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

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.

[1]  P. D. de Bakker,et al.  Genome‐wide meta‐analysis identifies novel multiple sclerosis susceptibility loci , 2011, Annals of neurology.

[2]  J. Casanova,et al.  Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015 , 2015, Journal of Clinical Immunology.

[3]  É. Oksenhendler,et al.  Clinical picture and treatment of 2212 patients with common variable immunodeficiency. , 2014, The Journal of allergy and clinical immunology.

[4]  Javier Martín,et al.  Specific association of a CLEC16A/KIAA0350 polymorphism with NOD2/CARD15− Crohn's disease patients , 2009, European Journal of Human Genetics.

[5]  Manuel A. R. Ferreira,et al.  Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype. , 2014, The Journal of allergy and clinical immunology.

[6]  Torsten Witte,et al.  A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci. , 2013, Human molecular genetics.

[7]  Ying Wang,et al.  Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus , 2009, Nature Genetics.

[8]  P. Donnelly,et al.  A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies , 2009, PLoS genetics.

[9]  Toshihiro Tanaka.  The International HapMap Project , 2003, Nature.

[10]  Qing Zhou,et al.  A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. , 2012, American journal of human genetics.

[11]  Serafim Batzoglou,et al.  Identifying a High Fraction of the Human Genome to be under Selective Constraint Using GERP++ , 2010, PLoS Comput. Biol..

[12]  C. Polychronakos,et al.  Functional evaluation of the role of C‐type lectin domain family 16A at the chromosome 16p13 locus , 2014, Clinical and experimental immunology.

[13]  Anne-Kathrin Kienzler,et al.  Genetic CD21 deficiency is associated with hypogammaglobulinemia. , 2012, The Journal of allergy and clinical immunology.

[14]  C. Galambos.  Common variable immunodeficiency disorders: division into distinct clinical phenotypes , 2009 .

[15]  Manolis Kellis,et al.  HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants , 2011, Nucleic Acids Res..

[16]  K. Hongo,et al.  A case report and review of the literature , 2006, Journal of Neuro-Oncology.

[17]  Joseph T. Glessner,et al.  Immune deficiencies , infection , and systemic immune disorders Genome-wide association identifies diverse causes of common variable immunodeficiency , 2011 .

[18]  A. Sadovnick,et al.  Risk alleles for multiple sclerosis in multiplex families , 2009, Neurology.

[19]  O. Delaneau,et al.  Supplementary Information for ‘ Improved whole chromosome phasing for disease and population genetic studies ’ , 2012 .

[20]  T. Kilpatrick,et al.  Fine mapping of multiple sclerosis susceptibility genes provides evidence of allelic heterogeneity at the IL2RA locus , 2009, Journal of Neuroimmunology.

[21]  I. Vořechovský,et al.  Family and linkage study of selective IgA deficiency and common variable immunodeficiency. , 1995, Clinical immunology and immunopathology.

[22]  Tariq Ahmad,et al.  Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci , 2010, Nature Genetics.

[23]  T. Speed,et al.  Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians , 2008, Genes and Immunity.

[24]  M. van der Burg,et al.  An antibody-deficiency syndrome due to mutations in the CD19 gene. , 2006, The New England journal of medicine.

[25]  F. Holsboer,et al.  More CLEC16A gene variants associated with multiple sclerosis , 2011, Acta neurologica Scandinavica.

[26]  O. Delaneau,et al.  A linear complexity phasing method for thousands of genomes , 2011, Nature Methods.

[27]  Yusuke Nakamura,et al.  Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population , 2012, Nature Genetics.

[28]  Michael Krawczak,et al.  PopGen – Bevölkerungsbasierte Rekrutierung von Patienten und Kontrollen für die Untersuchung komplexer Genotyp-Phänotyp-Beziehungen (PopGen – Population-based Recruitment of Patients and Controls for the Analysis of Complex Genotype-phenotype Relationships) , 2007, it Inf. Technol..

[29]  Matti Pirinen,et al.  Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity , 2012 .

[30]  M. Ban,et al.  Exploring the CLEC16A gene reveals a MS-associated variant with correlation to the relative expression of CLEC16A isoforms in thymus , 2011, Genes and Immunity.

[31]  J. Ott,et al.  A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjögren's syndrome at 7q11.23 , 2013, Nature Genetics.

[32]  K. Siminovitch,et al.  Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes , 2012, Genes and Immunity.

