Variants in RUNX3 contribute to susceptibility to psoriatic arthritis exhibiting further common ground with ankylosing spondylitis

Maria Apel, Steffen Uebe, John Bowes, Emiliano Giardina, Eleanor Korendowych, Kristina Juneblad, Francesca Pasutto, Arif B Ekici, Ross McManus, Pauline Ho, Ian N Bruce, Anthony W Ryan, Frank Behrens, Beate Böhm, Heiko Traupe, Jörg Lohmann, Christian Gieger, Heinz-Erich Wichmann, Leonid Padyukov, Oliver Fitzgerald & 7 others Gerd-Marie Alenius, Neil J McHugh, Giuseppe Novelli, Harald Burkhardt, Anne Barton, André Reis, Ulrike Hüffmeier

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Abstract

OBJECTIVE: Psoriatic arthritis (PsA) is a common inflammatory joint disease distinct from other chronic arthritides and frequently accompanied by psoriasis vulgaris (PsV). In a first genome-wide association study (GWAS), we were able to identify several genetic risk factors. However, even combined with previously identified factors, the genetic contribution to disease is not fully explained. Therefore we investigated further 17 loci from our GWAS which did not reach genome-wide significance levels of association in the initial analysis.

METHODS: 21 of 22 single nucleotide polymorphisms (SNPs) were successfully genotyped in independent cohorts of 1,398 PsA cases and 6,389 controls, and a group of 964 German PsV patients.

RESULTS: Association to a RUNX3 variant, rs4649038, was replicated in independent cases and controls and resulted in a combined p-value of 1.40E-08 in a Cochran-Mantel-Haenszel test and an OR of 1.24 (1.15-1.33). Further analyses based on linkage disequilibrium at RUNX3 refined the most significant association to a linkage disequilibrium (LD) block located in the first intron of one isoform. Weaker evidence for association was detected in German PsV patients (p-value 5.89E-02; OR 1.13 (1.00-1.28)), indicating a role in the skin manifestations of psoriasis.

CONCLUSION: Our analyses identified variants in RUNX3 as susceptibility factors for PsA. RUNX3 has already been implicated in susceptibility to ankylosing spondylitis, another spondylarthropathy, although its risk allele is independent from the PsA one. RUNX3 is involved in CD8 lymphocyte differentiation and therefore a good candidate for PsA and PsV as T-cell mediated diseases.
LanguageEnglish
Pages1224-1231
JournalArthritis & Rheumatism
Volume65
Issue number5
Early online date22 Apr 2013
DOIs
StatusPublished - May 2013

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Psoriatic Arthritis
Ankylosing Spondylitis
Psoriasis
Genome-Wide Association Study
Linkage Disequilibrium
Skin Manifestations
Spondylarthropathies
Joint Diseases
Introns
Arthritis
Single Nucleotide Polymorphism
Protein Isoforms
Alleles
Genome
Lymphocytes
T-Lymphocytes
Control Groups

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Apel, M., Uebe, S., Bowes, J., Giardina, E., Korendowych, E., Juneblad, K., ... Hüffmeier, U. (2013). Variants in RUNX3 contribute to susceptibility to psoriatic arthritis exhibiting further common ground with ankylosing spondylitis. Arthritis & Rheumatism, 65(5), 1224-1231. https://doi.org/10.1002/art.37885

Variants in RUNX3 contribute to susceptibility to psoriatic arthritis exhibiting further common ground with ankylosing spondylitis. / Apel, Maria; Uebe, Steffen; Bowes, John; Giardina, Emiliano; Korendowych, Eleanor; Juneblad, Kristina; Pasutto, Francesca; Ekici, Arif B; McManus, Ross; Ho, Pauline; Bruce, Ian N; Ryan, Anthony W; Behrens, Frank; Böhm, Beate; Traupe, Heiko; Lohmann, Jörg; Gieger, Christian; Wichmann, Heinz-Erich; Padyukov, Leonid; Fitzgerald, Oliver; Alenius, Gerd-Marie; McHugh, Neil J; Novelli, Giuseppe; Burkhardt, Harald; Barton, Anne; Reis, André; Hüffmeier, Ulrike.

