Identification and Functional Characterization of a Novel Susceptibility Locus for Small Vessel Vasculitis with MPO-ANCA

Johanna Dahlqvist; Diana Ekman; Bengt Sennblad; Sergey V Kozyrev; Jessika Nordin; Åsa Karlsson; Jennifer R S Meadows; Erik Hellbacher; 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; Gerli Rosengren Pielberg; Lina Hultin Rosenberg; Matteo Bianchi; Eva Murén; Roald Omdal; Roland Jonsson; Maija-Leena Eloranta; Lars Rönnblom; Peter Söderkvist; Ann Knight; Per Eriksson; Kerstin Lindblad-Toh

doi:10.1093/rheumatology/keab912

Identification and Functional Characterization of a Novel Susceptibility Locus for Small Vessel Vasculitis with MPO-ANCA

Johanna Dahlqvist, Diana Ekman, Bengt Sennblad, Sergey V Kozyrev, Jessika Nordin, Åsa Karlsson, Jennifer R S Meadows, Erik Hellbacher, 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 SvärdRille Pullerits, Hans Herlitz, Annika Söderbergh, Gerli Rosengren Pielberg, Lina Hultin Rosenberg, Matteo Bianchi, Eva Murén, Roald Omdal, Roland Jonsson, Maija-Leena Eloranta, Lars Rönnblom, Peter Söderkvist, Ann Knight, Per Eriksson, Kerstin Lindblad-Toh

Research output: Contribution to journal › Article › peer-review

Abstract

OBJECTIVE: To identify and characterize genetic loci associated with the risk of developing anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV).

METHODS: Genetic association analyses were performed after Illumina sequencing of 1,853 genes and subsequent replication with genotyping of selected SNPs in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) and 1589 controls. A novel AAV-associated SNP was analysed for allele-specific effects on gene expression using luciferase reporter assay.

RESULTS: Proteinase 3 ANCA positive (PR3-ANCA+) AAV was significantly associated with two independent loci in the HLA-DPB1/A1 region (rs1042335, p= 6.3 x 1 0 -61, Odds ratio (OR)= 0.10; rs9277341, p= 1.5 x 1 0 -44, OR = 0.22) and with rs28929474 in the SERPINA1 gene (p= 2.7 x 1 0 -10, OR = 2.9). Myeloperoxidase (MPO)-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, p= 5.4 x 1 0 -25, OR = 3.7) and with a rare variant in the BACH2 gene (rs78275221, p= 7.9 x 1 0 -7, OR = 3.0), the latter a novel susceptibility locus for MPO-ANCA+ GPA/MPA. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele.

CONCLUSION: We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.

Original language	English
Pages (from-to)	3461-3470
Journal	Rheumatology (Oxford, England)
Volume	61
Issue number	8
Early online date	2021
DOIs	https://doi.org/10.1093/rheumatology/keab912
Publication status	Published - 2022

Subject classification (UKÄ)

Rheumatology and Autoimmunity
Urology and Nephrology

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10.1093/rheumatology/keab912Licence: CC BY-NC

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Dahlqvist, J., Ekman, D., Sennblad, B., Kozyrev, S. V., Nordin, J., Karlsson, Å., Meadows, J. R. S., Hellbacher, E., Rantapää-Dahlqvist, S., Berglin, E., Stegmayr, B., Baslund, B., Palm, Ø., Haukeland, H., Gunnarsson, I., Bruchfeld, A., Segelmark, M., Ohlsson, S., Mohammad, A. J., ... Lindblad-Toh, K. (2022). Identification and Functional Characterization of a Novel Susceptibility Locus for Small Vessel Vasculitis with MPO-ANCA. Rheumatology (Oxford, England), 61(8 ), 3461-3470. https://doi.org/10.1093/rheumatology/keab912

@article{9eff6e3dc4ed4003a6ce37f03928a7fa,

title = "Identification and Functional Characterization of a Novel Susceptibility Locus for Small Vessel Vasculitis with MPO-ANCA",

abstract = "OBJECTIVE: To identify and characterize genetic loci associated with the risk of developing anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV).METHODS: Genetic association analyses were performed after Illumina sequencing of 1,853 genes and subsequent replication with genotyping of selected SNPs in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) and 1589 controls. A novel AAV-associated SNP was analysed for allele-specific effects on gene expression using luciferase reporter assay.RESULTS: Proteinase 3 ANCA positive (PR3-ANCA+) AAV was significantly associated with two independent loci in the HLA-DPB1/A1 region (rs1042335, p= 6.3 x 1 0 -61, Odds ratio (OR)= 0.10; rs9277341, p= 1.5 x 1 0 -44, OR = 0.22) and with rs28929474 in the SERPINA1 gene (p= 2.7 x 1 0 -10, OR = 2.9). Myeloperoxidase (MPO)-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, p= 5.4 x 1 0 -25, OR = 3.7) and with a rare variant in the BACH2 gene (rs78275221, p= 7.9 x 1 0 -7, OR = 3.0), the latter a novel susceptibility locus for MPO-ANCA+ GPA/MPA. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele.CONCLUSION: We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.",

