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Nat Genet. 2016 Nov;48(11):1425-1429. doi: 10.1038/ng.3675. Epub 2016 Oct 10.

Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency.

Author information

1
Department of Human Genetics, Genentech, Inc., South San Francisco, California, USA.
2
Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, California, USA.
3
Department of Biochemistry, School of Medicine, University of California, Davis, Davis, California, USA.
4
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Cambridge, UK.
5
Department of Immunology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, IdISSC, Madrid, Spain.
6
Department of Immunology, Hospital San Pedro de Alcántara, Cáceres, Spain.
7
Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain.
8
Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Brescia, Italy.
9
Institute for Molecular Medicine, A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Brescia, Italy.
10
Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden.
11
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Brno, Czech Republic.
12
Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
13
Department of Clinical Immunology and Allergy, Faculty of Medicine, Masaryk University, St. Anne's University Hospital, Brno, Czech Republic.
14
Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.
15
Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Stockholm, Sweden.

Abstract

Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Europeans. Our genome-wide association study (GWAS) meta-analysis of 1,635 patients with IgAD and 4,852 controls identified four new significant (P < 5 × 10-8) loci and association with a rare IFIH1 variant (p.Ile923Val). Peak new variants (PVT1, P = 4.3 × 10-11; ATG13-AMBRA1, P = 6.7 × 10-10; AHI1, P = 8.4 × 10-10; CLEC16A, P = 1.4 × 10-9) overlapped with autoimmune markers (3/4) and correlated with 21 putative regulatory variants, including expression quantitative trait loci (eQTLs) for AHI1 and DEXI and DNase hypersensitivity sites in FOXP3+ regulatory T cells. Pathway analysis of the meta-analysis results showed striking association with the KEGG pathway for IgA production (pathway P < 0.0001), with 22 of the 30 annotated pathway genes containing at least one variant with P ≤ 0.05 in the IgAD meta-analysis. These data suggest that a complex network of genetic effects, including genes known to influence the biology of IgA production, contributes to IgAD.

PMID:
27723758
PMCID:
PMC5086090
DOI:
10.1038/ng.3675
[Indexed for MEDLINE]
Free PMC Article

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