| Causes of Scleroderma (MAIN MENU) |
|
|
| Causes of Scleroderma: Genetics |
|
|
| Overview |
| Genetics and proteomics in scleroderma. Genetic, familial, and twin studies suggest that SSc occurs in genetically susceptible individuals. Recent high-throughput technologies, including gene expression profiling and proteomics, have accelerated the rate of information acquired on possible mechanisms involved in SSc pathogenesis. PubMed. Curr Rheumatol Rep. 2005 Apr;7(2):129-34. |
| Scleroderma Care and Research Journal (PDF) This journal for physicians focuses on elevating the standards of care for digital ischemia in scleroderma. Articles include The Genetics of Scleroderma: What Every Rheumatologist Should Know, as well as Digital Ulceration and Critical Digital Ischemia in Scleroderma. Journal of the Scleroderma Clinical Trials Consortium (SCTC) Vol 1, No. 2, Winter 2003. (Also see: Scleroderma DNA and Family Registry) |
| Gene profiling of scleroderma skin reveals robust signatures of disease that are imperfectly reflected in the transcript profiles of explanted fibroblasts. SSc has a distinct gene profile that is not confounded by geographic location, indicating that extended multicenter studies may be worthwhile to identify distinct subsets of disease by transcript profiling. PubMed. Arthritis Rheum. 2006 Jun;54(6):1961-73. |
| Choctaw Study |
| 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 Aug;124(4):373-9. |
| DNA |
| Genes Add Up Risk Of Autoimmune Disease. Geneticists have identified a link between the number of copies of a specific gene an individual has and their susceptibility to autoimmune diseases like lupus that affect the whole body. Research using DNA has revealed that people who have a below average number of copies of a gene, known as FCGR3B, have an increased risk of developing diseases caused when the body's immune system attacks its own tissue. Medical News Today. 05/25/07. (Also see: Lupus and Autoimmunity) |
| Scientists to unlock genes behind common serious illnesses. The biggest DNA analysis of whole human genomes will shed light on why some people are more at risk of developing a serious illness. They are examining 15,000 markers for genetic variations relating to another four diseases - breast cancer, autoimmune thyroid disease, multiple sclerosis, and ankylosing spondylitis. Guardian Unlimited. 04/14/07. (Also see: Thyroid Disease, Diabetes, and Multiple Sclerosis) |
| NALP1 in Vitiligo-Associated Multiple Autoimmune Disease. DNA sequence variants in the NALP1 region are associated with the risk of several epidemiologically associated autoimmune and autoinflammatory diseases, implicating the innate immune system in the pathogenesis of these disorders. New England Journal of Medicine. Vol 356:1216-1225 March 22, 2007 Number 12. |
| Unstabilized DNA breaks in lymphocytes of patients with systemic sclerosis. Our results indicate that in SSc patients there is an interference in the protective cellular mechanisms, normally stabilizing DNA breaks. PubMed. Eur J Dermatol. 2006 May-Jun;16(3):258-61. (Also see: What are Antibodies?) |
| HLA Markers for Susceptibility and Expression in Scleroderma. HLA alleles play a role in susceptibility to scleroderma and its disease expression. J Rheumatol. 2005 August;32:1481-7. |
| HLA associated genetic predisposition to autoimmune diseases: Genes involved and possible mechanisms. The HLA complex harbour both disease predisposing genes which are quite specific for some autoimmune diseases (e.g. HLA-B27 for ankylosing spondylitis) and others which may be more common for several diseases. PubMed. Transpl Immunol. 2005 Aug;14(3-4):175-82. |
| Skewed X chromosome inactivation in blood cells of women with scleroderma. Skewed XCI mosaicism may play a significant role in the pathogenesis of SSc. PubMed. Arthritis Rheum. 2005 May;52(5):1564-1570. |
| Shared gene expression profiles in individuals with autoimmune disease and unaffected first-degree relatives of individuals with autoimmune disease. Results support the hypothesis that these variations in gene transcript levels are associated with family resemblance rather than clinical manifestations of disease. PubMed. Hum Mol Genet. 2005 Apr 6. |
| Ethnicity, Race, and 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. |
| Familial scleroderma (FS): nature, nurture or both? Familial limited scleroderma has a longer prediagnostic latency than familial diffuse scleroderma. FS is likely under-ascertained. In limited scleroderma, Raynaud's or first symptom onset is possibly more genetically determined. A diagnosis due to second symptom onset is more environmentally determined. (PubMed) Intern Med J. 2008 Apr;38(4):235-42. (Also see: Difficult Diagnosis and Causes of Scleroderma: Environmental) |
| Familial progressive systemic sclerosis (scleroderma): immunological analysis of two patients and six siblings from a single kindred. Clin Exp Immunol 1982 Nov;50(2):275-82 Medline. |
| 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 |
| Geneticists Hunt For Scleroderma Triggers. A study reported in the October 2009 Journal of Investigative Dermatology reports a closer connection between a gene profile for the profibrotic pathway TGF-beta and a tendency in some scleroderma sufferers to develop lung problems. Science Daily. 10/30/09. |
| BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians. Our results suggest that BANK1 gene confers susceptibility to systemic scleroderma (SSc) in general, and specifically to the diffuse SSc and anti-topoisomerase-I antibody subsets. B Rueda. Ann Rheum Dis. 8 October 2009. |
| 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. (Also see: Polyautoimmunity) |
| It's Not All in the Genes. Your genes are not your destiny. Lifestyle and diet can play an important role on your genes. You can change the outcome even if it is "written" otherwise in your genes. RedOrbit. 06/30/08. (Also see: Alternative Therapies) |
| Dartmouth researchers discover gene signatures for scleroderma. Distinct genetic profiles can discern different groups of patients with scleroderma. This discovery of distinguishing molecular subtypes within the disease offers new insight into the complexity of a poorly understood and hard to treat illness and opens a window for better diagnosis and targeted therapies. Genetic Engineering & Biotechnology News. July 15, 2008. (Also see: Types of Scleroderma) |
| Genetic basis for systemic sclerosis. Investigations into the genetics of systemic sclerosis may shed light on the complex pathophysiology of this disease, help to identify factors that predict organ involvement, and suggest new treatment strategies. Science Direct. Oct 2007. (Also see: Causes of Scleroderma: Silica, Solvents, and Environmental Factors) |
| There's no cure, but scleroderma can be managed. We don't know what causes scleroderma. Researchers suspect that there is a genetic link. The theory is that while a specific genetic trait predisposes the individual, scleroderma will only occur after exposure to some environmental agent, such as a particular virus. Post-Bulletin. Mayo Clinic. 06/04/07. (Also see: Causes of Scleroderma: Infections, and What is Scleroderma?) |
| Genetic Association Studies in Systemic Sclerosis: More Evidence of a Complex Disease. Systemic sclerosis (SSc) clearly falls into the category of complex genetic disease, with well recognized variability in clinical and serological presentation and intricate underlying mechanisms, which involve vascular and immune activation within a fibrotic process. J Rheumatol 2007 May;34:903 Editorial. (Also see: Causes of Scleroderma: Environment) |
| Association of Polymorphisms in the IL1B and IL2 Genes with Susceptibility and Severity of Systemic Sclerosis. IL1B and IL2 gene polymorphisms may be involved in susceptibility to SSc. Moreover, the IL2-384-G allele may be a marker for the limited phenotype of SSc. J Rheumatol 2007 May;34:997-1004. (Also see: Limited Scleroderma) |
| Update on pathophysiology of scleroderma with special reference to immunoinflammatory events. Scleroderma or systemic sclerosis (SSc) is a complex disease in which the vasculopathy and the activation of the immune system with production of inflammatory mediators lead to dysregulated fibroblast activation. The resulting excessive deposition of collagens and other extracellular matrix proteins ends in fibrosis and organ dysfunction. The cause is unknown, but environmental factors are thought to play a role by triggering abnormal responses in genetically susceptible hosts. PubMed. Ann Med. 2007;39(1):42-53. (Also see: What is Scleroderma) |
| Disease Features, Disease Type, HLA Types, and Autoantibody Profile in 17 Multicase SSc Families. These findings suggest that the concordance for disease type and SSc specific autoantibodies is more common among SSc family members and the ACA positive limited SSc has a stronger genetic basis, and that the familial SSc does not represent a unique disease subset. Shervin Assassi. 1153/412 ACR 2006. (Also see: Scleroderma Family Registry and DNA Repository) |
| The X chromosome and systemic sclerosis. These observations, reproduced in other female-predominant autoimmune diseases, strongly support the role of the X chromosome in conferring susceptibility to tolerance breakdown and open novel scenarios to emphasize the unknown etiopathogenesis of systemic sclerosis. PubMed. Curr Opin Rheumatol. 2006 Nov;18(6):601-605. (Also see: Causes of Scleroderma: Hormones & Chromosomes) |
| IL13RA2 Gene Polymorphisms Are Associated with Systemic Sclerosis. Our data suggest that IL13RA2 gene polymorphisms may be involved in susceptibility to SSc. Further studies are under way to show that they contribute to disease. J Rheumatol 2006 October;33:2015-9. |
| In-depth Analysis Of Human Genetic Variation Will Enable Scientists To Identify Genetic Risk Factors For Common Immune Diseases. The work lays the scientific foundation for future efforts aimed at uncovering the genetic roots of immune-related diseases. Medical News Today. 09/28/06. |
| Monozygotic twins clinically discordant for scleroderma show concordance for fibroblast gene expression profiles. A stronger genetic predisposition to SSc (than can be detected clinically) is apparent at the molecular level in skin fibroblasts. PubMed. Arthritis Rheum. 2005 Oct;52(10):3305-14. |
| Genetics of scleroderma: update on single nucleotide polymorphism analysis and microarrays. Recent family, twin, and genetic association studies suggest a genetic basis for the susceptibility to systemic sclerosis or scleroderma. Candidate genes or pathways identified through microarrays can be explored as potential biomarkers, used for molecular phenotyping of systemic sclerosis, or targeted for future genetic association studies. PubMed. Curr Opin Rheumatol. 2005 Nov;17(6):761-7. |
