Scleroderma Symptoms Causes

Causes of Scleroderma: Genetics

Overview

Researchers have found some genes associated with the development of systemic sclerosis (scleroderma).

There are several types of scleroderma that are known to run in families, such as Familial CRST w/ Sicca, and Familial Progressive Systemic Sclerosis. Genes that predispose to scleroderma were found by studying the Choctaw Indian Tribe of Oklahoma, where those with scleroderma all shared a common ancestor.

This does not mean, however, that scleroderma is a "genetic illness" per se. They estimate that it is genetic in only 2% of scleroderma patients. However, there are some genes that set the stage for the development of autoimmune disease in general, and scleroderma in particular.

Should a parent with scleroderma worry about their child acquiring scleroderma? No, not unless there is a known pattern of scleroderma already established in the family.

However, that said, there is about a 30% chance that children from parents with any autoimmune disease might eventually develop any autoimmune disease or autoantibodies, or, more commonly, just a symptom or two of any autoimmune disease — due to general inherited and/or lifestyle susceptibility. (Also see What is Scleroderma?, Autoimmune Diseases, and Pregnancy and Scleroderma)

The Results of Your Genetic Test Are Reassuring, But That Can Change. Laboratories frequently "reclassify" genetic mutations, but here is no reliable system for telling patients or doctors that the results of their genetic tests are no longer valid. New York Times, 10/16/2018.

What’s Behind Many Mystery Ailments? Genetic Mutations, Study Finds. A new study suggests that many disorders go undetected and a team of scientists has found that 3.7 percent of patients in a hospital system carried a genetic variant linked to a disease. New York Times, 03/15/2018.

Birth Order

Parental Influence on Systemic Sclerosis (SSc). Birth order and maternal/paternal age at conception do not significantly affect SSc development even though heritable risk of SSc is observed. PubMed, Arthritis Care Res (Hoboken).

Choctaw Study

It was discovered that systemic scleroderma is sometimes hereditary through genetic research done on the Choctaw Indian Tribe of Oklahoma, where all of the scleroderma patients have one common ancestor. There is also an apparent scleroderma cluster (of unknown cause) in the Kahnawake Indian Tribe of Quebec, Canada.

Ethnicity, Race, and Geographical Regions

Familial CRST Syndrome with Sicca Complex

Familial CRST syndrome with sicca complex. PubMed, J Rheumatol.

Familial Progressive Systemic Sclerosis (FPSS)

Familial risk of systemic sclerosis (SSc) and co–aggregation of autoimmune diseases in affected families. The risks of SSc and other autoimmune diseases are increased in relatives of people with SSc, and family factors explain over two–thirds of the phenotypic variance of the disease. PubMed, Arthritis Res Ther.

(Case Report) Familial Occurrence of Collagen Diseases: II. Progressive Systemic Sclerosis and Dermatomyositis. A case report of progressive systemic scleroderma (mother), lupus (daughter), and dermatomyositis (son) in the same family. Wiley, Journal of Internal Medicine.

Dee: Daughter of Scleroderma Patient Three years ago my mother was diagnosed with scleroderma. My aunt died of scleroderma last year…

Iris: Family History of Scleroderma Is there anyone else who feels that their family has a history of scleroderma?

Rosemary F: Surviving Daughter of Diffuse Scleroderma Patient She tried to explain it, but it was hard for me to comprehend the disease's symptoms. Mom said that it was the same thing that her oldest sister died from…

Stephanie D: Scleroderma/Heparin-Induced Thrombocytopenia If I receive heparin again I will certainly die…

Genetics and Scleroderma

Expression quantitative trait loci, (eQTL) analysis in systemic sclerosis (SSc) identifies new candidate genes associated with multiple aspects of disease pathology. The data of the present study provides a new layer of the molecular complexity of SSc, contributing to a better understanding of the pathogenesis of the disease. PubMed, Arthritis Rheumatol, 01/17/2021.

Machine learning integration of scleroderma (SSc) histology and gene expression identifies fibroblast polarisation as a hallmark of clinical severity and improvement. CD34 and aSMA stains describe distinct fibroblast polarisation states and may be useful biomarkers of clinical severity and improvement in diffuse SSc. PubMed, Ann Rheum Dis, 10/07/2020. (Also see Fibroblasts)

Association of functional (GA)n microsatellite polymorphism in the FLI1 gene with susceptibility to human systemic sclerosis (SSc). Extended repeat alleles of FLI1 (GA)n microsatellite may be associated with lower FLI1 mRNA levels and susceptibility to human SSc. PubMed, Rheumatology (Oxford), 2020 Jul 22;keaa306.

