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

Member, Golden Key National Honor Society, 1999-present
Barrett Predoctoral Scholarship Fund Award, 2008-2009
Notable Poster Award, American College of Rheumatology Annual Scientific Meeting, San Francisco, CA, 2008
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, 2009
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
Outstanding Graduate Award (for a 4.0 GPA), OUHSC, 2010
Notable Poster Award, American College of Rheumatology Annual Scientific Meeting, Atlanta GA, 2010
Visiting Professor, Center for Autoimmune Disease Research (CREA), Universidad Del Rosario, Bogotá, Colombia, 2010
OMRF Outstanding Paper Award, FY 2010-2011
Notable Translational Abstract, EULAR, Rome, Italy, 2015
Donald and Patricia Capra Award for Scientific Achievement, 2015
European League Against Rheumatism E-Congress Basic Science Abstract Award, 2020
Arthritis & Rheumatology Outstanding Reviewer, 2020
European League Against Rheumatism Congress Basic Science Abstract Award, 2022

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 2007

Publications

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Recent Publications

Dezfulian MH, Kula T, Pranzatelli T, Kamitaki N, Meng Q, Khatri B, Perez P, Xu Q, Chang A, Kohlgruber AC, Leng Y, Jupudi AA, Joachims ML, Chiorini JA, Lessard CJ, Darise Farris A, Muthuswamy SK, Warner BM, Elledge SJ. TScan-II: A genome-scale platform for the de novo identification of CD4( ) T cell epitopes. Cell, 2023 November, PMID: 38016469, PMCID: PMC10841602

Wiley MM, Khatri B, Joachims ML, Tessneer KL, Stolarczyk AM, Rasmussen A, Anaya JM, Aqrawi LA, Bae SC, Baecklund E, Björk A, Brun JG, Bucher SM, Dand N, Eloranta ML, Engelke F, Forsblad-d'Elia H, Fugmann C, Glenn SB, Gong C, Gottenberg JE, Hammenfors D, Imgenberg-Kreuz J, Jensen JL, Johnsen SJA, Jonsson MV, Kelly JA, Khanam S, Kim K, Kvarnström M, Mandl T, Martín J, Morris DL, Nocturne G, Norheim KB, Olsson P, Palm Ø, Pers JO, Rhodus NL, Sjöwall C, Skarstein K, Taylor KE, Tombleson P, Thorlacius GE, Venuturupalli S, Vital EM, Wallace DJ, Grundahl KM, Radfar L, Brennan MT, James JA, Scofield RH, Gaffney PM, Criswell LA, Jonsson R, Appel S, Eriksson P, Bowman SJ, Omdal R, Rönnblom L, Warner BM, Rischmueller M, Witte T, Farris AD, Mariette X, Shiboski CH, Sjögren’s International Collaborative Clinical Alliance (SICCA), Wahren-Herlenius M, Alarcón-Riquelme ME, PRECISESADS Clinical Consortium, Ng WF, UK Primary Sjögren’s Syndrome Registry, Sivils KL, Guthridge JM, Adrianto I, Vyse TJ, Tsao BP, Nordmark G, Lessard CJ. Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland. bioRxiv, 2023 October, PMID: 39071447, PMCID: PMC11275775

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 3:e202, 2016 January, PMID: 26894205, PMCID: PMC4747480

Selected Publications

Joachims ML, Khatri B, Li C, Tessneer KL, Ice JA, Stolarczyk AM, Means N, Grundahl KM, Glenn SB, Kelly JA, Lewis DM, Radfar L, Stone DU, Guthridge JM, James JA, Scofield RH, Wiley GB, Wren JD, Gaffney PM, Montgomery CG, Sivils KL, Rasmussen A, Farris AD, Adrianto I, Lessard CJ. Dysregulated long non-coding RNA in Sjögren's disease impacts both interferon and adaptive immune responses. RMD Open. 2022 Nov;8(2):e002672. doi: 10.1136/rmdopen-2022-002672. PMID: 36456101; PMCID: PMC9717416.

