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

Isaac TW Harley^1,2,3, 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. Harley^11,41, 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

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. (P_meta < 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 January 28, 2020.

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