Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis.

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.

• Authors: Gang Xie, Delnaz Roshandel, Richard Sherva, Paul A Monach, Emily Yue Lu, Tabitha Kung, Keisha Carrington, Steven S Zhang, Sara L Pulit, Stephan Ripke, Simon Carette, Paul F Dellaripa, Jeffrey C Edberg, Gary S Hoffman, Nader Khalidi, Carol A Langford, Alfred D Mahr, E William St Clair, Philip Seo, Ulrich Specks, Robert F Spiera, John H Stone, Steven R Ytterberg, Soumya Raychaudhuri, Paul I W de Bakker, Lindsay A Farrer, Christopher I Amos, Peter A Merkel, Katherine A Siminovitch
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 65 Issue 9 Pg. 2457-68 (Sep 2013) ISSN: 1529-0131 [Electronic] United States
• PMID: 23740775 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 by the American College of Rheumatology.

Chemical References

• HLA-DP beta-Chains
• HLA-DPB1*04:01 antigen
• SEMA6A protein, human
• Semaphorins

Topics

• Adult
• Alleles
• Female
• Gene Frequency
• Genetic Association Studies
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Genotype
• Granulomatosis with Polyangiitis (genetics, immunology)
• HLA-DP beta-Chains (genetics)
• Haplotypes
• Humans
• Major Histocompatibility Complex
• Male
• Polymorphism, Single Nucleotide
• Semaphorins (genetics)