Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells

Jin Li, Silje F. Jørgensen, S. Melkorka Maggadottir, Marina Bakay, Klaus Warnatz, Joseph Glessner, Rahul Pandey, Ulrich Salzer, Reinhold E. Schmidt, Elena Perez, Elena Resnick, Sigune Goldacker, Mary Buchta, Torsten Witte, Leonid Padyukov, Vibeke Videm, Trine Folseraas, Faranaz Atschekzei, James T. Elder, Rajan P. NairJuliane Winkelmann, Christian Gieger, Markus M. Nöthen, Carsten Büning, Stephan Brand, Kathleen E. Sullivan, Jordan S. Orange, Børre Fevang, Stefan Schreiber, Wolfgang Lieb, Pål Aukrust, Helen Chapel, Charlotte Cunningham-Rundles, Andre Franke, Tom H. Karlsen, Bodo Grimbacher, Hakon Hakonarson*, Lennart Hammarström, Eva Ellinghaus

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)

Abstract

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10,999 controls across 123,127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P=2.0 × 10-9) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P=4.8 × 10-16). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition.

Original languageEnglish
Article number6804
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 20 Apr 2015

Bibliographical note

Funding Information:
We thank David Ellinghaus, Kristian Holm and Johannes Roksund Hov for helpful discussions and analytical support, and Liv Osnes for analysing the subphenotype flow data for the Norwegian panel. Benedicte A. Lie and The Norwegian Bone Marrow Donor Registry at Oslo University Hospital, Rikshospitalet in Oslo, as well as Matthew A. Brown and Kristian Hveem are acknowledged for sharing the healthy Norwegian control data. Markus M. Nöthen is a member of the DFG Excellence Cluster ‘ImmunoSenstation’. This study was supported by the Southern and Eastern Norway Regional Health Authority, the German Federal Ministry of Education and Research (BMBF) grants 01EO1303 (CCI) and 01GM0896 (PID-NET), and the DZIF project TTU 04.802. This work was further supported by EU grant HEALTH-F2-2008-201549 (EURO-PADnet), an Institute Development Fund from CHOP, U01HG006830, DP3 DK085708 and a donation to CAG from the Kubert Estate Foundation. The popgen 2.0 network provided the German control data and is supported by a grant from the German Ministry for Education and Research (BMBF; ID 01EY1103). Genotyping of the European case–control collection was supported by the DFG Excellence Cluster ‘Inflammation at Interfaces’ (EXC306, EXC306/2).This work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (grant 01ZX1306). S. Brand was supported by grants from the Deutsche Forschungsgemeinschaft (DFG, BR 1912/6-1) and the Else Kröner-Fresenius-Stiftung (Else Kröner Exzellenzstipendium 2010_EKES.32). The KORA research platform was initiated and financed by the Helmholtz Zentrum München - German Research Center for Environmental Health, funded by the German Federal Ministry of Education and Research and by the State of Bavaria. KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The authors are responsible for the contents of this publication.

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