10/27/2013. Biological Insights from Genetics of Rheumatoid Arthritis Contribute to Drug Discovery. Yukinori Okada, MD, PhD.

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1 ACR Meeting 2013, San Diego Biological Insights from Genetics of Rheumatoid Arthritis Contribute to Drug Discovery. ~ Disclosure ~ We declare no competing financial interests. Yukinori Okada, MD, PhD. Plenge and Raychaudhuri Labs Division of Rheumatology, Immunology, and Allergy Brigham and Women s Hospital, Harvard Medical School Broad Institute ~ Rheumatoid arthritis (RA) and genetic backgrounds ~ ~ Ethnically shared genetic risks of RA ~ Known RA risk loci Unknown RA risk loci Rheumatoid arthritis is an autoimmune disease destructing joints. Worldwide prevalence is ~1.0%. By 2012, ~60 genetic risk loci have been identified. (Nature Genetics. Stahl EA et al. 2010, Okada Y et al. 2012, Eyre S et al. 2012) Ethnically shared risk of RA has been implicated in both known and unknown genetic risk loci. Trans-ethnic GWAS should increase power to detect novel loci. (Nature Genetics. Okada Y et al. 2012) ~ Trans-ethnic GWAS of RA for >100,000 subjects ~ ~ Trans-ethnic GWAS of RA for >100,000 subjects ~ We conducted trans-ethnic GWAS meta-analysis of RA for >100,000 subjects. >25 study cohorts from Europeans and Asians were involved. (Nature. Okada Y et al. In Press) We evaluated ~10 million SNPs including X chromosome. We identified 42 novel loci with P < (in total 101). (Nature. Okada Y et al. In Press) 1

2 How to connect GWAS hits to biology and drug discovery? GWAS? Biology Drug To answer this question, we constructed an in-silico pipeline to systematically integrate RA GWAS risk loci with a variety of databases for biology and drug discovery. (2) (3) (2) Epigenetic histone marks (H3K4me3) in regulatory T cells. (3) (2) Epigenetic histone marks (H3K4me3) in regulatory T cells. (3) Shared pleiotropic effects with other human traits. ~ Functional enrichment of genes in RA risk loci ~ ~ Prioritization of biological RA risk genes ~ PID genes PTPRC CASP10 RAG1/2 AIRE CD40 IL2RA ATM IFNGR2 TYK2 IRF8 UNG MVK CASP8 C5 RA GWAS risk loci Somatic mutations Hematological cancers Lymphoma Lymphocytic leukemia Solid cancers KO mouse phenotype Immune Hematopoietic Sensory Neurological Body size 377 genes from 100 non-mhc RA risk loci Prioritization criteria 1. Missense SNPs 2. cis-eqtl 3. PubMed text mining 4. PPI 5. PID genes 6. Hematological cancer 7. KO mouse phenotype 8. Molecular pathway Protein-protein Interaction network 98 biological RA risk genes 871 drug target genes We observed significant overlap of RA GWAS risk loci with (1) Human primary immunodeficiency (PID) genes. (2) Hematological cancer somatic mutation genes. (3) Knockout mouse genes and phenotypes. We scored 377 genes from RA risk loci based on biological criteria. 98 biological RA biological risk genes satisfied 2 criteria. We systematically evaluated overlap with drug target genes. 2

3 ~ Overlap of RA risk genes and RA drug target genes ~ ~ Overlap of RA risk genes and RA drug target genes ~ RA risk biological genes were significantly enriched in overlap with target genes of approved RA treatment drugs. ~ Overlap of RA risk genes and RA drug target genes ~ ~ Overlap of RA risk genes and RA drug target genes ~ ~ Overlap of RA risk genes and RA drug target genes ~ ~ Overlap of RA risk genes and RA drug target genes ~ 3

4 ~ Drug repurposing using RA risk gene target connection ~ Directly targeted drugs of biological RA risk genes could be candidates for drug repurposing for RA treatment. CDK4/6 inhibitors for CDK4 and CDK6 could be a good example. Drugs targeting RA risk genes could be candidates for drug repurposing for RA treatment. Drugs targeting RA risk genes could be candidates for drug repurposing for RA treatment. Our study provides empirical evidences that genetics of diseases could contribute to biological insight and drug discovery. 4

5 Brigham and Women s Hospital Harvard Medical School Robert M. Plenge, Soumya Raychaudhuri, Eli A. Stahl, Dorothee Diogo, Gosia Trynka, Di Wu, Katherine Liao, Jing Cui, Elizabeth W. Karlson, Philip L. De Jager, Towfique Raj, Barbara E. Stranger. The Broad Institute, MIT Daniel Miel, Namrata Gupta, Hyon K. Choi. The Feinstein Institute for Medical Research Peter K. Gregersen. The University of Manchester Jane Worthington, Steve Eyre, John Bowes, Anne Barton. Karolinska University Leonid Padyukov, Lars Klareskog. Leiden University Medical Centre Tom W.J. Huizinga, Alexandra Zhernakova. ~ Acknowledgements ~ RACI and Immunochip consortium Javier Martin, Solbritt Rantapää-Dahlqvist, S. Louis Bridges Jr, Philippe Dieudé, Xavier Mariette, Marieke J.H. Coenen. University of Tronto Katherine A. Siminovitch. Vanderbilt University School of Medicine Joshua C. Denny. CORRONA Jeffrey D. Greenberg. Hauyang University Hospital Sang-Cheol Bae. Shanghai Changzheng Hospital Huji Xu. University of Queensland Diamantina Matthew A. Brown, Peter M. Visscher. Genentech Timothy W. Behrens, Robert R. Graham, Arun Monoharan. Center for Integrative Medical Science, RIKEN Kazuhiko Yamamoto, Akari Suzuki, Yuta Kochi, Yoichiro Kamatani, Atsushi Takahashi, Michiaki Kubo. Kyoto University Tuneyo Mimori, Koichiro Omura, Chikashi Terao, Takahisa Kawaguchi, Ryo Yamada, Fumihiko Matsuda. Tokyo Women s Medical University (IORRA) Hisashi Yamanaka, Shigeki Momohara, Katsunori Ikari. 5