[33]  P. Sham,et al.  Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians. , 2013, American journal of human genetics.

[34]  M. Nöthen,et al.  Follow-up study of the first genome-wide association scan in alopecia areata: IL13 and KIAA0350 as susceptibility loci supported with genome-wide significance. , 2012, The Journal of investigative dermatology.

[35]  Vincent Plagnol,et al.  Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci , 2008, Nature Genetics.

[36]  B. Lie,et al.  A CLEC16A variant confers risk for juvenile idiopathic arthritis and anti-cyclic citrullinated peptide antibody negative rheumatoid arthritis , 2009, Annals of the rheumatic diseases.

[37]  David J Balding,et al.  A genome-wide meta-analysis of genetic variants associated with allergic rhinitis and grass sensitization and their interaction with birth order. , 2011, The Journal of allergy and clinical immunology.

[38]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[39]  C. Gieger,et al.  KORA-gen - Resource for Population Genetics, Controls and a Broad Spectrum of Disease Phenotypes , 2005 .

[40]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[41]  T. Maruyama,et al.  Association of type 1 diabetes with two Loci on 12q13 and 16p13 and the influence coexisting thyroid autoimmunity in Japanese. , 2009, The Journal of clinical endocrinology and metabolism.

[42]  Simon C. Potter,et al.  Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis , 2011, Nature.

[43]  W. Pickl,et al.  B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ. , 2013, Blood.

[44]  A. Diantonio,et al.  Drosophila Golgi membrane protein Ema promotes autophagosomal growth and function , 2012, Proceedings of the National Academy of Sciences.

[45]  Michael Krawczak,et al.  PopGen: Population-Based Recruitment of Patients and Controls for the Analysis of Complex Genotype-Phenotype Relationships , 2006, Public Health Genomics.

[46]  Erika Salvi,et al.  Genome-Wide Scan Identifies TNIP1, PSORS1C1, and RHOB as Novel Risk Loci for Systemic Sclerosis , 2011, PLoS genetics.

[47]  T. Maruyama,et al.  Analysis of the HLA and non‐HLA susceptibility loci in Japanese type 1 diabetes , 2011, Diabetes/metabolism research and reviews.

[48]  Philip S Rosenberg,et al.  PGA: power calculator for case-control genetic association analyses , 2008, BMC Genetics.

[49]  Jon W. Huss,et al.  BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources , 2009, Genome Biology.

[50]  A. Orth,et al.  Large-scale analysis of the human and mouse transcriptomes , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[51]  M. Ban,et al.  Evaluation of the established non-MHC multiple sclerosis loci in an Indian population , 2011, Multiple sclerosis.

[52]  A. Schäffer,et al.  Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans , 2005, Nature Genetics.

[53]  Jun S. Liu,et al.  Genetics of rheumatoid arthritis contributes to biology and drug discovery , 2013 .

[54]  H. Harbo,et al.  From Identification to Characterization of the Multiple Sclerosis Susceptibility Gene CLEC16A , 2013, International journal of molecular sciences.

[55]  Soumya Raychaudhuri,et al.  Risk for myasthenia gravis maps to a 151Pro→Ala change in TNIP1 and to human leukocyte antigen‐B*08 , 2012, Annals of neurology.

[56]  Annette Lee,et al.  Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency , 2010, Nature Genetics.

[57]  S. Gabriel,et al.  Risk alleles for multiple sclerosis identified by a genomewide study. , 2007, The New England journal of medicine.

[58]  P. Deloukas,et al.  Multiple common variants for celiac disease influencing immune gene expression , 2010, Nature Genetics.

[59]  Min Liu,et al.  The Correlation between the CLEC16A Gene and Genetic Susceptibility to Type 1 Diabetes in Chinese Children , 2012, International journal of endocrinology.

[60]  S. Frøland,et al.  Persistent activation of the tumor necrosis factor system in a subgroup of patients with common variable immunodeficiency--possible immunologic and clinical consequences. , 1996, Blood.

[61]  R. A. Bailey,et al.  Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes , 2007, Nature Genetics.

[62]  F. Cucca,et al.  Variation within the CLEC16A gene shows consistent disease association with both multiple sclerosis and type 1 diabetes in Sardinia , 2009, Genes and Immunity.

[63]  R. Bende,et al.  CD20 deficiency in humans results in impaired T cell-independent antibody responses. , 2010, The Journal of clinical investigation.

[64]  David N. Groff,et al.  The Diabetes Susceptibility Gene Clec16a Regulates Mitophagy , 2014, Cell.

