Genetically distinct subsets within ANCA-associated vasculitis.
BACKGROUND
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis.


METHODS
A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria.


RESULTS
We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding α(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P=6.2×10(-89), P=5.6×10(-12,) and P=2.6×10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P=2.1×10(-8)).


CONCLUSIONS
This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.).
Cambridge Institute for Medical Research, and Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom. kgcs2@cam.ac.uk
Paul A
PA
Lyons
Tim F
TF
Rayner
Sapna
S
Trivedi
Julia U
JU
Holle
Richard A
RA
Watts
David R W
DR
Jayne
Bo
B
Baslund
Paul
P
Brenchley
Annette
A
Bruchfeld
Afzal N
AN
Chaudhry
Jan Willem
JW
Cohen Tervaert
Panos
P
Deloukas
Conleth
C
Feighery
Wolfgang L
WL
Gross
Loic
L
Guillevin
Iva
I
Gunnarsson
Lorraine
L
Harper
Zdenka
Z
Hrušková
Mark A
MA
Little
Davide
D
Martorana
Thomas
T
Neumann
Sophie
S
Ohlsson
Sandosh
S
Padmanabhan
Charles D
CD
Pusey
Alan D
AD
Salama
Jan-Stephan F
JS
Sanders
Caroline O
CO
Savage
Mårten
M
Segelmark
Coen A
CA
Stegeman
Vladimir
V
Tesař
Augusto
A
Vaglio
Stefan
S
Wieczorek
Benjamin
B
Wilde
Jochen
J
Zwerina
Andrew J
AJ
Rees
David G
DG
Clayton
Kenneth G C
KG
Smith
D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D014890:Granulomatosis with Polyangiitis / Q000235:genetics; D006682:HLA-DP Antigens / Q000235:genetics; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D055953:Microscopic Polyangiitis / Q000235:genetics; D053146:Myeloblastin / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D000515:alpha 1-Antitrypsin / Q000235:genetics
D006682:HLA-DP Antigens; D000515:alpha 1-Antitrypsin; D053146:Myeloblastin