In: Arthritis & Rheumatism, Vol. 65, No. 5, 05.2013, p. 1224-1231.

Research output: Contribution to journalArticle

Apel, M, Uebe, S, Bowes, J, Giardina, E, Korendowych, E, Juneblad, K, Pasutto, F, Ekici, AB, McManus, R, Ho, P, Bruce, IN, Ryan, AW, Behrens, F, Böhm, B, Traupe, H, Lohmann, J, Gieger, C, Wichmann, H-E, Padyukov, L, Fitzgerald, O, Alenius, G-M, McHugh, NJ, Novelli, G, Burkhardt, H, Barton, A, Reis, A & Hüffmeier, U 2013, 'Variants in RUNX3 contribute to susceptibility to psoriatic arthritis exhibiting further common ground with ankylosing spondylitis' Arthritis & Rheumatism, vol. 65, no. 5, pp. 1224-1231. https://doi.org/10.1002/art.37885
Apel, Maria ; Uebe, Steffen ; Bowes, John ; Giardina, Emiliano ; Korendowych, Eleanor ; Juneblad, Kristina ; Pasutto, Francesca ; Ekici, Arif B ; McManus, Ross ; Ho, Pauline ; Bruce, Ian N ; Ryan, Anthony W ; Behrens, Frank ; Böhm, Beate ; Traupe, Heiko ; Lohmann, Jörg ; Gieger, Christian ; Wichmann, Heinz-Erich ; Padyukov, Leonid ; Fitzgerald, Oliver ; Alenius, Gerd-Marie ; McHugh, Neil J ; Novelli, Giuseppe ; Burkhardt, Harald ; Barton, Anne ; Reis, André ; Hüffmeier, Ulrike. / Variants in RUNX3 contribute to susceptibility to psoriatic arthritis exhibiting further common ground with ankylosing spondylitis. In: Arthritis & Rheumatism. 2013 ; Vol. 65, No. 5. pp. 1224-1231.
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abstract = "OBJECTIVE: Psoriatic arthritis (PsA) is a common inflammatory joint disease distinct from other chronic arthritides and frequently accompanied by psoriasis vulgaris (PsV). In a first genome-wide association study (GWAS), we were able to identify several genetic risk factors. However, even combined with previously identified factors, the genetic contribution to disease is not fully explained. Therefore we investigated further 17 loci from our GWAS which did not reach genome-wide significance levels of association in the initial analysis. METHODS: 21 of 22 single nucleotide polymorphisms (SNPs) were successfully genotyped in independent cohorts of 1,398 PsA cases and 6,389 controls, and a group of 964 German PsV patients. RESULTS: Association to a RUNX3 variant, rs4649038, was replicated in independent cases and controls and resulted in a combined p-value of 1.40E-08 in a Cochran-Mantel-Haenszel test and an OR of 1.24 (1.15-1.33). Further analyses based on linkage disequilibrium at RUNX3 refined the most significant association to a linkage disequilibrium (LD) block located in the first intron of one isoform. Weaker evidence for association was detected in German PsV patients (p-value 5.89E-02; OR 1.13 (1.00-1.28)), indicating a role in the skin manifestations of psoriasis. CONCLUSION: Our analyses identified variants in RUNX3 as susceptibility factors for PsA. RUNX3 has already been implicated in susceptibility to ankylosing spondylitis, another spondylarthropathy, although its risk allele is independent from the PsA one. RUNX3 is involved in CD8 lymphocyte differentiation and therefore a good candidate for PsA and PsV as T-cell mediated diseases.",
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TY - JOUR

T1 - Variants in RUNX3 contribute to susceptibility to psoriatic arthritis exhibiting further common ground with ankylosing spondylitis

