028
16. Salazar G, Mayes MD. Genetics, epigenetics and genomics of systemic sclerosis. Rheum Dis Clin North Am. 2015;41(3):345-366. doi:10.1016/j.rdc.2015.04.001

Reviewed by Harshi Dhingra, MD, on 4/28/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.