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

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 SpecksRobert 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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2457-2468
Number of pages12
JournalArthritis and Rheumatism
Volume65
Issue number9
DOIs
StatePublished - Aug 2013

Fingerprint

Semaphorins
Granulomatosis with Polyangiitis
Nucleotides
Genome-Wide Association Study
Alleles
Genome
Major Histocompatibility Complex
HLA-DP Antigens
Genes
Immunogenetics
Chromosomes, Human, Pair 5
MHC Class II Genes
Single Nucleotide Polymorphism
Cohort Studies
HLA-DPB1 antigen
Proteins

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants : Evidence grom genome-wide analysis. / Xie, Gang; Roshandel, Delnaz; Sherva, Richard; Monach, Paul A.; Lu, Emily Yue; Kung, Tabitha; Carrington, Keisha; Zhang, Steven S.; Pulit, Sara L.; Ripke, Stephan; Carette, Simon; Dellaripa, Paul F.; Edberg, Jeffrey C.; Hoffman, Gary S.; Khalidi, Nader; Langford, Carol A.; Mahr, Alfred D.; St.clair, E. William; Seo, Philip; Specks, Ulrich; Spiera, Robert F.; Stone, John H.; Ytterberg, Steven R; Raychaudhuri, Soumya; De Bakker, Paul I W; Farrer, Lindsay A.; Amos, Christopher I.; Merkel, Peter A.; Siminovitch, Katherine A.

In: Arthritis and Rheumatism, Vol. 65, No. 9, 08.2013, p. 2457-2468.

Research output: Contribution to journalArticle

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 2013, 'Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: Evidence grom genome-wide analysis', Arthritis and Rheumatism, vol. 65, no. 9, pp. 2457-2468. https://doi.org/10.1002/art.38036
Xie, Gang ; Roshandel, Delnaz ; Sherva, Richard ; Monach, Paul A. ; Lu, Emily Yue ; Kung, Tabitha ; Carrington, Keisha ; Zhang, Steven S. ; Pulit, Sara L. ; Ripke, Stephan ; Carette, Simon ; Dellaripa, Paul F. ; Edberg, Jeffrey C. ; Hoffman, Gary S. ; Khalidi, Nader ; Langford, Carol A. ; Mahr, Alfred D. ; St.clair, E. William ; Seo, Philip ; Specks, Ulrich ; Spiera, Robert F. ; Stone, John H. ; Ytterberg, Steven R ; Raychaudhuri, Soumya ; De Bakker, Paul I W ; Farrer, Lindsay A. ; Amos, Christopher I. ; Merkel, Peter A. ; Siminovitch, Katherine A. / Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants : Evidence grom genome-wide analysis. In: Arthritis and Rheumatism. 2013 ; Vol. 65, No. 9. pp. 2457-2468.
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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.",
author = "Gang Xie and Delnaz Roshandel and Richard Sherva and Monach, {Paul A.} and Lu, {Emily Yue} and Tabitha Kung and Keisha Carrington and Zhang, {Steven S.} and Pulit, {Sara L.} and Stephan Ripke and Simon Carette and Dellaripa, {Paul F.} and Edberg, {Jeffrey C.} and Hoffman, {Gary S.} and Nader Khalidi and Langford, {Carol A.} and Mahr, {Alfred D.} and St.clair, {E. William} and Philip Seo and Ulrich Specks and Spiera, {Robert F.} and Stone, {John H.} and Ytterberg, {Steven R} and Soumya Raychaudhuri and {De Bakker}, {Paul I W} and Farrer, {Lindsay A.} and Amos, {Christopher I.} and Merkel, {Peter A.} and Siminovitch, {Katherine A.}",
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T1 - Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants

T2 - Evidence grom genome-wide analysis

AU - Xie, Gang

AU - Roshandel, Delnaz

AU - Sherva, Richard

AU - Monach, Paul A.

AU - Lu, Emily Yue

AU - Kung, Tabitha

AU - Carrington, Keisha

AU - Zhang, Steven S.

AU - Pulit, Sara L.

AU - Ripke, Stephan

AU - Carette, Simon

AU - Dellaripa, Paul F.

AU - Edberg, Jeffrey C.

AU - Hoffman, Gary S.

AU - Khalidi, Nader

AU - Langford, Carol A.

AU - Mahr, Alfred D.

AU - St.clair, E. William

AU - Seo, Philip

AU - Specks, Ulrich

AU - Spiera, Robert F.

AU - Stone, John H.

AU - Ytterberg, Steven R

AU - Raychaudhuri, Soumya

AU - De Bakker, Paul I W

AU - Farrer, Lindsay A.

AU - Amos, Christopher I.

AU - Merkel, Peter A.

AU - Siminovitch, Katherine A.

PY - 2013/8

Y1 - 2013/8

N2 - 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.

AB - 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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