Lessard, Christopher J.

My 101

When the initial draft of the human genome was sequenced and released (2003) to researchers, many scientists thought it would immediately reveal the genetic basis for human disease. We soon realized that the human genome is much more complex than was ever imagined. Since then, technological advances have allowed us to evaluate thousands of genetic variants in large populations and conduct genome-wide association studies to identify which genes predispose a person to a particular disease or trait. More recently, we have entered a new era of affordable, rapid sequencing, which has provided scientists with unparalleled access to the high-quality, informative data needed to unravel the genetic relationships to human disease.

Not all diseases are created equal. Some diseases result from disruptions in a single gene, while others, including autoimmune diseases like lupus and Sjögren’s syndrome, are influenced by multiple genes. In autoimmunity, the immune system mistakenly recognizes self-molecules as foreign, leading to inflammatory processes and tissue damage to organs and worse prognosis if not treated. While the precise causes of autoimmune diseases are not fully known, it is well accepted that most arise from a complex interplay of multiple genetic risk factors and environmental triggers. Genetic studies in these diseases require international collaborations to assemble the large patient and healthy control populations needed to conduct large-scale genome-wide associations studies. To date researchers have identified more than 100 genes in lupus. In contrast, only 15 genes have been identified in Sjögren’s syndrome. The disparity between Sjögren’s and lupus is largely due to the lack of large, well-characterized patient collections and the later age of disease onset.

My lab studies the genetics of autoimmune-related traits. Our goal is to understand the complex interactions between the elements of the human genome to identify new biomarkers and to develop therapeutics that will ultimately improve the lives of patients affected by these serious autoimmune disorders.

Research

In the post genome-wide association (GWA) era, my lab has been focused on determining the mechanisms by which these associations contribute to disease risk. Since more than 80% of the variants associated with complex traits are not coding and many of the molecular methods used to determine the functional/causal variant(s) have been low throughput, most risk loci have not been characterized mechanistically. Many large consortiums have worked to catalog features of the human genome outside of the coding sequence, which has helped us prioritize variants for functional characterization; however, many regulatory elements are cell type and/or context specific. Thus, these data only provide a selected view of the possible ways a variant may alter genomic regulation. One major observation made by ENCODE and other groups was that more than 60% of the human genome yields RNA molecules of more than 200bp in length; the functions of which are largely unknown. However, many of those that have been functionally determined work to regulate transcription both in cis and trans. Recent work, driven by advances in technology to evaluate single cells, have also opened new avenues into our understanding of cell populations, differentiation, and cell type specific differences between patients and healthy subjects.

The goal of my research is to better understand how regulation of protein coding gene expression is controlled by the non-coding genome, and how genetic variation and long non-coding RNAs can lead to dysregulation. We use bioinformatics, high throughput genotyping, short and long read sequencing, basic cell biology, biochemistry, and various in vitro cellular models. To date, my research has primarily focused on understanding the genetics of systemic lupus erythematosus and Sjögren’s syndrome. However, more recently, my work has expanded to include neuromyelitis optica (NMO), multiple sclerosis (MS), and rheumatoid arthritis. While all of these diseases have autoimmune phenotypes and established genetic influences, our research is aimed at uncovering how similarities and differences between these traits could synergistically improve our understanding of genomic regulation of the human immune system.

Brief CV

Education
B.Sc., University of Minnesota, Minneapolis, MN, 2000
Ph.D., Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 2010
Postdoctoral Studies, Oklahoma Medical Research Foundation, 2012