Defining genetic risk factors for scleroderma-associated interstitial lung disease (SSc-ILD) : IRF5 and STAT4 gene variants are associated with scleroderma while STAT4 is protective against scleroderma-associated interstitial lung disease. Further work is required to understand the genetic basis of lung fibrosis in association with scleroderma. PubMed, Clin Rheumatol, 01/08/2020. (Also see Pulmonary Fibrosis Diagnosis)

Genetic Interactions Affect Lung Function in Patients with Systemic Sclerosis. We identified a three-gene network comprising WNT5A, RBMS3 and MSI2, which in combination influenced multiple pulmonary pathology measures. PubMed, G3 (Bethesda), 11/06/2019. (Also see Pulmonary Fibrosis Diagnosis)

Mutations of FAM111B gene are not associated with Systemic Sclerosis (SSc). One rare variant was found in a patient with SSc but has no functional or structural impact on the FAM111B gene. PubMed, Sci Rep, 2018 Oct 30;8(1):15988.

Changes in macrophage transcriptome associate with systemic sclerosis (SSc) and mediate GSDMA contribution to disease risk. Our data further establish the link between macrophages and SSc, and suggest that the contribution of the rs3894194 risk variant to SSc susceptibility can be mediated by GSDMA (gene) expression in macrophages. PubMed, Ann Rheum Dis, 01/17/2018.

FOXP3, ICOS and ICOSL gene polymorphisms in systemic sclerosis (SSc). This study provides evidence of the association of rs2294020 with SSc evolution in female patients, while no effect on SSc susceptibility per se was found. PubMed, Immunobiology, 2018 Jan;223(1):112-117.

Homocysteine and MTHFR C677T Gene Mutation

Plasma Homocysteine Levels and the Prevalence of Methylenetetrahydrofolate Reductase Gene C677T Polymorphism in Systemic Sclerosis. The presence of MTHFR C677T mutation influences the incidence of macrovascular abnormalities in SSc. Elevated Hcy levels may be associated with disease duration and the evolution of macrovascular disorders and pulmonary hypertension in SSc. Clinical Reviews in Allergy and Immunology.

Human Genome Project and Scleroderma

Genetic Alliance Resources. Genetic Alliance is a network of thousands of health related organizations, including more than 600 advocacy organizations. Genetic Alliance.

Scleroderma Gene Project Advances to Human Tissue Study. The power of the Human Genome Project has been harnessed for scleroderma research at the Centre for Immunology, St Vincent's Hospital. Scleroderma Association of New South Wales, Inc.

Human Genome Project Boosts Scleroderma Research. A group at the Centre for Immunology, St Vincent's Hospital Sydney is at the vanguard of this research, employing the latest "Gene array" technology to determine the patterns of gene expression that occur in scleroderma. Scleroderma Association of New South Wales, Inc.

Scleroderma Registries

Scleroderma Family Registries are available in many countries and they are very important for tracking the incidence of scleroderma as well as providing valuable clues for research. If you or a family member has scleroderma, consider registering today! ISN.

Shared Autoimmunity

Immunogenetics of systemic sclerosis (SSc): Defining heritability, functional variants and shared-autoimmunity pathways. Future research will be successful in understanding the relevant altered pathways in SSc and in identifying new biomarkers and therapeutic targets for the disease. PubMed, J Autoimmun. (Also see Shared Autoimmunity)

Clinical implications of shared genetics and pathogenesis in autoimmune diseases. Most of the genetic variants associated with a particular autoimmune endocrine disease are shared between other systemic and organ-specific autoimmune and inflammatory diseases, such as rheumatoid arthritis, coeliac disease, systemic lupus erythematosus and psoriasis. PubMed, Nature Reviews Endocrinology.

Overlap syndromes in the context of shared autoimmunity. The coexistence of autoimmune rheumatic diseases may be partially explained by the interplay of environmental factors with genes that predispose to autoimmunity in general and to manifestations of specific diseases. This is part of the concept of Shared Autoimmunity. PubMed, Autoimmunity. (Also see Shared Autoimmunity)

Telomere

Telomere is the segment of DNA at the ends of chromosomes.

Telomeres and the Aging Immune System. Although the clinical significance of telomere shortening in the context of chronic inflammation or advanced age is still not fully understood, it is an area of active investigation that is uncovering an important link to the immune response and to inflammatory conditions. The Rheumatologist.

Twins and Siblings With and Without Autoimmune Diseases

Still enrolling as of 10/15/12.

Families with Twins or Siblings where one has Systemic Rheumatic Disorders (Rheumatoid Arthritis, Juvenile Rheumatoid Arthritis, Lupus, Scleroderma, or Myositis) and one does not. The goal of study 03-E-0099 is to assess why one twin or sibling developed disease and why the other brother or sister did not.

The siblings may or may not be twins, but must be of the same gender and be within a 3-year age difference. Biological parents, or, in some cases, children, will also be included in the study.

Families may enroll at the NIH Clinical Center in Bethesda, Maryland, just 9 miles north of Washington, DC or at their local physician's office. Transportation assistance may be available and there is no charge for study-related evaluations and medical tests.

For information on the study, call the NIH patient recruiting office toll free at 1-800-411-1222 (For TTY: 1-866-411-1010). National Institutes of Health Clinical Center (NIH). Last verified March 2015. (Also see Scleroderma Research Registries and Causes of Scleroderma: Genetics)

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