author = "Johanna Dahlqvist and Diana Ekman and Bengt Sennblad and Kozyrev, {Sergey V} and Jessika Nordin and {\AA}sa Karlsson and Meadows, {Jennifer R S} and Erik Hellbacher 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 {Rosengren Pielberg}, Gerli and {Hultin Rosenberg}, Lina and Matteo Bianchi and Eva Mur{\'e}n and Roald Omdal and Roland Jonsson and Maija-Leena Eloranta and Lars R{\"o}nnblom and Peter S{\"o}derkvist and Ann Knight and Per Eriksson and Kerstin Lindblad-Toh",

note = "{\textcopyright} The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.",

year = "2022",

doi = "10.1093/rheumatology/keab912",

language = "English",

volume = "61",

pages = "3461--3470",

journal = "Rheumatology (Oxford, England)",

issn = "1462-0332",

publisher = "Oxford University Press",

number = "8 ",

}

Dahlqvist, J, Ekman, D, Sennblad, B, Kozyrev, SV, Nordin, J, Karlsson, Å, Meadows, JRS, Hellbacher, E, 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, Rosengren Pielberg, G, Hultin Rosenberg, L, Bianchi, M, Murén, E, Omdal, R, Jonsson, R, Eloranta, M-L, Rönnblom, L, Söderkvist, P, Knight, A, Eriksson, P & Lindblad-Toh, K 2022, 'Identification and Functional Characterization of a Novel Susceptibility Locus for Small Vessel Vasculitis with MPO-ANCA', Rheumatology (Oxford, England), vol. 61, no. 8 , pp. 3461-3470. https://doi.org/10.1093/rheumatology/keab912

TY - JOUR

T1 - Identification and Functional Characterization of a Novel Susceptibility Locus for Small Vessel Vasculitis with MPO-ANCA

AU - Dahlqvist, Johanna

AU - Ekman, Diana

AU - Sennblad, Bengt

AU - Kozyrev, Sergey V

AU - Nordin, Jessika

AU - Karlsson, Åsa

AU - Meadows, Jennifer R S

AU - Hellbacher, Erik

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 - Rosengren Pielberg, Gerli

AU - Hultin Rosenberg, Lina

AU - Bianchi, Matteo

AU - Murén, Eva

AU - Omdal, Roald

AU - Jonsson, Roland

AU - Eloranta, Maija-Leena

AU - Rönnblom, Lars

AU - Söderkvist, Peter

AU - Knight, Ann

AU - Eriksson, Per

AU - Lindblad-Toh, Kerstin

PY - 2022

Y1 - 2022

N2 - OBJECTIVE: To identify and characterize genetic loci associated with the risk of developing anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV).METHODS: Genetic association analyses were performed after Illumina sequencing of 1,853 genes and subsequent replication with genotyping of selected SNPs in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) and 1589 controls. A novel AAV-associated SNP was analysed for allele-specific effects on gene expression using luciferase reporter assay.RESULTS: Proteinase 3 ANCA positive (PR3-ANCA+) AAV was significantly associated with two independent loci in the HLA-DPB1/A1 region (rs1042335, p= 6.3 x 1 0 -61, Odds ratio (OR)= 0.10; rs9277341, p= 1.5 x 1 0 -44, OR = 0.22) and with rs28929474 in the SERPINA1 gene (p= 2.7 x 1 0 -10, OR = 2.9). Myeloperoxidase (MPO)-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, p= 5.4 x 1 0 -25, OR = 3.7) and with a rare variant in the BACH2 gene (rs78275221, p= 7.9 x 1 0 -7, OR = 3.0), the latter a novel susceptibility locus for MPO-ANCA+ GPA/MPA. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele.CONCLUSION: We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.

AB - OBJECTIVE: To identify and characterize genetic loci associated with the risk of developing anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV).METHODS: Genetic association analyses were performed after Illumina sequencing of 1,853 genes and subsequent replication with genotyping of selected SNPs in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) and 1589 controls. A novel AAV-associated SNP was analysed for allele-specific effects on gene expression using luciferase reporter assay.RESULTS: Proteinase 3 ANCA positive (PR3-ANCA+) AAV was significantly associated with two independent loci in the HLA-DPB1/A1 region (rs1042335, p= 6.3 x 1 0 -61, Odds ratio (OR)= 0.10; rs9277341, p= 1.5 x 1 0 -44, OR = 0.22) and with rs28929474 in the SERPINA1 gene (p= 2.7 x 1 0 -10, OR = 2.9). Myeloperoxidase (MPO)-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, p= 5.4 x 1 0 -25, OR = 3.7) and with a rare variant in the BACH2 gene (rs78275221, p= 7.9 x 1 0 -7, OR = 3.0), the latter a novel susceptibility locus for MPO-ANCA+ GPA/MPA. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele.CONCLUSION: We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.

U2 - 10.1093/rheumatology/keab912

DO - 10.1093/rheumatology/keab912

M3 - Article

C2 - 34888651

SN - 1462-0332

VL - 61

SP - 3461

EP - 3470

JO - Rheumatology (Oxford, England)

JF - Rheumatology (Oxford, England)

IS - 8

ER -

Identification and Functional Characterization of a Novel Susceptibility Locus for Small Vessel Vasculitis with MPO-ANCA

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