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Abstract Number: 1869

Association of CLEC16A with SLE in a Large Multi-Ancestry Cohort and Implication in B-Cell Receptor Signaling

Isaac TW Harley1,2,3, Samuel Vaughn4, Adrienne H. Williams5, Julie T. Ziegler6, Mary Comeau7, Miranda Marion8, Stuart Glenn9, Adam Adler10, Kenneth M. Kaufman11, Sang-Cheol Bae12, Carl D. Langefeld13, Jennifer Kelly14, Patrick M. Gaffney15, R. Hal Scofield16, Michelle Petri17, Jeffrey C. Edberg18, Joel M. Guthridge15, Susan A. Boackle19, Barry Freedman20, Diane L. Kamen21, Elizabeth E. Brown on behalf of PROFILE22, Gary S. Gilkeson23, John D. Reveille24, Joan T. Merrill25, Marta E. Alarcón-Riquelme26, Timothy Vyse27, Lindsey A. Criswell28, Rosalind Ramsey-Goldman29, Juan-Manuel Anaya30, Betty P. Tsao31, Judith A. James32, Graciela S. Alarcón33, Anne M. Stevens34, Kathy Moser Sivils15, Robert P. Kimberly35, Luis M. Vilá36, Chaim O. Jacob37, Bahram Namjou38, Leah C. Kottyan39, Timothy B. Niewold40 and John B. Harley11,41, 1Division of Internal Medicine, University of Colorado, Aurora, CO, 2Immunobiology Graduate Program and Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, 3Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 4Division of Rheumatology and The Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 5Dept of Med, Div of Rheum, NYU School of Medicine, New York, NY, 6Biostatistical Sciences and Center for Public Health Genomics, Wake Forest University Health Sciences, Winston-Salem, NC, 7Wake Forest University Health Sciences, Winston-Salem, NC, 8Department of Biostatistical Sciences, Wake Forest University Health Sciences, Wake Forest, NC, 9Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 10Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City,, OK, 11US Department of Veterans Affairs Medical Center, Cincinnati, OH, 12Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea, 13Wake Forest University, Wake Forest, NC, 14Oklahoma Medical Research Foundation, Oklahoma City, OK, 15Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, 16Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 17Rheumatology, Johns Hopkins University Hospital, Baltimore, MD, 18Medicine/Rheumatology, University of Alabama at Birmingham, Birmingham, AL, 19Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO, 20Department of Internal Medicine, Wake Forest University Health Sciences, Wake Forest, NC, 21Medicine, Medical University of South Carolina, Charleston, SC, 22University of Alabama at Birmingham, Birmingham, AL, 23Department of Rheumatology, Medical University of South Carolina, Charleston, SC, 24Rheumatology, University of Texas Health Science Center at Houston, Houston, TX, 25Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, OK, 26Oklahoma Medical Research Foundation and Centro de Genómica e Investigación Oncológica Pfizer-Universidad de Granada-Junta de Andalucía (GENYO), Granada, Spain, Oklahoma City, OK, 27Division of Genetics and Molecular Medicine and Division of Immunology, Infection and Inflammatory Disease, King's College London, London, United Kingdom, 28Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, CA, 29Northwestern University Feinberg School of Medicine, Chicago, IL, 30Cell Biol and Immunogenetics, CIB-Rosario University, Medellin, Colombia, 31Medicine/Rheumatology, Division of Rheumatology, UCLA, Los Angeles, CA, 32Arthritis and Clinical Immunology, University of Oklahoma Health Sciences Center and Oklahoma Medical Research Foundation, Oklahoma City, OK, 33U of Alabama, Birmingham, AL, 34Seattle Children's Res Inst, Seattle Children's Hospital, Seattle, WA, 35Medicine, Clinical Immun & Rheumatology, University of Alabama at Birmingham, Birmingham, AL, 36Department of Medicine, Division of Rheumatology, University of Puerto Rico Medical Sciences Campus, San Juan, PR, 37Medicine/Div of Rheumatology, USC School of Medicine, Los Angeles, CA, 38Oklahoma Medical Research Foundation, Edmond, OK, 393333 Burnet Ave., Ml 15012, Cincinnati, OH, 40Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, MN, 41Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Lupus and genetics

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Session Information

Date: Monday, November 9, 2015

Session Title: Systemic Lupus Erythematosus - Human Etiology and Pathogenesis Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Immune-mediated diseases appear to share a common genetic basis. Here we describe genetic association of single nucleotide polymorphisms (SNPs) within CLEC16A with SLE in a large multi-ancestry cohort of SLE cases and controls. In immune-mediated diseases where this locus has been implicated, it appears to have complex genetic architecture with multiple independent association signals and multiple plausible candidate genes. Few studies to date have focused on the function of human CLEC16A. However, recent studies defining the role of the Drosophila ortholog of CLEC16A, Ema, suggest several plausible mechanisms through which variation at this gene might plausibly influence autoimmunity and SLE risk. Here, we also undertake evaluation of one such hypothesis, that variation in CLEC16A modulates B-cell receptor (BCR) signaling and thus autoimmunity.

