Association of Granulomatosis With Polyangiitis (Wegener's) With HLA–DPB1*04 and SEMA6A Gene Variants: Evidence From Genome‐Wide Analysis
Open Access
- 5 June 2013
- journal article
- vasculitis
- Published by Wiley in Arthritis & Rheumatism
- Vol. 65 (9), 2457-2468
- https://doi.org/10.1002/art.38036
Abstract
Objective To identify genetic determinants of granulomatosis with polyangiitis (Wegener's) (GPA). Methods We carried out a genome‐wide association study (GWAS) of 492 GPA cases and 1,506 healthy controls (white subjects of European descent), followed by replication analysis of the most strongly associated signals in an independent cohort of 528 GPA cases and 1,228 controls. Results Genome‐wide significant associations were identified in 32 single‐nucleotide polymorphic (SNP) markers across the HLA region, the majority of which were located in the HLA–DPB1 and HLA–DPA1 genes encoding the class II major histocompatibility complex (MHC) DPβ chain 1 and DPα chain 1 proteins, respectively. Peak association signals in these 2 genes, emanating from SNPs rs9277554 (for DPβ chain 1) and rs9277341 (DPα chain 1) were strongly replicated in an independent cohort (in the combined analysis of the initial cohort and the replication cohort, P = 1.92 × 10−50 and 2.18 × 10−39, respectively). Imputation of classic HLA alleles and conditional analyses revealed that the SNP association signal was fully accounted for by the classic HLA–DPB1*04 allele. An independent single SNP, rs26595, near SEMA6A (the gene for semaphorin 6A) on chromosome 5, was also associated with GPA, reaching genome‐wide significance in a combined analysis of the GWAS and replication cohorts (P = 2.09 × 10−8). Conclusion We identified the SEMA6A and HLA–DP loci as significant contributors to risk for GPA, with the HLA–DPB1*04 allele almost completely accounting for the MHC association. These two associations confirm the critical role of immunogenetic factors in the development of GPA.Keywords
Funding Information
- Erna Baird Memorial Grant
- Vasculitis Foundation Canada
- Ontario Research Fund (RE-01-061)
- Vasculitis Foundation
- Vasculitis Clinical Research Consortium (NIH grants U54-RR-019497, U54-AR-47785, R01-AR-047799, R01-AG025259)
- Arthritis Foundation
- Société Nationale Française de Médecine Interne
- Vidi Award from The Netherlands Organization for Scientific Research
- Mid-Career Development Award in Clinical Investigation (NIH-National Institute of Arthritis and Musculoskeletal and Skin Diseases) (K24-AR-02224)
This publication has 52 references indexed in Scilit:
- Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritisNature Genetics, 2012
- Mapping copy number variation by population-scale genome sequencingNature, 2011
- The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide PresentationScience, 2010
- Alpha1‐antitrypsin deficiency–related alleles Z and S and the risk of Wegener's granulomatosisArthritis & Rheumatism, 2010
- A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association StudiesPLoS Genetics, 2009
- Overview of the MHC fine mapping dataDiabetes, Obesity and Metabolism, 2009
- Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1Nature Genetics, 2008
- PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage AnalysesAmerican Journal of Human Genetics, 2007
- FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunityNature Genetics, 2007
- Principal components analysis corrects for stratification in genome-wide association studiesNature Genetics, 2006