Download to read offline
Uploaded byScleroderma Foundation of Greater Chicago
Genetic Studies in Scleroderma
Scleroderma is a complex, polygenic disease influenced by both genetic and environmental factors, with evidence of heritability demonstrated through familial studies. Genetic research, particularly genome-wide association studies (GWAS), has identified over 30 genetic variants associated with scleroderma that primarily affect immune-related pathways. Specific antibodies related to scleroderma exhibit a genetic basis, notably linked to the HLA region on chromosome 6.
More Related Content
Similar to Genetic Studies in Scleroderma
More from Scleroderma Foundation of Greater Chicago
Genetic Studies in Scleroderma
- 1. Genetic Studies inScleroderma Shervin Assassi, MD, MS Associate Professor McGovern Medical School School of Biomedical Informatics University of Texas Health Science Center at Houston
- 2. What causes adisease? Genes Disease Environment
- 5. Royal Disease =Hemophilia B = Alteration (mutation) in the gene F9 leads to disease Monogenic diseases: Alteration in one gene leads to disease
- 6. Monogenic diseases vs.polygenic diseases • Monogenic diseases (like Hemophilia B) Alterations in one gene leads to disease • Complex, polygenic diseases: Predisposition to these diseases is caused by several genes, with each gene contributing a relatively small effect • Scleroderma (systemic sclerosis) like most human diseases is a complex, polygenic disease
- 7. WHAT CAUSES SCLERODERMA? NATUREor NURTURE (ENVIRONMENT)? YES and YES
- 8. EVIDENCE for HERITABILITY:Family Studies Systemic Lupus Erythematosus Familial Recurrence Rate in 1st Degree Relatives: ~ 5% Scleroderma Familial Recurrence Rate in 1st Degree Relatives: 1.6% (1st Degree Relatives have 98.4% chance of NOT developing SSc)
- 9. Examples of multicasescleroderma families 201 202 101 102 203 204 SSc Limited ANA 1:80 Speckled Scl 70 - Date Raynaud's: 1991 Date Dx: 1996 Age Dx: 16 SSc Limited ANA 1:160 Speckled Scl 70 - Date Raynaud's: 1993 Date Dx: 1995 Age Dx: 22
- 10. Examples of poly-autoimmunefamilies 204 101 102 103 205201 202 203 301 2 ANA + Date Dx: 1978 Age Dx: 59 SSc Limited ANA 1:640 Centromere Scl 70 - Date Dx: 1988 Age Dx: 47 SLE SLE MS
- 11.
- 12. 46 Human Chromosomes: 44 somatic XYdetermine sex
- 13.
- 14. WHAT ARE THEGENE VARIANTS RESPONSIBLE FOR SSc HERITABILITY?
- 15. Genome Wide Association Study(GWAS) Collaboration with 10 U.S. sites (including Northwestern University) Canadian Scleroderma Research Group Multiple European Researchers
- 16.
- 17. GWAS of 2,296SSc Patients and 5,171 Healthy Controls – Discovery Cohort Radstake et al. Nature Genetics 42:426-9 (2010)
- 18. Selected Genetic Associationsand SSc (2016) Non-MHC (MORE THAN 30) CD247 IL2/IL21 TN1P1 IL2RA RHOB ENDRB BANK1 ENDRA IRF5 TNFAIP3 IRF7 MIF IRF8 CSK STAT4 IL12RB2 BLK X Chromosome TNFSF4 IRAK1/MECP2 ITGAM MIF PTPN22 GRB10 MHC- HLA Chromosome 6 HLA-DPB1 *1301 ATA+ (White) *0901 ATA+ (Asian) *0402 ACA+ (Asian) HLA-DQA1 multiple HLA-DQB1 multiple HLA-DRB1 multiple MHC- non HLA NOTCH4 PSORS1C1
- 19. INTERPRETATION of GENETICSTUDIES • Most of the associated genes influence immune-related pathways (T- cells, B-cells, and interferon) rather than fibrosis or vascular pathways • The precise role of the genetic variants has not yet been identified How does the alteration in the gene leads to autoimmunity, vascular damage, and fibrosis?
- 20. Autoimmune diseases inthe first degree relatives of scleroderma patients • 4612 first degree relatives of 1071 scleroderma patients were investigated. • The most common autoimmune diseases in the families were: Hypothyroidism (4%), rheumatoid arthritis (1.5%), hyperthyroidism (1.3%), and systemic lupus erythematosus (0.4%) • Compared to control families, the most striking difference for familial occurrence was for systemic lupus erythematosus (Odds ratio= 17) Arora-Singh et al. Journal of Autoimmunity. 2010
- 21. Many of susceptibilitygenes are in common between scleroderma and lupus Martin et al. Humn Genet. 2012
- 22. How can thesame genes lead to different autoimmune diseases? • Immune cells that target our own body (autoreactive immune cells) are produced as part of normal immune system • However, they are usually kept in check by regulatory mechanisms • The cumulative effect of several autoimmunity genes Impairment of necessary biological processes for destruction of self-reactive immune cells
- 23. What do weknow about scleroderma related antibodies and genetics • The majority of persons with scleroderma have antibodies that only occur with this disease • Examples are anti-Scl-70, anti-centromere, and anti-RNA polymerase III antibodies • Do genetics play a role in determining what type of antibodies occurs in an individual patient?
- 25. Scleroderma antibodies inmulticase families • Investigation of 18 scleroderma multicase families • There was no significant difference between the observed and expected rates of disease type (limited vs. diffuse) concordance among multicase families (P = 0.52). • The concordance rate for scleroderma antibodies was higher than expected by chance (p=0.007). In 12 families, both affected members were concordant for SSc-specific autoantibodies, whereas 6 families were discordant. The observed autoantibody concordance rate for SSc-specific autoantibodies was 66.7%. Assassi et al. Arthritis and Rheumatology. 2007
- 26. The genetic basisfor scleroderma specific antibodies is mainly in the HLA region Gorlova et al. PLOS Genetics. 2011
- 27. Summary • Scleroderma relatedantibodies are specific for this disease • There is a genetic basis for the occurrence of these antibodies • The HLA region on chromosome 6 is the main genetic basis for antibody occurrence.