Genetics of Scleroderma: Towards Personalized Medicine in the Genomic Age

Benjamin Korman, MD

10/11/14

The Genomic Era• DNA era – May 25, 1953 – Watson and Crick characterize

DNA

• First DNA characterization of human disease – thalassemia - 1979

• Genomic Era - April 14, 2003 – The Human Genome Project completed, full sequencing of a human’s DNA

The Human Genome

• 3+ billion base pairs of DNA• > 99.9% of human’s DNA is identical

• 33,000 genes

• Millions of polymorhpic alleles• 2.6 million SNPs with >1% frequency• Many more rare variants

The Human Genome - Scope of Human Disease

• 100,000+ mutations in 3,700 genes have been identified that correlate with human disease

• It is thought that mutations in 15,000+ genes cause heritable human disease

“Simple Genetics”

• Mendelian inheritance, high penetrance

• Single gene disorders, causative mutations

• Multiple examples of relatively common diseases in clinic medicine: cystic fibrosis, sickle cell, Huntington’s, BRCA breast cancer

What about complicated diseases like scleroderma?

Enter: Genomics

Metagenomics

Genomics… of complex diseases• Multiple genes involved

• Each contributes only a small part to disease susceptibility

• Having any one variant doesn’t cause disease

• Also complicated by environmental factors

• Furthermore, gene-gene and gene-environment interactions

Disease susceptibility

Evidence Scleroderma Has a Genetic Component

• Family preponderance of autoimmune diseases

• Twin and sibling concordance studies• Siblings of scleroderma patients are 15 times more likely to

develop scleroderma than non-relatives• But…..

• It is a rare disease and • only 2.6% of patients’ siblings develop SSc

Genetics of Scleroderma - GWAS

The list of scleroderma genes keeps growing

Symbol Gene Name case/control OR p-valueATG5 Autophagy Related 5 1833/3466 1.19 3.8*10^-8

CD247 T-cell receptor zeta-chain

2296/5171 0.82 3.4*10^-9

CSK c-src 5270/8326 1.20 5.0*10^-12

DNASE1L3 Deoxyribonuclease I-Like 3

1833/3466 2.03 4.3*10^-31

IL12RB1 IL-12 receptor beta-1 8697/5032 0.81 4.3*10^-10

IL12RB2 IL-12 receptor beta-2 3344/3848 1.17 2.8*10^-9

IRF5 Interferon responsive factor 5

2296/5171 1.49 3.8*10^-14

IRF8 Interferon responsive factor 8

3360/10143 0.75 2.3*10^-12

PSORS1C1 Psoriasis Susceptibility 1 Candidate 1

564/1776 1.25 5.7*10^-10

SCHIP1-IL12A

Schwannomin interacting protein 1 / Interleukin 12 alpha

1833/3466 2.57 1.2*10^-11

STAT4 Signal Transducer and Activator of Transciption 4

2296/5171 1.30 3.9*10^-9

TNFAIP3 TNF Associated Interacting Protein 3

1202/1196 2.08 1.2*10^-7

TNFSF4 TNF superfamily member 4

1031/1014 1.33 1.3*10^-5

13 Confirmed Genomewide Significant andIndependently Replicated Associations

Symbol Gene Name OR p-value

BANK1B-cell scaffold protein with ankyrin repeats 1 1.30 4.0*10^-4

BLK/C8orf13

B-lymphocyte kinase / Chromosome 8 open reading frame 13 1.27 6.8*10^-5

CD226Cluster of differentiation 226 1.22 5.7*10^-5

GRB10Growth factor receptor bound protein 10 1.15 1.3*10^-6

IL2RA IL-2 receptor alpha 1.30 2.1*10^-4JAZF1 JAZF Zinc Finger 1 1.14 3.6*10^-5

KCNA5

Potassium Voltage-Gated Channel, Shaker-Related Subfamily, Member 5 0.64 3.0*10^-4

