Stratified Genetic Analysis Reveals Sex Differences In MPO-ANCA-associated Vasculitis

Diana Ekman; Bengt Sennblad; Ann Knight; Åsa Karlsson; Solbritt Rantapää-Dahlqvist; Ewa Berglin; Bernd Stegmayr; Bo Baslund; Øyvind Palm; Hilde Haukeland; Iva Gunnarsson; Annette Bruchfeld; Mårten Segelmark; Sophie Ohlsson; Aladdin J Mohammad; Anna Svärd; Rille Pullerits; Hans Herlitz; Annika Söderbergh; Roald Omdal; Roland Jonsson; Lars Rönnblom; Per Eriksson; Kerstin Lindblad-Toh; Johanna Dahlqvist

doi:10.1093/rheumatology/kead152

Stratified Genetic Analysis Reveals Sex Differences In MPO-ANCA-associated Vasculitis

Diana Ekman, Bengt Sennblad, Ann Knight, Åsa Karlsson, Solbritt Rantapää-Dahlqvist, Ewa Berglin, Bernd Stegmayr, Bo Baslund, Øyvind Palm, Hilde Haukeland, Iva Gunnarsson, Annette Bruchfeld, Mårten Segelmark, Sophie Ohlsson, Aladdin J Mohammad, Anna Svärd, Rille Pullerits, Hans Herlitz, Annika Söderbergh, Roald OmdalRoland Jonsson, Lars Rönnblom, Per Eriksson, Kerstin Lindblad-Toh, Johanna Dahlqvist^*

^*Corresponding author for this work

Department for Rheumatology and Spine Diseases

Abstract

OBJECTIVE: To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype.

METHODS: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems.

RESULTS: rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619.

CONCLUSIONS: Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.

Original language	English
Journal	Rheumatology (Oxford, England)
Volume	62
Issue number	9
Pages (from-to)	3213-3218
Number of pages	6
ISSN	1462-0324
DOIs	https://doi.org/10.1093/rheumatology/kead152
Publication status	Published - 1 Sept 2023

Keywords

Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/genetics
Antibodies, Antineutrophil Cytoplasmic/immunology
Female
Humans
Male
Myeloblastin/genetics
Peroxidase/genetics
Sex Characteristics

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10.1093/rheumatology/kead152

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Ekman, D., Sennblad, B., Knight, A., Karlsson, Å., Rantapää-Dahlqvist, S., Berglin, E., Stegmayr, B., Baslund, B., Palm, Ø., Haukeland, H., Gunnarsson, I., Bruchfeld, A., Segelmark, M., Ohlsson, S., Mohammad, A. J., Svärd, A., Pullerits, R., Herlitz, H., Söderbergh, A., ... Dahlqvist, J. (2023). Stratified Genetic Analysis Reveals Sex Differences In MPO-ANCA-associated Vasculitis. Rheumatology (Oxford, England), 62(9), 3213-3218. https://doi.org/10.1093/rheumatology/kead152

Ekman, D, Sennblad, B, Knight, A, Karlsson, Å, Rantapää-Dahlqvist, S, Berglin, E, Stegmayr, B, Baslund, B, Palm, Ø, Haukeland, H, Gunnarsson, I, Bruchfeld, A, Segelmark, M, Ohlsson, S, Mohammad, AJ, Svärd, A, Pullerits, R, Herlitz, H, Söderbergh, A, Omdal, R, Jonsson, R, Rönnblom, L, Eriksson, P, Lindblad-Toh, K & Dahlqvist, J 2023, 'Stratified Genetic Analysis Reveals Sex Differences In MPO-ANCA-associated Vasculitis', Rheumatology (Oxford, England), vol. 62, no. 9, pp. 3213-3218. https://doi.org/10.1093/rheumatology/kead152

@article{f7321944f3334986ad16614214405cb5,

title = "Stratified Genetic Analysis Reveals Sex Differences In MPO-ANCA-associated Vasculitis",

abstract = "OBJECTIVE: To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype.METHODS: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems.RESULTS: rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619.CONCLUSIONS: Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.",

keywords = "Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/genetics, Antibodies, Antineutrophil Cytoplasmic/immunology, Female, Humans, Male, Myeloblastin/genetics, Peroxidase/genetics, Sex Characteristics",

author = "Diana Ekman and Bengt Sennblad and Ann Knight and {\AA}sa Karlsson and Solbritt Rantap{\"a}{\"a}-Dahlqvist and Ewa Berglin and Bernd Stegmayr and Bo Baslund and {\O}yvind Palm and Hilde Haukeland and Iva Gunnarsson and Annette Bruchfeld and M{\aa}rten Segelmark and Sophie Ohlsson and Mohammad, {Aladdin J} and Anna Sv{\"a}rd and Rille Pullerits and Hans Herlitz and Annika S{\"o}derbergh and Roald Omdal and Roland Jonsson and Lars R{\"o}nnblom and Per Eriksson and Kerstin Lindblad-Toh and Johanna Dahlqvist",

note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.",

year = "2023",

month = sep,

day = "1",

doi = "10.1093/rheumatology/kead152",

language = "English",

volume = "62",

pages = "3213--3218",

journal = "Rheumatology (Oxford, England)",

issn = "1462-0324",

publisher = "Oxford University Press",

number = "9",

}

TY - JOUR

T1 - Stratified Genetic Analysis Reveals Sex Differences In MPO-ANCA-associated Vasculitis

AU - Ekman, Diana

AU - Sennblad, Bengt

AU - Knight, Ann

AU - Karlsson, Åsa

AU - Rantapää-Dahlqvist, Solbritt

AU - Berglin, Ewa

AU - Stegmayr, Bernd

AU - Baslund, Bo

AU - Palm, Øyvind

AU - Haukeland, Hilde

AU - Gunnarsson, Iva

AU - Bruchfeld, Annette

AU - Segelmark, Mårten

AU - Ohlsson, Sophie

AU - Mohammad, Aladdin J

AU - Svärd, Anna

AU - Pullerits, Rille

AU - Herlitz, Hans

AU - Söderbergh, Annika

AU - Omdal, Roald

AU - Jonsson, Roland

AU - Rönnblom, Lars

AU - Eriksson, Per

AU - Lindblad-Toh, Kerstin

AU - Dahlqvist, Johanna

PY - 2023/9/1

Y1 - 2023/9/1

N2 - OBJECTIVE: To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype.METHODS: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems.RESULTS: rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619.CONCLUSIONS: Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.

AB - OBJECTIVE: To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype.METHODS: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems.RESULTS: rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619.CONCLUSIONS: Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.

KW - Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/genetics

KW - Antibodies, Antineutrophil Cytoplasmic/immunology

KW - Female

KW - Humans

KW - Male

KW - Myeloblastin/genetics

KW - Peroxidase/genetics

KW - Sex Characteristics

UR - http://www.scopus.com/inward/record.url?scp=85171998269&partnerID=8YFLogxK

U2 - 10.1093/rheumatology/kead152

DO - 10.1093/rheumatology/kead152

M3 - Journal article

C2 - 37004177

SN - 1462-0324

VL - 62

SP - 3213

EP - 3218

JO - Rheumatology (Oxford, England)

JF - Rheumatology (Oxford, England)

IS - 9

ER -

Stratified Genetic Analysis Reveals Sex Differences In MPO-ANCA-associated Vasculitis

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