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

Publication ,  Journal Article
Xie, G; Roshandel, D; Sherva, R; Monach, PA; Lu, EY; Kung, T; Carrington, K; Zhang, SS; Pulit, SL; Ripke, S; Carette, S; Dellaripa, PF ...
Published in: Arthritis Rheum
September 2013

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.

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Published In

Arthritis Rheum

DOI

EISSN

1529-0131

Publication Date

September 2013

Volume

65

Issue

9

Start / End Page

2457 / 2468

Location

United States

Related Subject Headings

  • Semaphorins
  • Polymorphism, Single Nucleotide
  • Male
  • Major Histocompatibility Complex
  • Humans
  • Haplotypes
  • HLA-DP beta-Chains
  • Granulomatosis with Polyangiitis
  • Genotype
  • Genome-Wide Association Study
 

Citation

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Xie, G., Roshandel, D., Sherva, R., Monach, P. A., Lu, E. Y., Kung, T., … Siminovitch, K. A. (2013). Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis. Arthritis Rheum, 65(9), 2457–2468. https://doi.org/10.1002/art.38036
Xie, Gang, Delnaz Roshandel, Richard Sherva, Paul A. Monach, Emily Yue Lu, Tabitha Kung, Keisha Carrington, et al. “Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis.Arthritis Rheum 65, no. 9 (September 2013): 2457–68. https://doi.org/10.1002/art.38036.
Xie G, Roshandel D, Sherva R, Monach PA, Lu EY, Kung T, et al. Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis. Arthritis Rheum. 2013 Sep;65(9):2457–68.
Xie, Gang, et al. “Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis.Arthritis Rheum, vol. 65, no. 9, Sept. 2013, pp. 2457–68. Pubmed, doi:10.1002/art.38036.
Xie G, Roshandel D, Sherva R, Monach PA, Lu EY, Kung T, Carrington K, Zhang SS, Pulit SL, Ripke S, Carette S, Dellaripa PF, Edberg JC, Hoffman GS, Khalidi N, Langford CA, Mahr AD, St Clair EW, Seo P, Specks U, Spiera RF, Stone JH, Ytterberg SR, Raychaudhuri S, de Bakker PIW, Farrer LA, Amos CI, Merkel PA, Siminovitch KA. Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis. Arthritis Rheum. 2013 Sep;65(9):2457–2468.
Journal cover image

Published In

Arthritis Rheum

DOI

EISSN

1529-0131

Publication Date

September 2013

Volume

65

Issue

9

Start / End Page

2457 / 2468

Location

United States

Related Subject Headings

  • Semaphorins
  • Polymorphism, Single Nucleotide
  • Male
  • Major Histocompatibility Complex
  • Humans
  • Haplotypes
  • HLA-DP beta-Chains
  • Granulomatosis with Polyangiitis
  • Genotype
  • Genome-Wide Association Study