Khatri B, Tessneer KL, Rasmussen A, Aghakhanian F, Reksten TR, Adler A, Alevizos I, Anaya JM, Aqrawi LA, Baecklund E, Brun JG, Bucher SM, Eloranta ML, Engelke F, Forsblad-d'Elia H, Glenn SB, Hammenfors D, Imgenberg-Kreuz J, Jensen JL, Johnsen SJA, Jonsson MV, Kvarnström M, Kelly JA, Li H, Mandl T, Martín J, Nocturne G, Norheim KB, Palm Ø, Skarstein K, Stolarczyk AM, Taylor KE, Teruel M, Theander E, Venuturupalli S, Wallace DJ, Grundahl KM, Hefner KS, Radfar L, Lewis DM, Stone DU, Kaufman CE, Brennan MT, Guthridge JM, James JA, Scofield RH, Gaffney PM, Criswell LA, Jonsson R, Eriksson P, Bowman SJ, Omdal R, Rönnblom L, Warner B, Rischmueller M, Witte T, Farris AD, Mariette X, Alarcon-Riquelme ME; PRECISESADS Clinical Consortium; Shiboski CH; Sjögren’s International Collaborative Clinical Alliance (SICCA); Wahren-Herlenius M, Ng WF; UK Primary Sjögren’s Syndrome Registry; Sivils KL, Adrianto I, Nordmark G, Lessard CJ. Genome-wide association study identifies Sjögren's risk loci with functional implications in immune and glandular cells. Nat Commun. 2022 Jul 27;13(1):4287. doi: 10.1038/s41467-022-30773-y. Erratum in: Nat Commun. 2022 Oct 31;13(1):6519. Erratum in: Nat Commun. 2023 Feb 3;14(1):598. PMID: 35896530; PMCID: PMC9329286.

Verstappen GM, Ice JA, Bootsma K, 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. 2020 May;109:102439. doi: 10.1016/j.jaut.2020.102439. Epub 2020 Mar 20. PMID: 32201227, PMCID: PMC7337041. (* indicates co-senior authorship)

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, Eloranta ML, Brun JG, Gøransson LG, Harboe E, Guthridge JM, Kaufman KM, Kvarnström M, Graham DSC, Patel K, Adler AJ, Farris AD, Brennan MT, Chodosh J, Gopalakrishnan R, Weisman MH, Venuturupalli S, Wallace DJ, Heffner KS, Houston GD, Huang AJW, Hughes PJ, 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 L, Witte T, Rischmueller M, Wahren-Herlenius M, Omdal R, Jonsson R, Ng WF, 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).

Zhao J, Ma J, Deng Y, Kelly JA, Kim K, Bang SY, Lee HS, Li QZ, Wakeland EK, Qiu R, Liu M, Guo J, Li Z, Tan W, Rasmussen A, Lessard CJ, Sivils KL, Hahn BH, Grossman JM, Kamen DK, Gilkeson GS, Bae SC, Gaffney PM, Shen N, Tsao BP. A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases. Nat Genet, 2017 Mar;49(3):433-437. doi:10.1038/ng.3782. Epub 2017 Jan 30. PMID:28135245, PMCID: PMC5400098

Lessard CJ, Li H, Adrianto I, Ice JA, Rasmussen A, Grundahl KM, Kelly JA, Dozmorov MG, Miceli-Richard C, Bowman S, Lester S, Eriksson P, Eloranta ML, Brun JG, Gøransson LG, Harboe E, Gutheridge JM, Kaufman KM, Kvarnström M, Jazebi H, Graham DSC, Grandits ME, Nazmul-Hossain ANM, Patel K, Adler AJ, Maier-Moore JS, Farris AD, Brennan MT, Lessard JA, Chodosh J, Gopalakrishnan R, Hefner KS, Houston GD, Huang AJW, Hughes PJ, Lewis DM, Radfar L, Rohrer MD, Stone DU, Wren JD, Vyse TJ, Gaffney PM, James JA, Omdal R, Wahren-Herlenius M, Illei GG, Witte T, Jonsson R, Rischmueller M, Rönnblom L, Nordmark G, Ng WF, Mariette X, Anaya JM, Rhodus NL, Segal BM, Scofield RH, Montgomery CG, Harley JB, Sivils KL. 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