Honors and Awards


1999-present	Member, Golden Key National Honor Society
2008-2009	Barrett Predoctoral Scholarship Fund Award
2008	Notable Poster Award, American College of Rheumatology Annual Scientific Meeting, San Francisco, CA
2009	Paul Kimmelstiel Graduate Student Award for Excellence in Research and Presentation Skills, Department of Pathology, University of Oklahoma Health Sciences Center
2009	American College of Rheumatology Research and Education Foundation/Abbott Health Professional Graduate Student Research Preceptorship Award
2010	Paul Kimmelstiel Graduate Student Award for Excellence in Research and Presentation Skills, Department of Pathology, OUHSC
2010	Graduate Student Association Award for Outstanding Academic Achievement, OUHSC
2010	Outstanding Graduate Award (for a 4.0 GPA), OUHSC
2010	Notable Poster Award, American College of Rheumatology Annual Scientific Meeting, Atlanta GA
2011-present	Visiting Professor, Center for Autoimmune Disease Research (CREA), Universidad Del Rosario, Bogotá, Colombia
2011	OMRF Outstanding Paper Award for FY 2010-2011
2015	Notable Translational Abstract, EULAR 2015 (Rome, Italy)
2016	J. Donald and Patricia Capra Award for Scientific Achievement
2020	European League Against Rheumatism (EULAR) E-Congress Basic Science Abstract Award

Professional Membership
American Society of Human Genetics, 2007-present
American College of Rheumatology, 2016-present
American Academy of Neurology, 2015-2016

Joined OMRF Scientific Staff in 2014

Publications

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Recent Publications

Joachims ML, Leehan KM, Dozmorov MG, Georgescu C, Pan Z, Lawrence C, Marlin MC, Macwana S, Rasmussen A, Radfar L, Lewis DM, Stone DU, Grundahl K, Scofield RH, Lessard CJ, Wren JD, Thompson LF, Guthridge JM, Sivils KL, Moore JS, Farris AD. Sjögren's Syndrome Minor Salivary Gland CD4 Memory T Cells Associate with Glandular Disease Features and have a Germinal Center T Follicular Helper Transcriptional Profile. J Clin Med 9, 2020 July, PMID: 32650575, PMCID: PMC7408878

Agasing AM, Wu Q, Khatri B, Borisow N, Ruprecht K, Brandt AU, Gawde S, Kumar G, Quinn JL, Ko RM, Mao-Draayer Y, Lessard CJ, Paul F, Axtell RC. Transcriptomics and proteomics reveal a cooperation between interferon and T-helper 17 cells in neuromyelitis optica. Nat Commun 11:2856, 2020 June, PMID: 32503977, PMCID: PMC7275086

Verstappen GM, Ice JA, Bootsma H, Pringle S, Haacke EA, de Lange K, van der Vries GB, Hickey P, Vissink A, Spijkervet FKL, Lessard CJ, Kroese FGM. Gene expression profiling of epithelium-associated FcRL4 B cells in primary Sjögren's syndrome reveals a pathogenic signature. J Autoimmun 109:102439, 2020 May, PMID: 32201227

Selected Publications

Lessard CJ, Adrianto I, Kelly JA, Kaufman KM, Grundahl KM, Adler A, Williams AH, Gallant CJ; Marta E. Alarcón-Riquelme on behalf of the BIOLUPUS and GENLES Networks, Anaya JM, Bae SC, Boackle SA, Brown EE, Chang DM, Criswell LA, Edberg JC, Freedman BI, Gregersen PK, Gilkeson GS, Jacob CO, James JA, Kamen DL, Kimberly RP, Martin J, Merrill JT, Niewold TB, Park SY, Petri MA, Pons-Estel BA, Ramsey-Goldman R, Reveille JD, Song YW, Stevens AM, Tsao BP, Vila LM, Vyse TJ, Yu CY, Guthridge JM, Bruner GR, Langefeld CD, Montgomery C, Harley JB, Scofield RH, Gaffney PM, Moser KL. Identification of a systemic lupus erythematosus susceptibility locus at 11p13 between PDHX and CD44 in a multiethnic study. Am J Hum Genet. 2011 Jan 7;88(1):83-91. Epub 2010 Dec 30. PMID: 21194677 PMCID: PMC3014359

