TheGenecsofPemphigus DermaThetologicBGenomicEra · DermaThetologicBGenomicEra...
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DermaThe tologic B-‐Genomic Era
The Gene4cs of Pemphigus
Self/
Animesh A. Sinha, MD, PhD
Rita M and Ralph T. Professor of Dermatology Department of Dermatology University at Buffalo
09/17/17
No conflicts
IPPF Newport Beach, CA
• >100 human autoimmune diseases
• 10-20% of population
• 3rd highest disease burden
Defini'on: Autoimmunity is the failure of an organism to recognize its own cons4tuent parts as "self", which results in an immune response against its own cells and 4ssues.
Autoimmune Disease
Genes
Environment Immune Regula4on
Autoimmune Disease
suscep4bility to disease is COMPLEX
mul'factorial polygenic
Autoimmune Disease
• Gene4c basis of disease
what is the evidence?
• Iden4fica4on of disease suscep4bility genes what genes cause disease?
• Explora4on of func4onal pathways how do genes cause disease?
Gene4cs
• Gene4c basis of disease
what is the evidence?
• Iden4fica4on of disease suscep4bility genes what genes cause disease?
• Explora4on of func4onal pathways how do genes cause disease?
Gene4cs
USA Jewish 32 Jews (Jerusalem) 16.1 Greek 9.3 Bulgarian 4.7 Southern Indians 4.4 USA non-‐Jewish 4.2 Malaysian 2.0 Saudi Arabian 1.6 French 1.3 German 0.98 Finnish 0.76
range: 0.76 -‐ 32 per million
Popula4on Incidence per 1x106
Popula4on Studies Gazit and Loewenthal, Autoimmunity Reviews 4:16 (2005) World-‐wide Incidence -‐ PV
Literature: 1.1 : 1 -‐ 2.25 : 1
Sinha study: 2 : 1
Female Predominance in Autoimmune Disease
Gupta et al. Dermatol. Clin. 29(3):393-‐404.
Pemphigus Incidence Worldwide
0 2 4 6 8 10 12 14 16 18
Myasthenia Gravis
Lupus Erythematosus
Vitiligo
Ulcerative Colitis
Type 1 Diabetes
Alopecia Areata
Fibromyalgia
Psoriasis
Rheumatoid Arthritis
Thyroid Disease16 (45.7%)
5 (14.3%)
4 (11.4%)
4 (11.4%)
3 (8.6%)
2 (5.7%)
2 (5.7%)
1 (2.9%)
1 (2.9%)
1 (2.9%)
Autoimmune Co-‐Morbidity
21% of all PV pts report having a co-‐morbid autoimmune diseases
Gupta et al. Dermatol. Clin. 29(3):393-‐404. Sinha study
*
1 (0.6%) 1 (0.6%) 1 (0.6%)
2 (1.2%) 2 (1.2%) 2 (1.2%)
3 (1.8%) 3(1.8%) 3 (1.8%)
4 (2.3%) 5 (2.9%)
6 (3.5%) 7 (4.1%)
9 (5.3%) 9 (5.3%)
10 (5.9%) 13 (7.6%)
25 (14.6%) 27 (15.8%)
0 5 10 15 20 25 30
Autoimmune Hepatitis Scleroderma
Sjorgrens Pemphigus Foliaceous
Fibromyalgia Celiac Disease
Bullous Pemphigoid Alopecia Areata
Thrombopenic Purpura Vitiligo
Pemphigus Vulgaris Multiple Sclerosis Ulcerative Colitis Crohn’s Disease
Lupus Rheumatoid Arthritis
Psoriasis Thyroid Diseases Diabetes - Type I
48% of all PV pa4ents report having one or more rela4ves with autoimmune disease
Autoimmune Disease -‐ Familial Aggrega4on
First Degree 50.6%
Second Degree 34.3%
Third Degree 15.1%
No concordance rates available for monozygo'c vs dyzygo'c twins
Gupta et al. Dermatol. Clin. 29(3):393-‐404. Sinha study
Autoimmune Clusters
Autoimmune Comorbidity
Family History of Comorbidity
Cluster 1 PV AITD RA DM1
Cluster 2 PV AITD RA SLE
Parameswaran A, Sato R, Seiffert-‐Sinha K, Sinha AA (2013) Br J Dermatol 172(3)729-‐38.
• Gene4c basis of disease
what is the evidence?
• Iden4fica4on of disease suscep4bility genes what genes cause disease?
• Explora4on of func4onal pathways how do genes cause disease?
