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

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

doi:10.1038/ncomms7804

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 knock down (KD) mice showed reduced number of B cells and elevated IgM levels compared to 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.

Highlights

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response
The human leukocyte antigen (HLA) haplotype association with CVID was found earlier by tissue typing[13] and a recent genome-wide association study in CVID further supports a complex genetic heritability in CVID, with common variants within the HLA complex associating with disease development[14]
We perform dense autoimmune risk loci genotyping on the Immunochip in 778 CVID cases and 10,999 controls, representing the largest CVID study panel investigated for genetic risk factors to date

Summary

Introduction

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. 6 Division of Pediatric Allergy and Immunology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. Section of Immunology, Allergy and Rheumatology, Department of Pediatric Medicine, Texas Children’s Hospital, Houston, Texas 77030, USA. Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, 0424 Oslo, Norway. Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. In Clec[16] knockdown (KD) mice, we found a reduced proportion of B cells and elevated IgM secretion, pointing to a role of CLEC16A in B-cell function of potential relevance to CVID and other CLEC16A associated conditions

Methods

Results

Conclusion