Date: Monday, November 9, 2015
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.
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). http://acrabstracts.org/abstract/association-of-clec16a-with-sle-in-a-large-multi-ancestry-cohort-and-implication-in-b-cell-receptor-signaling/. Accessed October 22, 2017.
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