Genetic Studies in Scleroderma
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Transcript of Genetic Studies in Scleroderma
Genetic Studies in Scleroderma
Shervin Assassi, MD, MSAssociate ProfessorMcGovern Medical School
School of Biomedical Informatics
University of Texas Health Science Center at Houston
What causes a disease?
Genes
Disease
Environment
Royal Disease = Hemophilia B = Alteration (mutation) in the gene F9 leads to disease
Monogenic diseases: Alteration in one gene leads to disease
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
WHAT CAUSES SCLERODERMA?
NATURE or NURTURE (ENVIRONMENT)?YES and YES
EVIDENCE for HERITABILITY: Family Studies
Systemic Lupus Erythematosus
Familial Recurrence Rate in 1st Degree Relatives: ~ 5%
SclerodermaFamilial Recurrence Rate in 1st
Degree Relatives: 1.6%
(1st Degree Relatives have
98.4% chance of NOT developing SSc)
Examples of multicase scleroderma families
201 202
101 102
203 204SSc LimitedANA 1:80 Speckled
Scl 70 -Date Raynaud's: 1991
Date Dx: 1996Age Dx: 16
SSc LimitedANA 1:160 Speckled
Scl 70 -Date Raynaud's: 1993
Date Dx: 1995Age Dx: 22
Examples of poly-autoimmune families
204
101 102 103
205201 202 203
301
2
ANA +Date Dx: 1978Age Dx: 59
SSc LimitedANA 1:640 Centromere Scl 70 -Date Dx: 1988Age Dx: 47
SLE
SLE MS
GENETICS 101Refresher
46 HumanChromosomes:
44 somaticXY determine
sex
Variations in Genome
WHAT ARE THE GENE VARIANTS RESPONSIBLE FOR SSc
HERITABILITY?
Genome Wide Association Study
(GWAS)Collaboration with 10 U.S. sites (including Northwestern University)
Canadian Scleroderma Research GroupMultiple European Researchers
SSc GWAS Results
GWAS of 2,296 SSc Patients and 5,171 Healthy Controls – Discovery Cohort
Radstake et al. Nature Genetics 42:426-9 (2010)
Selected Genetic Associations and 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 ChromosomeTNFSF4 IRAK1/MECP2
ITGAM
MIF
PTPN22
GRB10
MHC- HLA Chromosome 6HLA-DPB1
*1301 ATA+ (White)
*0901 ATA+ (Asian)
*0402 ACA+ (Asian)
HLA-DQA1 multipleHLA-DQB1 multipleHLA-DRB1 multiple
MHC- non HLANOTCH4PSORS1C1
INTERPRETATION of GENETIC STUDIES• 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?
Autoimmune diseases in the 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
Many of susceptibility genes are in common between scleroderma and lupus
Martin et al. Humn Genet. 2012
How can the same 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
What do we know 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?
Scleroderma antibodies in multicase 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
The genetic basis for scleroderma specific antibodies is mainly in the HLA region
Gorlova et al. PLOS Genetics. 2011
Summary • Scleroderma related antibodies 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.