KIAA0319L KIAA0319L 1.46 3.9*10^-6

NKFB1Nuclear factor kappa beta 1 1.14 1.0*10^-6

PPARG

Peroxisome proliferator-activated receptor gamma 1.25 5.0*10^-7

PSD3Pleckstrin And Sec7 Domain Containing 3 1.18 3.0*10^-7

PXK

PX Domain Containing Serine/Threonine Kinase 1.21 4.4*10^-7

RHOB1 Ras Homolog Family B 1.21 3.7*10^-6

RPL41 Ribosomal Protein L41 1.23 6.0*10^-8

SOX5Sex Determining Region Y-Box 5 1.36 1.4*10^-7

TLR2 Toll Like Receptor 2 2.24 3.0*10^-4

TNIP1TNFAIP3 interacting protein 1 1.19 1.9*10^-4

17 Additional Probable Genetic Associations

Significant Overlap with Other Autoimmune Diseases

• Most genes we have found in scleroderma are the same genes that have been found in other autoimmune disease like lupus and RA

• HLA is the biggest genetic risk factor for all of these diseases

• Its unclear why individuals with the same “genetic background” develop one autoimmune disease instead of another

Immune Genes in Scleroderma

What We’ve Learned• Lots of genetic associations – now 30 and probably 100s

of genes

• Genetics doesn’t explain everything (~50%)

• Genetics probably make patients susceptible not only to getting scleroderma but also getting different types of scleroderma

What we still don’t know• Why there aren’t any fibrosis/scarring genes showing up

• How having a given gene influences getting scleroderma or a scleroderma manifestation

• The role of environmental factors

• Are there “private mutations” that cause individual patients’ disease entirely?• Next-generation sequencing

Not Just DNA… Whole Genome Expression (mRNA) Microarrays

• RNA expression of probes across the genome in a given tissue

• Which genes are actually doing something where the disease is happening?

Just a research tool?• Not totally

Expression Profiling in Scleroderma

Pharmacogenetics• The study of the genetic determinants of drug effects

What can pharmacogenetics do for you?

• Create More Powerful Medicines

• Better, Safer Drugs the First Time

• More Accurate Methods of Determining Appropriate Drug Dosages

• Improvements in the Drug Discovery and Approval Process

• Targeted therapies• Lots of examples in oncology

Personalized Medicine

“Personalized medicine refers to the tailoring of medical treatment to the individual characteristics of each patient. It does not literally mean the creation of drugs or medical devices that are unique to a patient but rather the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment. Preventive or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not.”

The right treatment for the right patient

Personalized Medicine in the Genomic Era

• Goal:

• To use information ascertained from genomic technologies to treat patients based on their genetic makeup

Personalized Medicine Should…• Aid in diagnosis, prediction of risk

• Help doctors detect disease earlier when it’s easier to treat

• Classify disease subtypes• define prognosis• predict and prevent complications

• Treat patients with drugs they are likely to respond to

• Not treat patients with drugs they are unlikely to respond to

• Reduce adverse drug reactions

• Identify new molecular targets, develop therapies directed at the molecular problem in appropriate patients

Scleroderma is a VERY complex disease, and is therefore a very good candidate for personalized medicine techniques

• Subtypes• Limited• Diffuse

• Autoantibodies• Centromere• Scl70• RNA Pol III

• Organ Involvement• Skin• Lung• Heart• Kidney

• Molecular subtypes• Diffuse-proliferative• Inflammatory

The path to personalized medicine

Personalized Medicine• The right treatment for the right patient

• Multiple facets• Correct diagnosis• Understanding disease type, prognosis• Genetic counseling / risk• Pharmacology and Pharmacogenetics• Preventative medicine – doing the right screening• Patient preference / doctor-patient relationship

How do we interpret all this?

“A lot of clinicians don’t know how to interpret genetic results, they know how to look at a graph of chemistry results. They know how to read a pathology report. But they actually don’t know how to look at this data and to make decisions based on it.”

–John Glaser, Chief Information Officer, Partners Healthcare

Too Much Information!

Challenges for personalized medicine

• Current tests aren’t that useful

• Confusion/lack of information

• Genetic Privacy

• Cost

More challenges for personalized medicine

• Genotype/phenotype discordance• Same disease may be caused by many varied mechanisms / genetic defects• Environmental factors• Multiple gene effects• Epigenetics / copy number variation

• Direct to consumer genetic testing

• Interpretation of personal implications of population test results

Conclusions

• Genetics and genomics are complicated, and getting more so every day

• Every patient is genetically unique

• New technology will make it easier to understand individuals’ genetic susceptibility to disease and response to therapy

• We’ve learned a lot about the genetics of scleroderma but we still have a lot to learn