Potential Of Integrating Human Genetics and Electronic Medical Records For Drug Discovery: The Example Of TYK2 and Rheumatoid Arthritis

Dorothee Diogo¹, Katherine P. Liao², Robert S. Fulton³, Robert R. Graham⁴, Jing Cui⁵, Jeffrey D. Greenberg⁶, Stephen Eyre⁷, John Bowes⁸, Annette T. Lee⁹, Dimitrios A. Pappas¹⁰, Joel M. Kremer¹¹, Anne Barton⁷, Marieke J.H. Coenen¹², Xavier Mariette¹³, Corrine Richard-Miceli¹⁴, Helena Canhão¹⁵, João E. Fonseca¹⁶, Niek de Vries¹⁷, Fina Kurreeman¹⁸, Ted R. Mikuls¹⁹, Yukinori Okada¹, Isaac Kohane²⁰, Joshua C. Denny²¹, Jane Worthington²², Soumya Raychaudhuri¹, Timothy W. Behrens²³, Michael F. Seldin²⁴, Peter K. Gregersen²⁵, Elaine R. Mardis³ and Robert M. Plenge²⁶, ¹Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, ²Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, ³The Genome Institute, Washington University School of Medicine, Saint Louis, MO, ⁴ITGR Human Genetics, Genentech, Inc., South San Francisco, CA, ⁵Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, ⁶NYU Hospital for Joint Diseases, New York, NY, ⁷Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester, United Kingdom, ⁸Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester, United Kingdom, ⁹Genomics & Human Genetics, Feinstein Institute for Medical Research, Manhasset, NY, ¹⁰Department of Medicine, Division of Rheumatology, Columbia University, College of Physicians and Surgeons, New York, NY, ¹¹Center for Rheumatology, Albany Medical College, Albany, NY, ¹²Human Genetics (855), Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, ¹³Rheumatology Service, Bicêtre University Hospital, Le Kremlin Bicetre, France, ¹⁴Hôpital Bicêtre, Université Paris-sud, Paris, France, ¹⁵Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa and Rheumatology Department, Centro Hospitalar de Lisboa Norte, EPE, Hospital de Santa Maria, Lisboa, Portugal, ¹⁶Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal, ¹⁷Division of Clinical Immunology and Rheumatology and Department of Experimental Immunology, Division of Clinical Immunology and Rheumatology and Department of Experimental Immunology, Academic Medical Center / University of Amsterdam, Amsterdam, Netherlands, ¹⁸Rheumatology, Leiden University Medical Center, Leiden, Netherlands, ¹⁹Omaha VA Medical Center and University of Nebraska Medical Center, Omaha, NE, ²⁰on behalf of i2b2 ; Brigham and Women's Hospital, Boston, MA, ²¹Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, ²²Arthritis Research UK Centre for Genetics and Genomics, The University of Manchester, Manchester, United Kingdom, ²³Genentech, Inc, South San Francisco, CA, ²⁴Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CA, ²⁵Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, NY, ²⁶Division of Rheumatology, Immunology and Allergy and Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Rheumatoid arthritis (RA)

Session Information

Title: Rheumatoid Arthritis - Pathogenetic Pathways

Session Type: Abstract Submissions (ACR)

Background/Purpose: Human genetics has the potential to identify promising drug targets for complex traits such as rheumatoid arthritis (RA). Genes with a series of disease-associated functional alleles mimic the effect of pharmacological modulation, thereby allowing estimates of efficacy and toxicity before clinical trials in humans.

Methods: To search for genes with alleles that protect from RA susceptibility, we sequenced the protein-coding exons of 845 genes in 1,118 RA cases and 1,118 matched controls, and investigated excess of potentially damaging variants in controls compared to RA patients by gene-based association tests. We replicated findings at one gene, TYK2, by direct genotyping in two large datasets (9,372 RA cases and 18,868 controls). To investigate phenotypes that serve as proxies for potential adverse drug events, we performed a phenome-wide association study (PheWAS) with RA-associated TYK2 variants and clinical data from electronic medical records (EMR).

Results: We demonstrate that multiple protein-coding variants in tyrosine kinase 2 (TYK2), including variants reported to be loss-of function (LOF), independently protect from RA risk (P=0.0018 in sequencing, P=1.6×10^-27 in replication genotyping). Using EMR clinical data from 3,102 individuals, we observe an enrichment of associations with TYK2 LOF alleles for diagnoses related to infections.

Conclusion: Our findings identify a series of LOF alleles in TYK2 that protect against RA and are associated with increased risk of clinical diagnoses that may be considered adverse drug events, suggesting that drugs that inhibit TYK2 may be an effective treatment in RA with predictable side effects.

Disclosure:

D. Diogo,
None;

K. P. Liao,
None;

R. S. Fulton,
None;

R. R. Graham,

Genentech and Biogen IDEC Inc.,

J. Cui,
None;

J. D. Greenberg,
None;

S. Eyre,
None;

J. Bowes,
None;

A. T. Lee,
None;

D. A. Pappas,
None;

J. M. Kremer,
None;

A. Barton,
None;

M. J. H. Coenen,
None;

X. Mariette,
None;

C. Richard-Miceli,
None;

H. Canhão,
None;

J. E. Fonseca,
None;

N. de Vries,
None;

F. Kurreeman,
None;

T. R. Mikuls,
None;

Y. Okada,
None;

I. Kohane,
None;

J. C. Denny,
None;

J. Worthington,
None;

S. Raychaudhuri,
None;

T. W. Behrens,

Genentech and Biogen IDEC Inc.,

M. F. Seldin,
None;

P. K. Gregersen,
None;

E. R. Mardis,
None;

R. M. Plenge,
None.

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