[65]  P. D. De Jager,et al.  Multiple sclerosis susceptibility alleles in African Americans , 2009, Genes and Immunity.

[66]  Chuong B. Do,et al.  A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci , 2013, Nature Genetics.

[67]  A. Schäffer,et al.  Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency , 2003, Nature Immunology.

[68]  Joseph T. Glessner,et al.  A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene , 2007, Nature.

[69]  Karl-Heinz Jöckel,et al.  Variation at 3p24.1 and 6q23.3 influences the risk of Hodgkin’s Lymphoma , 2013, Nature Communications.

[70]  L. Alfredsson,et al.  Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases , 2003, Annals of the rheumatic diseases.

[71]  L. Peltonen,et al.  Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis , 2011, Nature Genetics.

[72]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[73]  Richard W. Daniels,et al.  The novel endosomal membrane protein Ema interacts with the class C Vps–HOPS complex to promote endosomal maturation , 2010, The Journal of cell biology.

[74]  S. Gabriel,et al.  Two independent alleles at 6q23 associated with risk of rheumatoid arthritis , 2007, Nature Genetics.

[75]  Robert M. Plenge,et al.  Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci , 2011, PLoS genetics.

[76]  Ludwig Kappos,et al.  Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci , 2009, Nature Genetics.

[77]  Bodo Grimbacher,et al.  Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. , 2012, American journal of human genetics.

[78]  L. Liang,et al.  Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions , 2012, Nature Genetics.

[79]  Y. Liu,et al.  Intron polymorphism in the KIAA0350 gene is reproducibly associated with susceptibility to type 1 diabetes (T1D) in the Han Chinese population , 2009, Clinical endocrinology.

[80]  J. Sterne,et al.  Essential Medical Statistics , 2003 .

[81]  C. Cunningham-Rundles,et al.  Common variable immunodeficiency: clinical and immunological features of 248 patients. , 1999, Clinical immunology.

[82]  Xiaohui Xie,et al.  Identifying novel constrained elements by exploiting biased substitution patterns , 2009, Bioinform..

[83]  M. van der Burg,et al.  CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. , 2010, The Journal of clinical investigation.

[84]  H. Kanegane,et al.  Primary Immunodeficiency Diseases Report of an IUIS Scientific Committee , 1999 .

[85]  David Altshuler,et al.  Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus , 2008, Nature Genetics.

[86]  S. Batzoglou,et al.  Distribution and intensity of constraint in mammalian genomic sequence. , 2005, Genome research.

[87]  ENCODEConsortium,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[88]  L. Hammarström,et al.  Shared HLA class II-associated genetic susceptibility and resistance, related to the HLA-DQB1 gene, in IgA deficiency and common variable immunodeficiency. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[89]  S. Holland,et al.  MonoMAC syndrome in a patient with a GATA2 mutation: case report and review of the literature. , 2013, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[90]  P. Donnelly,et al.  A new multipoint method for genome-wide association studies by imputation of genotypes , 2007, Nature Genetics.

[91]  T. Egeland,et al.  Polymorphisms in CLEC16A and CIITA at 16p13 are associated with primary adrenal insufficiency. , 2008, The Journal of clinical endocrinology and metabolism.

[92]  Miles Parkes,et al.  Genetic insights into common pathways and complex relationships among immune-mediated diseases , 2013, Nature Reviews Genetics.

[93]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[94]  J. Todd,et al.  Genetic Analysis of Adult-Onset Autoimmune Diabetes , 2011, Diabetes.

[95]  J. Haines,et al.  Interrogating the complex role of chromosome 16p13.13 in multiple sclerosis susceptibility: independent genetic signals in the CIITA-CLEC16A-SOCS1 gene complex. , 2011, Human molecular genetics.

[96]  A. Janssens,et al.  Replication of CD58 and CLEC16A as genome-wide significant risk genes for multiple sclerosis , 2009, Journal of Human Genetics.

[97]  Buhm Han,et al.  Imputing Amino Acid Polymorphisms in Human Leukocyte Antigens , 2013, PloS one.

[98]  David C. Wilson,et al.  Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease , 2012, Nature.

[99]  Sarah Edkins,et al.  Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease , 2011, Nature Genetics.

[100]  E. G. de la Concha,et al.  Chromosomal region 16p13: further evidence of increased predisposition to immune diseases , 2009, Annals of the rheumatic diseases.

[101]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.