Methods: First, we genotyped a panel of previously reported immune mediated disease susceptibility loci in a large collection of SLE case-matched control samples as part of the collaborative Large Lupus Association Study 2 (LLAS2). As part of the panel, we tested SNPs in CLEC16A for genetic association with SLE. After adjusting for admixture using a panel of ancestry informative markers, filtering for SNP missingness, departure from Hardy-Weinberg equilibrium and minor allele frequency, SNPs were tested for association using an additive genetic model. Association testing was carried out in each AIM-defined ancestry subgroup and meta-analysis of the population specific results was also performed. All SLE patients met the 1997 ACR criteria for classification of SLE. In addition, B cells from control subjects were incubated with anti-BCR for 30 min at 4°C, then placed at 37°C as indicated. Cross-linked surface remnant BCR was detected with fluorescent-tag secondary antibody and co-localization with labelled CLEC16A was then calculated.

Results: We found evidence for association at previously defined autoimmune susceptibility loci was stronger than expected by chance. In addition to this, a SNP in CLEC16A was associated in each AIM-defined ancestry subgroup (European, African, Asian and Native American/Hispanic Ancestry groups) with the same allele in the same direction. (Pmeta < 4.96*10-7, Phet = 0.6874, N = 15751). We find that while CLEC16A co-localizes with the BCR following BCR internalization. This occurs in the endosomal compartment, where the Drosophila ortholog of CLEC16A, Ema, also operates.

Conclusion: Taken together, our data confirm the association of this locus with SLE in multiple ancestry groups and suggest a role for human CLEC16A in BCR signaling in the endosome, where its Drosophila ortholog, Ema has been shown to operate.


Disclosure: I. T. Harley, None; S. Vaughn, None; A. H. Williams, None; J. T. Ziegler, None; M. Comeau, None; M. Marion, None; S. Glenn, None; A. Adler, None; K. M. Kaufman, None; S. C. Bae, None; C. D. Langefeld, None; J. Kelly, None; P. M. Gaffney, None; R. H. Scofield, None; M. Petri, None; J. C. Edberg, None; J. M. Guthridge, None; S. A. Boackle, None; B. Freedman, None; D. L. Kamen, None; E. E. Brown on behalf of PROFILE, None; G. S. Gilkeson, None; J. D. Reveille, None; J. T. Merrill, None; M. E. Alarcón-Riquelme, None; T. Vyse, None; L. A. Criswell, None; R. Ramsey-Goldman, None; J. M. Anaya, None; B. P. Tsao, NIH, 2; J. A. James, None; G. S. Alarcón, None; A. M. Stevens, None; K. Moser Sivils, None; R. P. Kimberly, None; L. M. Vilá, None; C. O. Jacob, None; B. Namjou, None; L. C. Kottyan, None; T. B. Niewold, None; J. B. Harley, None.

To cite this abstract in AMA style:

Harley IT, Vaughn S, Williams AH, Ziegler JT, Comeau M, Marion M, Glenn S, Adler A, Kaufman KM, Bae SC, Langefeld CD, Kelly J, Gaffney PM, Scofield RH, Petri M, Edberg JC, Guthridge JM, Boackle SA, Freedman B, Kamen DL, Brown on behalf of PROFILE EE, Gilkeson GS, Reveille JD, Merrill JT, Alarcón-Riquelme ME, Vyse T, Criswell LA, Ramsey-Goldman R, Anaya JM, Tsao BP, James JA, Alarcón GS, Stevens AM, Moser Sivils K, Kimberly RP, Vilá LM, Jacob CO, Namjou B, Kottyan LC, Niewold TB, Harley JB. Association of CLEC16A with SLE in a Large Multi-Ancestry Cohort and Implication in B-Cell Receptor Signaling [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/association-of-clec16a-with-sle-in-a-large-multi-ancestry-cohort-and-implication-in-b-cell-receptor-signaling/. Accessed December 15, 2019.
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