AU - Apel, Maria

AU - Uebe, Steffen

AU - Bowes, John

AU - Giardina, Emiliano

AU - Korendowych, Eleanor

AU - Juneblad, Kristina

AU - Pasutto, Francesca

AU - Ekici, Arif B

AU - McManus, Ross

AU - Ho, Pauline

AU - Bruce, Ian N

AU - Ryan, Anthony W

AU - Behrens, Frank

AU - Böhm, Beate

AU - Traupe, Heiko

AU - Lohmann, Jörg

AU - Gieger, Christian

AU - Wichmann, Heinz-Erich

AU - Padyukov, Leonid

AU - Fitzgerald, Oliver

AU - Alenius, Gerd-Marie

AU - McHugh, Neil J

AU - Novelli, Giuseppe

AU - Burkhardt, Harald

AU - Barton, Anne

AU - Reis, André

AU - Hüffmeier, Ulrike

PY - 2013/5

Y1 - 2013/5

N2 - OBJECTIVE: Psoriatic arthritis (PsA) is a common inflammatory joint disease distinct from other chronic arthritides and frequently accompanied by psoriasis vulgaris (PsV). In a first genome-wide association study (GWAS), we were able to identify several genetic risk factors. However, even combined with previously identified factors, the genetic contribution to disease is not fully explained. Therefore we investigated further 17 loci from our GWAS which did not reach genome-wide significance levels of association in the initial analysis. METHODS: 21 of 22 single nucleotide polymorphisms (SNPs) were successfully genotyped in independent cohorts of 1,398 PsA cases and 6,389 controls, and a group of 964 German PsV patients. RESULTS: Association to a RUNX3 variant, rs4649038, was replicated in independent cases and controls and resulted in a combined p-value of 1.40E-08 in a Cochran-Mantel-Haenszel test and an OR of 1.24 (1.15-1.33). Further analyses based on linkage disequilibrium at RUNX3 refined the most significant association to a linkage disequilibrium (LD) block located in the first intron of one isoform. Weaker evidence for association was detected in German PsV patients (p-value 5.89E-02; OR 1.13 (1.00-1.28)), indicating a role in the skin manifestations of psoriasis. CONCLUSION: Our analyses identified variants in RUNX3 as susceptibility factors for PsA. RUNX3 has already been implicated in susceptibility to ankylosing spondylitis, another spondylarthropathy, although its risk allele is independent from the PsA one. RUNX3 is involved in CD8 lymphocyte differentiation and therefore a good candidate for PsA and PsV as T-cell mediated diseases.

AB - OBJECTIVE: Psoriatic arthritis (PsA) is a common inflammatory joint disease distinct from other chronic arthritides and frequently accompanied by psoriasis vulgaris (PsV). In a first genome-wide association study (GWAS), we were able to identify several genetic risk factors. However, even combined with previously identified factors, the genetic contribution to disease is not fully explained. Therefore we investigated further 17 loci from our GWAS which did not reach genome-wide significance levels of association in the initial analysis. METHODS: 21 of 22 single nucleotide polymorphisms (SNPs) were successfully genotyped in independent cohorts of 1,398 PsA cases and 6,389 controls, and a group of 964 German PsV patients. RESULTS: Association to a RUNX3 variant, rs4649038, was replicated in independent cases and controls and resulted in a combined p-value of 1.40E-08 in a Cochran-Mantel-Haenszel test and an OR of 1.24 (1.15-1.33). Further analyses based on linkage disequilibrium at RUNX3 refined the most significant association to a linkage disequilibrium (LD) block located in the first intron of one isoform. Weaker evidence for association was detected in German PsV patients (p-value 5.89E-02; OR 1.13 (1.00-1.28)), indicating a role in the skin manifestations of psoriasis. CONCLUSION: Our analyses identified variants in RUNX3 as susceptibility factors for PsA. RUNX3 has already been implicated in susceptibility to ankylosing spondylitis, another spondylarthropathy, although its risk allele is independent from the PsA one. RUNX3 is involved in CD8 lymphocyte differentiation and therefore a good candidate for PsA and PsV as T-cell mediated diseases.

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DO - 10.1002/art.37885

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SP - 1224

EP - 1231

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