Lessard CJ, Adrianto I, Ice JA, Wiley GB, Kelly JA, Glenn SB, Adler AJ, Li H, Rasmussen A, Williams AH, Ziegler J, Comeau ME, Marion M, Wakeland BE, Liang C, Ramos PS, Grundahl KM, Gallant CJ, Alarcón-Riquelme ME, Alarcón GS, Anaya JM, Bae SC, Boackle SA, Brown EE, Chang DM, Cho SK, Criswell LA, Edberg JC, Freedman BI, Gilkeson GS, Jacob CO, James JA, Kamen DL, Kimberly RP, Kim JH, Martin J, Merrill JT, Niewold TB, Park SY, Petri MA, Pons-Estel BA, Ramsey-Goldman R, Reveille JD, Scofield RH, Song YW, Stevens AM, Tsao BP, Vila LM, Vyse TJ, Yu CY, Guthridge JM, Kaufman KM, Harley JB, Wakeland EK, Langefeld CD, Gaffney PM, Montgomery CG, Moser KL; BIOLUPUS Network; GENLES Network. Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study. Am J Hum Genet. 2012 Apr 6;90(4):648-60. Epub 2012 Mar 29. PMID: 22464253 PMCID: PMC3322228

Lessard CJ, Li H, Adrianto I, Ice JA, . Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome. Nat Genet. 2013 Nov;45(11):1284-92. Epub 2013 Oct 6. PMID: 24097067 PMCID: PMC3867192

Li H, Reksten TR, Ice JA, Kelly JA, Adrianto I, Rasmussen A, Wang S, He B, Grundahl KM, Glenn SB, Miceli-Richard C, Bowman S, Lester S, Eriksson P, Elorants ML, Brun JG, Gøransson L, Harboe E, Guthridge JM, Kaufman KM, Kvarnström M, Cunningham Graham DS, Patel K, Adler AJ, Farris AD, Brennan MT, Chodosh J, Gopalakrishnan R, Weisman MH, Venuturupalli S, Wallace DJ, Hefner KS, Houston GD, Huang AJ, Hughes PM, Lewis DM, Radfar L, Vista ES, Edgar CE, Rohrer MD, Stone DU, Vyse TJ, Harley JB, Gaffney PM, James JA, Turner S, Alevizos I, Anaya JM, Rhodus NL, Segal BM, Montgomery CG, Scofield RH, Kovats S, Mariette X, Rönnblom R, Witte T, Rischmueller M, Wahren-Herlenius M, Omdal R, Jonsson R, Ng WF for the UK Primary Sjögren's Syndrome Registry, Nordmark G, Lessard CJ*, Sivils KL*. Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. PLoS Genet. 2017 Jun 22;13(6):e1006820. doi: 10.1371/journal.pgen.1006820. eCollection 2017 Jun. PMID: 28640813 PMCID: PMC5501660 (*co-senior authors).

Lessard CJ, Sajuthi S, Zhao J, Kwangwoo K, Ice JA, Li H, Ainsworth H, Rasmussen A, Kelly JA, Marion M, Bang SY, Joo YB, Choi J, Lee HS, Kang YM, Suh CH, Chung WT, Lee SK, Choe JY, Shim SC, Oh JH, Kim YJ, Han BG, Shen N, Howe HS, Wakeland EK, Li QZ, Song YW, Gaffney PM, Alarcón-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Vyse TJ, Harley JB, Sivils KL, Bae SC, Langefeld CD, Tsao BP. Identification of a systemic lupus erythematosus risk locus spanning ATG16L2, FCHSD2 and P2RY2 in Koreans. Arthritis Rheumatol. 2016 May;68(5):1197-209. PMID: 26663301 PMCID: PMC4981330. (^#authors contributed equally).

Hegen H, Adrianto I, Lessard CJ, Millonig A, Bertolotto A, Comabella M, Giovannoni G, Guger M, Hoelzl M, Khalil M, Fazekas F, Killestein J, Lindberg RL, Malucchi S, Mehling M, Montalban X, Rudzki D, Schautzer F, Sellebjerg F, Sorensen PS, Deisenhammer F, Steinman L, Axtell RC. Cytokine profiles show heterogeneity of interferon-β response in multiple sclerosis patients. Neurol Neuroimmunol Neuroinflamm. 2016 Jan 27;3(2):e202. eCollection 2016 Apr. PMID: 26894205 PMCID: PMC4747480.