Genetics of toll like receptor 9 in ANCA associated vasculitides

C A Husmann; J. U. Holle; F Moosig; S Mueller; B Wilde; J W Cohen Tervaert; L Harper; G Assmann; W L Gross; J T Epplen; S Wieczorek

doi:10.1136/annrheumdis-2012-202803

Genetics of toll like receptor 9 in ANCA associated vasculitides

C A Husmann, J. U. Holle, F Moosig, S Mueller, B Wilde, J W Cohen Tervaert, L Harper, G Assmann, W L Gross, J T Epplen, S Wieczorek

Applied Health Research

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24 Citations (Scopus)

Abstract

OBJECTIVES: To investigate the contribution of genetic polymorphisms of toll like receptor (TLR) 9 and related genes on the susceptibility and clinical manifestation of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV).

METHODS: Four single nucleotide polymorphisms (SNPs) in TLR9 were genotyped in 863 German AAV cases and 1344 healthy controls. Significant results were replicated in a cohort of 426 Dutch and British AAV cases. 11 polymorphisms in TLR9 related genes were studied concomitantly.

RESULTS: A strong association of TLR9 genotypes and haplotypes with granulomatosis with polyangiitis was observed as well as a contrariwise association with microscopic polyangiitis. The association was confirmed when cases were compared according to ANCA status rather than to clinical entity. This was partly replicated in the second cohort leading to a striking overall difference in TLR9 allele/haplotype frequencies between proteinase 3 (PR3) ANCA+ and myeloperoxidase (MPO) ANCA+ cases (p=0.00000398, pc=0.000016, OR 1.68 (95% CI 1.35 to 2.1) for rs352140; p=0.000011, pc=0.000044, OR 1.64 (95% CI 1.31 to 2.04) for a 3-SNP haplotype). No significant association or epistatic effect was detected for TLR9 related genes: interleukin 6, interleukin 23 receptor, myeloid differentiation primary response 88, TNF receptor-associated factor 6, interleukin-1 receptor-associated kinase 4, discs large homolog 5 and nucleotide-binding oligomerisation domain containing 2.

CONCLUSIONS: We provide further evidence that PR3-ANCA+ AAV differs genetically from MPO-ANCA+ AAV. TLR9 signalling may be involved in disease pathology, favouring models of infectious agents triggering AAV development.

Original language	English
Pages (from-to)	890-896
Number of pages	7
Journal	Annals of the Rheumatic Diseases
Volume	73
Issue number	5
Early online date	16 Apr 2013
DOIs	https://doi.org/10.1136/annrheumdis-2012-202803
Publication status	Published - 1 May 2014

Keywords

Adult
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Case-Control Studies
Female
Genetic Predisposition to Disease
Genotype
Humans
Linkage Disequilibrium
Male
Polymorphism, Single Nucleotide
Toll-Like Receptor 9

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http://dx.doi.org/10.1136/annrheumdis-2012-202803Licence: None: All rights reserved

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@article{981b71f4bc5041cab7ea130ec825b28c,

title = "Genetics of toll like receptor 9 in ANCA associated vasculitides",

abstract = "OBJECTIVES: To investigate the contribution of genetic polymorphisms of toll like receptor (TLR) 9 and related genes on the susceptibility and clinical manifestation of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV).METHODS: Four single nucleotide polymorphisms (SNPs) in TLR9 were genotyped in 863 German AAV cases and 1344 healthy controls. Significant results were replicated in a cohort of 426 Dutch and British AAV cases. 11 polymorphisms in TLR9 related genes were studied concomitantly.RESULTS: A strong association of TLR9 genotypes and haplotypes with granulomatosis with polyangiitis was observed as well as a contrariwise association with microscopic polyangiitis. The association was confirmed when cases were compared according to ANCA status rather than to clinical entity. This was partly replicated in the second cohort leading to a striking overall difference in TLR9 allele/haplotype frequencies between proteinase 3 (PR3) ANCA+ and myeloperoxidase (MPO) ANCA+ cases (p=0.00000398, pc=0.000016, OR 1.68 (95% CI 1.35 to 2.1) for rs352140; p=0.000011, pc=0.000044, OR 1.64 (95% CI 1.31 to 2.04) for a 3-SNP haplotype). No significant association or epistatic effect was detected for TLR9 related genes: interleukin 6, interleukin 23 receptor, myeloid differentiation primary response 88, TNF receptor-associated factor 6, interleukin-1 receptor-associated kinase 4, discs large homolog 5 and nucleotide-binding oligomerisation domain containing 2.CONCLUSIONS: We provide further evidence that PR3-ANCA+ AAV differs genetically from MPO-ANCA+ AAV. TLR9 signalling may be involved in disease pathology, favouring models of infectious agents triggering AAV development.",

keywords = "Adult, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Case-Control Studies, Female, Genetic Predisposition to Disease, Genotype, Humans, Linkage Disequilibrium, Male, Polymorphism, Single Nucleotide, Toll-Like Receptor 9",

author = "Husmann, {C A} and Holle, {J. U.} and F Moosig and S Mueller and B Wilde and {Cohen Tervaert}, {J W} and L Harper and G Assmann and Gross, {W L} and Epplen, {J T} and S Wieczorek",

year = "2014",

month = may,

day = "1",

doi = "10.1136/annrheumdis-2012-202803",

language = "English",

volume = "73",

pages = "890--896",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

publisher = "BMJ Publishing Group",

number = "5",

}

TY - JOUR

T1 - Genetics of toll like receptor 9 in ANCA associated vasculitides

AU - Husmann, C A

AU - Holle, J. U.

