The Gene4cs of Pemphigus

Transcription

1 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 No conflicts 09/17/17 IPPF Newport Beach, CA

2 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. >100 human autoimmune diseases 10-20% of population 3rd highest disease burden

3 Autoimmune Disease Autoimmune Disease Genes Autoimmune Disease Immune Regula4on Environment suscep4bility to disease is COMPLEX mul'factorial polygenic

4 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?

5 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?

6 Popula4on Studies World- wide Incidence - PV range: per million Gazit and Loewenthal, Autoimmunity Reviews 4:16 (2005) Popula4on Incidence per 1x10 6 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 Female Predominance in Autoimmune Disease Literature: 1.1 : : 1 Sinha study: 2 : 1 Gupta et al. Dermatol. Clin. 29(3):

7 Pemphigus Incidence Worldwide

8 Autoimmune Co- Morbidity Thyroid Disease Rheumatoid Arthritis Psoriasis Fibromyalgia Alopecia Areata Type 1 Diabetes Ulcerative Colitis Vitiligo Lupus Erythematosus Myasthenia Gravis 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%) 16 (45.7%) % of all PV pts report having a co- morbid autoimmune diseases Sinha study Gupta et al. Dermatol. Clin. 29(3):

9 Autoimmune Disease - Familial Aggrega4on 48% of all PV pa4ents report having one or more rela4ves with autoimmune disease Diabetes - Type I Thyroid Diseases Psoriasis Rheumatoid Arthritis Lupus Crohn s Disease Ulcerative Colitis Multiple Sclerosis * Pemphigus Vulgaris Vitiligo Thrombopenic Purpura Alopecia Areata Bullous Pemphigoid Celiac Disease Fibromyalgia Pemphigus Foliaceous Sjorgrens Scleroderma Autoimmune Hepatitis 10 (5.9%) 9 (5.3%) 9 (5.3%) 7 (4.1%) 6 (3.5%) 5 (2.9%) 4 (2.3%) 3 (1.8%) 3(1.8%) 3 (1.8%) 2 (1.2%) 2 (1.2%) 2 (1.2%) 1 (0.6%) 1 (0.6%) 1 (0.6%) 13 (7.6%) 27 (15.8%) 25 (14.6%) First Degree 50.6% Second Degree 34.3% No concordance rates available for monozygo'c vs dyzygo'c twins Third Degree 15.1% Sinha study Gupta et al. Dermatol. Clin. 29(3):

10 Autoimmune Clusters Cluster 1 PV AITD RA DM1 Autoimmune Comorbidity Cluster 2 PV AITD RA SLE Family History of Comorbidity Parameswaran A, Sato R, Seiffert- Sinha K, Sinha AA (2013) Br J Dermatol 172(3)

11 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?

12 Disease Suscep4bility Genes Inheritance is polygenic HLA genes non HLA genes

13 Disease Suscep4bility Genes Inheritance is polygenic HLA genes non HLA genes

14 HLA Gene4c Region Chromosome 6 HLA HLA DP DM DQ DR Bf β α α β LMP/TAP β α β β α C4 C2Hsp70TNF B C E A G F Class II Class III Class I Class II

15 HLA and PV > 95% of PV pa4ents type as: DR4 DR6 Rela4ve Risk (RR) = a ra'o of the probability of the disease occurring in the presence of the allele vs in its absence

16 HLA II and PV DR4 DR6 serological DRB1*0402 DQB1*0503 molecular/ allele Self/ HLA P1 P4 P6 P7 P9 P4 P9 pocket D70, E71 D57 residue 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

17 Disease Suscep4bility Genes Inheritance is polygenic HLA genes non HLA genes

18 non HLA genes Strategies to iden'fy risk loci: candidate gene screen the usual suspects genome wide screen shotgun strategy genome- wide associa4on study (GWAS) next- genera4onal sequencing

19 Candidate Gene Screen IGHC IGKC Gibson W et al, Hum Genet 94:675 (1994) 12 pts 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)

20 discovery driven Genome Wide Screen Genome Wide Association Studies (GWAS) Sarig et al, J. Invest. Dermatolol. 132:1798 (2012).

21 Genome Wide Screen Next-gen Sequencing Exome Whole genome

22 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?

23 Pathway to Disease The Ternary Complex Immune Regulation Genes Autoimmune Disease Environment T Cell B Cell Self/ Kera4nocyte HLA Dsg3 Dsg1

24 HLA and PV PV HLA+ controls 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 Gene expression cluster together (unbiased)

25 Gene Expression PV blood Microarray experiment gene chip AFFYMETRIX HuU133A array 1. HLA- driven genes (>54,000 transcripts) 2. HLA- independent genes Protec4ve genes PV HLA + CR 1 HLA- driven genes HLA- driven genes Immune system processes 2 HLA- independent genes - Cell structural process 3 - Protec4ve genes Biogenesis + metabolic processes

26 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

27 Pemphigus Vulgaris a mobile health perspec4ve New App currently under development in Sinha lab Allows user- friendly delivery of pa4ent survey ios 9+/Android Sinha Lab - Leo Pharm Monitor pa4ent condi4on and disease ac4vity in real- -me Faster data collec4on Increased data accuracy Photo capable; med log, sleep log, food log Ensure secure / HIPAA compliant data transmission Empower pa4ents with resources and care op4ons Access to providers, research opportuni4es

28 Acknowledgements The Sinha Lab 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 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

29 Thank you!! And remember to donate BLOOD! PaBents Family members

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