Gene4cs
Disease Suscep4bility Genes
• HLA genes
• non HLA genes
Inheritance is polygenic
Disease Suscep4bility Genes
• HLA genes
• non HLA genes
Inheritance is polygenic
Chromosome 6
HLA
Class II Class III Class I
β α α β LMP/TAP β α β β α B C E A G F
HLA
DP DQ
C4 C2Hsp70TNF
DM DR Bf
HLA Gene4c Region
Class II
HLA and PV
> 95% of PV pa4ents type as:
DR4
DR6
Rela4ve Risk (RR) = 15.2 -‐ 127.1
a ra'o of the probability of the disease occurring in the presence of the allele vs in its absence
P1P4 P6 P7 P9
Self/
DR4 DR6 serological
DRB1*0402 DQB1*0503 molecular/ allele
P4 P9 pocket
D70, E71 D57 residue
HLA
HLA II and PV
Sinha et al. A newly characterized HLA DQ beta allele associated with pemphigus vulgaris. Science 239:1026. Todd et al. A molecular basis for MHC class II--associated autoimmunity. Science 240:1003. Sinha et al. Autoimmunity: A failure of self-tolerance. Science 248:1380. Lee et al. Disease relevant HLA class II alleles isolated by genotypic, haplotypic, and sequence analysis in North American Caucasians with pemphigus vulgaris. Hum. Immunol. 68(7):630
Disease Suscep4bility Genes
• HLA genes
• non HLA genes
Inheritance is polygenic
• candidate gene screen the usual suspects
• genome wide screen shotgun strategy
genome-‐wide associa4on study (GWAS) next-‐genera4onal sequencing
Strategies to iden'fy risk loci:
non HLA genes
• IGHC Gibson W et al, Hum Genet 94:675 (1994) 12 pts
• IGKC no associa'on
• DSG3 Capon F et al, Clin Lab Invest 154:67 (2005)
• TNFα, TGFβ, IL-‐10 no associa'on
• TAP2*C, TAP2*D Slomov E et al, Hum Immunol 66:1213 (2005)
• PTPN22 no associa'on Sachdev et al, Exp Dermatol 20:514( 2011)
Candidate Gene Screen
*
discovery driven
Sarig et al, J. Invest. Dermatolol. 132:1798 (2012).
Genome Wide Association Studies (GWAS)
Genome Wide Screen
Exome Whole genome
Genome Wide Screen
Next-gen Sequencing
• Gene4c basis of disease
what is the evidence?
• Iden4fica4on of disease suscep4bility genes what genes cause disease?
• Explora4on of func4onal pathways how do genes cause disease?
Gene4cs
The Ternary Complex
B Cell
Kera4nocyte
Dsg3 Dsg1
Self/
HLA
T Cell
Pathway to Disease Genes
Environment Immune Regulation
Autoimmune Disease
HLA and PV
HLA-‐ controls
Cytokines é IL-‐1α, IL-‐1β, IL-‐6, IL-‐8, IL-‐13, IL-‐21, IL-‐23, and TNF-‐α
AnBoxidants ê Total anBoxidant capacity (TAC)
AutoanBbodies cluster together based on an4-‐Dsg3, an4-‐TPO, mAChR3, -‐4, -‐5
reac4vity é levels in serum
PV
Gene expression cluster together (unbiased)
HLA+ controls
430
274
110
97
805
119
PV HLA+ CR
HLA-‐driven genes HLA-‐driven genes 1
1. HLA-‐ driven genes
Immune system processes
HLA-‐independent genes 2 -‐
2. HLA-‐independent genes
Cell structural process
Protec4ve genes 3 -‐
3. Protec4ve genes
Biogenesis + metabolic processes
Gene Expression PV blood Microarray experiment – gene chip
AFFYMETRIX HuU133A array
(>54,000 transcripts)
Genetics - Clinical Relevance
• Iden4fy individuals at risk develop new gene'c screening tests
• Predict course of disease early interven'on
• Predict response to therapy tailored therapy • Understand disease mechanisms new therapeu'c targets
New era of personalized medicine
Innova-on plan: Pa4ent crowd-‐sourced study
Pemphigus Vulgaris – a mobile health perspec4ve
• Monitor pa4ent condi4on and disease ac4vity in real-‐-me • Faster data collec4on • Increased data accuracy • Photo capable; med log, sleep log, food log
• New App currently under development in Sinha lab • Allows user-‐friendly delivery of pa4ent survey • iOS 9+/Android
• Ensure secure / HIPAA compliant data transmission
• Empower pa4ents with resources and care op4ons • Access to providers, research opportuni4es
Sinha Lab - Leo Pharm
The Sinha Lab
Acknowledgements
Selwyn Chow, MD Amit Sachdev, MD Alvin Coda, MD Veronic Russo, MD Monica Van Acker Maulik Dhanda, MD Razvan Opreanu, MD Jason Smith, PhD Venice Cercado, MD Map Stepanovich, MD Jack Talsma, MD
Ryan Diesler, MD Viola Hysa, MD Megan Olsen, MD Rahgu Ragananthan, MD Erica Lee, MD Carina Rizzo, MD Achim Moesta, PhD Michael Offers, MD
Stephan Stevanovich, PhD Univ Tübingen Sanil Manavalan, MD Columbia University John Gerlach, PhD Michigan State Univ Bill Robinson, MD Stanford University Brian Haab, PhD Van Andel Inst Victor Tong, PhD Univ Singapore
Kris4na Seiffert Sinha, MD Rama Dey-‐Rao, PhD Amit Shah, MD Dhaval Banusali, MD Sreedevi Chintamani, PhD Elizabeth Heller Ankit Gor Tom Sadja Melissa Hoffman Guneet Singh Priya Sansakan Andrew Gaddi
Thank you!!
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