Causes of Scleroderma: Genetics

Author: Shelley Ensz. Scleroderma is highly variable. See Types of Scleroderma. Read Disclaimer
Birth Order
Choctaw Study
Ethnicity, Race, Geography
Familial CRST w/ Sicca
Genetics and Scleroderma
Homocysteine/MTHFR C677T Gene Mutation
Human Genome Project
Scleroderma Registries
Shared Autoimmunity
Twins and Siblings Study


Photo of white trees against black backgroundResearchers 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)

There’s a Gene Mutation That Makes You a Reckless Drunk, Study Suggests. New research suggests there may be a genetic explanation for why some people are more likely to get out of control under the influence of alcohol. Time Healthland, 11/19/2015.

A new biological clock measures altered DNA, not birthday candles. Move over birthday candles, and step aside telomeres; there may be a new kind of biological clock in town. And this one may prove useful in predicting where age-related diseases such as cancer are most likely to strike. Los Angeles Times, 10/21/2013.

Unraveling the genetic component of systemic sclerosis. During the last years, the number of genetic markers convincingly associated with systemic sclerosis (SSc) has exponentially increased. Human Genetics, 2012 Jan 5.

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), 2014 Apr 22.

Systemic sclerosis, birth order and parity. Parity, age at first pregnancy and the gender of the first child are not relevant factors in our understanding of the epidemiology and pathogenesis of SSc. PubMed, Int J Rheum Dis, 2013 Nov 29.

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.

Genetic signatures of pre-expansion bottleneck in the Choctaw population of Oklahoma. This investigation utilizes genome-scan data on 175 dinucleotide loci from 76 Choctaw individuals to seek genetic evidence of the demographic history of the Choctaw Nation. PubMed, Am J Phys Anthropol, [2004].

Ethnicity, Race, and Geographical Regions

Race and Ethnicity
Geographical Regions

Familial CRST Syndrome with Sicca Complex

Familial CRST syndrome with sicca complex. PubMed, J Rheumatol. 1977 Spring;4(1):53-8.

Familial Progressive Systemic Sclerosis (FPSS)

Familial Progressive Scleroderma is a form of systemic scleroderma that is known to be hereditary.

Familial progressive systemic scleroderma. This isolate is a group of families who have been inbreeding since 1660 and now have the highest gene frequencies for sickle cell anemia and oculocutaneous albinism in the United States. Arch Dermatol 1975 Jan;111(1):81-5 Medline.

Heritability of vasculopathy, autoimmune disease, and fibrosis in systemic sclerosis (SSc): a population-based study. These data suggest that SSc pedigrees include more Raynaud's Phenomenon (RP), autoimmune inflammatory disease, and Interstitial Lung Disease (ILD) than would be expected by chance. In SSc pedigrees, genetic predisposition to vasculopathy is the most frequent risk among first-degree relatives. Frech T. (PubMed) Arthritis Rheum, 2010 Jul;62(7):2109-16.

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

Epigenetics and systemic sclerosis. The environment can trigger epigenetic regulation that in turn establishes a molecular framework linking environmental exposures to genetics, leading to the disease process, possibly in a genetically predisposed host. PubMed, Semin Immunopathol, 07/11/2015.

Patients with Systemic Sclerosis (SSc) Present Increased DNA Damage Differentially Associated with DNA Repair Gene Polymorphisms. Polymorphic sites of the XRCC1 and XRCC4 DNA repair genes may differentially influence DNA damage and the development of autoantibodies. PubMed, J Rheumatol, 2014 Feb 1.

Systemic Sclerosis (SSc) in Canada's North American Native (NAN) Population: Assessment of Clinical and Serological Manifestations. NAN patients with SSc have a distinct clinical phenotype. Our study provides a strong rationale to pursue further research into genetic and environmental determinants of SSc. Journal of Rheumatology, 2013 May 15.

Indoleamine 2,3 dioxygenase (IDO) gene polymorphisms correlate with CD8+ Treg impairment in systemic sclerosis. Our unprecedented data show that a specific IDO gene SNP is associated with an autoimmune disease such as systemic sclerosis. PubMed, Hum Immunol, 2013 Feb;74(2):166-9.

Association of TNFSF4 (OX40L) polymorphisms with susceptibility to Systemic Sclerosis. It is increasingly being appreciated that multiple autoimmune diseases share common susceptibility genes. Polymorphisms in the TNFSF4 gene region are associated with susceptibility to SSc and its clinical and autoantibody subsets. TNFSF4 may be another gene that confers risk to multiple autoimmune diseases. Pravitt Gourh Ann Rheum Dis. 23 September 2009.

Genetics of scleroderma: implications for personalized medicine? Significant advances have been made in understanding the genetic basis of systemic sclerosis (scleroderma) in recent years which might lead to individualized monitoring and treatment. BMC Medicine, 2013, 11:9.

Influence of the IL6 Gene in Susceptibility to Systemic Sclerosis. Our results suggest that the IL6 gene may influence the development of SSc and its progression. The Journal of Rheumatology, 120506. October 2012.

Candidate gene study in systemic sclerosis identifies a rare and functional variant of the TNFAIP3 locus as a risk factor for polyautoimmunity. The present findings establish the TNFAIP3 locus as a susceptibility factor for the subset of systemic sclerosis (SSc) with a polyautoimmune phenotype. PubMed, Arthritis Rheum, 2012 Aug;64(8):2746-52.

Scleroderma — New aspects in pathogenesis and treatment. Future research will be directed at genetic factors, diagnostic and prognostic markers for fibrosis and microangiopathy, and development of drugs directed to pathogenic key cells and mediators. Best Practice & Research Clinical Rheumatology Volume 26, Issue 1 , Pages 13-24, February 2012. (Also see Dr. Alexandra Balbir-Gurman)

Genomewide Scan Identifies Tnip1, Psors1c1 And Rhob As Novel Risk Loci For Systemic Sclerosis (SSc). We have identified two new SSc-risk loci, PSORS1C1 and TNIP1, and a putative one close to RHOB gene. Y. Allanore. EULAR 2011 OPO234.Ann Rheum Dis 2011;70(Suppl3):148.

Scientists Identify New Genetic Region Associated with Scleroderma. New research has identified a new genetic link to systemic sclerosis (Also known as systemic scleroderma) and confirmed three previously discovered links to the disease, which can cause thickening of the skin, narrowing of blood vessels and scarring of internal organs. January 2011. NIAMS.

The Genetics of Scleroderma. Multiple genes have been consistently associated with susceptibility to scleroderma, and interestingly, several of them are involved in immune regulation. Martin J. (PubMed) Curr Rheumatol Rep, 2010 Oct 20.

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, Volume 36, Numbers 2-3/June, 2009.

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

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, November 2013.


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

Association of increased telomere lengths in limited scleroderma (lcSSc), with a lack of age-related telomere erosion. Telomere lengths in lcSSc subjects were longer than controls, did not show age-related telomere erosion and differed significantly from age-matched controls only after 50 years of age. MacIntyre A. (PubMed) Ann Rheum Dis. 2008 Dec;67(12):1780-2.

Twins and Siblings With and Without Autoimmune Diseases

Still enrolling as of 10/15/12.

NIH Autoimmune Twins and Siblings StudyFamilies 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). 11/25/05. (Also see Scleroderma Research Registries and Causes of Scleroderma: Genetics)

Go to Causes of Scleroderma: Ethnicity, Race and Geographical Region

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