AU - Moosig, F

AU - Mueller, S

AU - Wilde, B

AU - Cohen Tervaert, J W

AU - Harper, L

AU - Assmann, G

AU - Gross, W L

AU - Epplen, J T

AU - Wieczorek, S

PY - 2014/5/1

Y1 - 2014/5/1

N2 - OBJECTIVES: To investigate the contribution of genetic polymorphisms of toll like receptor (TLR) 9 and related genes on the susceptibility and clinical manifestation of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV).METHODS: Four single nucleotide polymorphisms (SNPs) in TLR9 were genotyped in 863 German AAV cases and 1344 healthy controls. Significant results were replicated in a cohort of 426 Dutch and British AAV cases. 11 polymorphisms in TLR9 related genes were studied concomitantly.RESULTS: A strong association of TLR9 genotypes and haplotypes with granulomatosis with polyangiitis was observed as well as a contrariwise association with microscopic polyangiitis. The association was confirmed when cases were compared according to ANCA status rather than to clinical entity. This was partly replicated in the second cohort leading to a striking overall difference in TLR9 allele/haplotype frequencies between proteinase 3 (PR3) ANCA+ and myeloperoxidase (MPO) ANCA+ cases (p=0.00000398, pc=0.000016, OR 1.68 (95% CI 1.35 to 2.1) for rs352140; p=0.000011, pc=0.000044, OR 1.64 (95% CI 1.31 to 2.04) for a 3-SNP haplotype). No significant association or epistatic effect was detected for TLR9 related genes: interleukin 6, interleukin 23 receptor, myeloid differentiation primary response 88, TNF receptor-associated factor 6, interleukin-1 receptor-associated kinase 4, discs large homolog 5 and nucleotide-binding oligomerisation domain containing 2.CONCLUSIONS: We provide further evidence that PR3-ANCA+ AAV differs genetically from MPO-ANCA+ AAV. TLR9 signalling may be involved in disease pathology, favouring models of infectious agents triggering AAV development.

AB - OBJECTIVES: To investigate the contribution of genetic polymorphisms of toll like receptor (TLR) 9 and related genes on the susceptibility and clinical manifestation of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV).METHODS: Four single nucleotide polymorphisms (SNPs) in TLR9 were genotyped in 863 German AAV cases and 1344 healthy controls. Significant results were replicated in a cohort of 426 Dutch and British AAV cases. 11 polymorphisms in TLR9 related genes were studied concomitantly.RESULTS: A strong association of TLR9 genotypes and haplotypes with granulomatosis with polyangiitis was observed as well as a contrariwise association with microscopic polyangiitis. The association was confirmed when cases were compared according to ANCA status rather than to clinical entity. This was partly replicated in the second cohort leading to a striking overall difference in TLR9 allele/haplotype frequencies between proteinase 3 (PR3) ANCA+ and myeloperoxidase (MPO) ANCA+ cases (p=0.00000398, pc=0.000016, OR 1.68 (95% CI 1.35 to 2.1) for rs352140; p=0.000011, pc=0.000044, OR 1.64 (95% CI 1.31 to 2.04) for a 3-SNP haplotype). No significant association or epistatic effect was detected for TLR9 related genes: interleukin 6, interleukin 23 receptor, myeloid differentiation primary response 88, TNF receptor-associated factor 6, interleukin-1 receptor-associated kinase 4, discs large homolog 5 and nucleotide-binding oligomerisation domain containing 2.CONCLUSIONS: We provide further evidence that PR3-ANCA+ AAV differs genetically from MPO-ANCA+ AAV. TLR9 signalling may be involved in disease pathology, favouring models of infectious agents triggering AAV development.

KW - Adult

KW - Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis

KW - Case-Control Studies

KW - Female

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Humans

KW - Linkage Disequilibrium

KW - Male

KW - Polymorphism, Single Nucleotide

KW - Toll-Like Receptor 9

U2 - 10.1136/annrheumdis-2012-202803

DO - 10.1136/annrheumdis-2012-202803

M3 - Article

C2 - 23592712

SN - 0003-4967

VL - 73

SP - 890

EP - 896

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 5

ER -

Genetics of toll like receptor 9 in ANCA associated vasculitides

Abstract

Keywords

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