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.