The document discusses the evolution and significance of genomic research, particularly highlighting the advancement of the Human Genome Project and its implications for understanding human disease, particularly scleroderma. It details the genetic associations found in scleroderma and the complexity of its genetics, including the influence of multiple genes and environmental factors on disease susceptibility. Additionally, it explores the potential of personalized medicine to tailor treatments based on individual genetic makeup, while also addressing the challenges faced in interpreting genomic data and implementing personalized approaches in clinical settings.

2. 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

3. 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

4. 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

5. “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

6. What about complicated diseases like
scleroderma?
Enter: Genomics

7. Metagenomics

8. 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

9. Disease
susceptibility

10. 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

11. Genetics of Scleroderma - GWAS

12. The list of scleroderma genes keeps growing
13 Confirmed Genomewide Significant and
Independently Replicated Associations
Symbol Gene Name case/control OR p-value
ATG5 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
17 Additional Probable
Genetic Associations
Symbol Gene Name OR p-value
BANK1
B-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
CD226
Cluster of differentiation
226 1.22 5.7*10^-5
GRB10
Growth factor receptor
bound protein 10 1.15 1.3*10^-6
IL2RA IL-2 receptor alpha 1.30 2.1*10^-4
JAZF1 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
NKFB1
Nuclear factor kappa
beta 1 1.14 1.0*10^-6
PPARG
Peroxisome proliferator-activated
receptor
gamma 1.25 5.0*10^-7
PSD3
Pleckstrin 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
SOX5
Sex Determining Region
Y-Box 5 1.36 1.4*10^-7
TLR2 Toll Like Receptor 2 2.24 3.0*10^-4
TNFAIP3 interacting

13. 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

14. Immune Genes in Scleroderma

15. 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

16. 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

17. 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?

18. Just a research tool?
• Not totally

19. Expression Profiling in Scleroderma

20. Pharmacogenetics
• The study of the genetic determinants of drug effects

21. 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

22. Personalized Medicine
The right treatment for the right patient
“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.”

23. Personalized Medicine in the Genomic Era
• Goal:
• To use information ascertained from genomic
technologies to treat patients based on their
genetic makeup

24. 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

25. 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

26. The path to personalized medicine

27. 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

28. 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

29. Too Much Information!

30. Challenges for personalized medicine
• Current tests aren’t that useful
• Confusion/lack of information
• Genetic Privacy
• Cost

31. 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

32. 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