| X Chromosome Monosomy: A Common Mechanism for Autoimmune Diseases. Chromosome instability is common to women with SSc and AITD (autoimmune thyroid disease) and haploinsufficiency for X-linked genes may be a critical factor for the female predominance of autoimmune diseases. PubMed. J Immunol. 2005 Jul 1;175(1):575-578. (Also see: Thyroid Disease) |
| Genetic factors predisposing to fibrosis in systemic sclerosis. Identification of genetic factors involved in the susceptibility to fibrosis of systemic sclerosis would lead to a better understanding of physiopathological mechanisms of this disease and to therapeutic targets using immunomodulation with drugs, such as already performed in rheumatoid arthritis. PubMed. Rev Med Interne. 2005 Apr;26(4):294-303. (Also see: Skin Fibrosis) |
| Transgenic analysis of scleroderma: understanding key pathogenic events in vivo. These experiments implicate the IL-4 ligand-receptor axis in the development of skin fibrosis. Modern molecular genetic methods have allowed better understanding of established mouse models of scleroderma and also facilitated the development of new and better defined mouse strains for investigating the pathogenesis of the disease. PubMed. Autoimmun Rev. 2004 Jun;3(4):285-93. |
| Keys to unlocking the mysteries of rheumatic autoimmune disease. Identification of susceptibility genes and dysregulated biological pathways for these diseases is likely to foster development of novel diagnostic and therapeutic approaches that are increasingly tailored to the underlying pathological mechanisms. PubMed. Minn Med. 2004 May;87(5):46-51. |
| Association of killer cell immunoglobulin-like receptors with scleroderma. A genetic contribution has been demonstrated, and genes influencing activation of the immune system have been potentially identified as candidate genes in this process. The repertoire of killer cell immunoglobulin-like receptors (KIRs) that are involved in the activation of T cells and natural killer cells is highly variable. The genetic combination of KIR2DS2+ and KIR2DL2- is associated with scleroderma. PubMed. Arthritis Rheum. 2004 May;50(5):1561-5. |
| Gene expression signatures for autoimmune disease in peripheral blood mononuclear cells. The relatively new technology of DNA microarrays offers the possibility to probe the human genome for clues to the pathogenesis and treatment of human disease. Of special interest are studies that have used peripheral blood samples because, unlike tissue biopsies, these are readily available from all subjects. Using this approach, patterns of gene expression can be detected that distinguish patients with autoimmune conditions from normal subjects. PubMed. Arthritis Res Ther. 2004;6(3):120-8. |
| Profiles of gene expression in human autoimmune disease. All autoimmune individuals, including unaffected first-degree relatives, share a common gene expression profile that is completely distinct from the immune profile. These data argue that that there is a constant pattern of gene expression in autoimmunity that is independent of the specific autoimmune disease and clinical parameters associated with any individual autoimmune disease. PubMed. Cell Biochem Biophys. 2004;40(2):81-96. |
| Vascular Injury in Systemic Sclerosis: Angiotensin-converting Enzyme Insertion/Deletion Polymorphism. ACE D allele frequency of the I/D polymorphism was associated with an increased risk of SSc, suggesting a genetic contribution to the disease. PubMed. Curr Rheumatol Rep. 2004 Apr;6(2):149-55. |
| Coexistence of HLA-B*08 and HLA-B*18 in Four Siblings with Lichen sclerosus. HLA-B*08 and HLA-B*18 alleles were detected in children with LS, but not in a healthy sister. None of the patients had autoimmune disease. In our opinion, coexistence of these two alleles may play a role in the development of LS. PubMed. Dermatology. 2004; 208(1): 64-6. (Also see: Lichen Sclerosis) |
| 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. Gabriella Szücs. FRI0288 EULAR 2004. |
| 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 |
| Co-occurrence of celiac disease and other autoimmune diseases in celiacs and their first-degree relatives. These results indicate that the presence of insulin dependent diabetes mellitus within our celiac disease families may be due to shared genetic susceptibility predisposing to these diseases or autoimmune diseases in general. (UnBound Medline) S.L. Neuhausen. J Autoimmun 2008 Aug 7. (Also see: Celiac Disease and Shared Autoimmunity) |
| Overlap syndromes in the context of shared autoimmunity. "Shared autoimmunity" is the term being used for the presence of autoimmune rheumatic diseases in several members of the same family, the concurrence of autoimmune rheumatic with non-rheumatic diseases in relatives of patients, the presence of autoantibodies in sera from healthy relatives of autoimmune-disease patients, the development of two or more autoimmune rheumatic diseases in one patient and the interplay of genetic and environmental factors leading to the presence of several autoimmune disease and/or their autoantibodies in families. PubMed. Autoimmunity. 2005 May;38(3):219-23. (Also see: Overlap Syndrome: MCTD) |
| Twins and Siblings With and Without Autoimmune Diseases |
| Open Enrollment (A 5-year study) |
 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). 11/25/05. (Also see: Scleroderma Research Registries) |
| Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. PubMed Arthritis Rheum. 2003 Jul;48(7):1956-63. |
