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A genetic variant in granzyme B is associated with progression of joint destruction in rheumatoid arthritis

Knevel, R. ; Krabben, A. ; Wilson, A. G. ; Brouwer, E. ; Leijsma, M. K. ; Lindqvist, Elisabet LU orcid ; de Rooy, D. P. C. ; Daha, N. A. ; van der Linden, M. P. M. and Tsonaka, S. , et al. (2013) In Arthritis and Rheumatism 65(3). p.582-589
Abstract
Objective Genetic factors account for an estimated 4558% of the variance in joint destruction in rheumatoid arthritis (RA). The serine proteinase granzyme B induces target cell apoptosis, and several in vitro studies suggest that granzyme B is involved in apoptosis of chondrocytes. Serum levels of granzyme B are increased in RA and are also associated with radiographic erosions. The aim of this study was to investigate GZMB as a candidate gene accounting for the severity of joint destruction in RA. Methods A total of 1,418 patients with 4,885 radiograph sets of the hands and feet from 4 independent cohorts were studied. First, explorative analyses were performed in 600 RA patients in the Leiden Early Arthritis Clinic cohort. Fifteen... (More)
Objective Genetic factors account for an estimated 4558% of the variance in joint destruction in rheumatoid arthritis (RA). The serine proteinase granzyme B induces target cell apoptosis, and several in vitro studies suggest that granzyme B is involved in apoptosis of chondrocytes. Serum levels of granzyme B are increased in RA and are also associated with radiographic erosions. The aim of this study was to investigate GZMB as a candidate gene accounting for the severity of joint destruction in RA. Methods A total of 1,418 patients with 4,885 radiograph sets of the hands and feet from 4 independent cohorts were studied. First, explorative analyses were performed in 600 RA patients in the Leiden Early Arthritis Clinic cohort. Fifteen single-nucleotide polymorphisms (SNPs) tagging GZMB were tested. Significantly associated SNPs were genotyped in data sets representing patients from the Groningen, Sheffield, and Lund cohorts. In each data set, the relative increase in the annual rate of progression in the presence of a genotype was assessed. Data were summarized in a meta-analysis. The association of GZMB with the RNA expression level of the GZMB genomic region was tested by mapping expression quantitative trait loci (QTLs) on 1,469 whole blood samples. Results SNP rs8192916 was significantly associated with the rate of joint destruction in the first cohort and in the meta-analysis of all data sets. Patients homozygous for the minor allele of rs8192916 had a higher rate of joint destruction per year compared with other patients (P = 7.8 x 104). Expression QTL of GZMB identified higher expression in the presence of the minor allele of rs8192916 (P = 2.27 x 105). Conclusion SNP rs8192916 located in GZMB is associated with the progression of joint destruction in RA as well as with RNA expression in whole blood. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Arthritis and Rheumatism
volume
65
issue
3
pages
582 - 589
publisher
John Wiley & Sons Inc.
external identifiers
  • wos:000315452400006
  • scopus:84874441173
  • pmid:23440692
ISSN
1529-0131
DOI
10.1002/art.37808
language
English
LU publication?
yes
id
c8e32276-5fd4-4abc-942a-12b1c0c99722 (old id 3669973)
date added to LUP
2016-04-01 10:51:55
date last changed
2022-01-26 03:12:08
@article{c8e32276-5fd4-4abc-942a-12b1c0c99722,
  abstract     = {{Objective Genetic factors account for an estimated 4558% of the variance in joint destruction in rheumatoid arthritis (RA). The serine proteinase granzyme B induces target cell apoptosis, and several in vitro studies suggest that granzyme B is involved in apoptosis of chondrocytes. Serum levels of granzyme B are increased in RA and are also associated with radiographic erosions. The aim of this study was to investigate GZMB as a candidate gene accounting for the severity of joint destruction in RA. Methods A total of 1,418 patients with 4,885 radiograph sets of the hands and feet from 4 independent cohorts were studied. First, explorative analyses were performed in 600 RA patients in the Leiden Early Arthritis Clinic cohort. Fifteen single-nucleotide polymorphisms (SNPs) tagging GZMB were tested. Significantly associated SNPs were genotyped in data sets representing patients from the Groningen, Sheffield, and Lund cohorts. In each data set, the relative increase in the annual rate of progression in the presence of a genotype was assessed. Data were summarized in a meta-analysis. The association of GZMB with the RNA expression level of the GZMB genomic region was tested by mapping expression quantitative trait loci (QTLs) on 1,469 whole blood samples. Results SNP rs8192916 was significantly associated with the rate of joint destruction in the first cohort and in the meta-analysis of all data sets. Patients homozygous for the minor allele of rs8192916 had a higher rate of joint destruction per year compared with other patients (P = 7.8 x 104). Expression QTL of GZMB identified higher expression in the presence of the minor allele of rs8192916 (P = 2.27 x 105). Conclusion SNP rs8192916 located in GZMB is associated with the progression of joint destruction in RA as well as with RNA expression in whole blood.}},
  author       = {{Knevel, R. and Krabben, A. and Wilson, A. G. and Brouwer, E. and Leijsma, M. K. and Lindqvist, Elisabet and de Rooy, D. P. C. and Daha, N. A. and van der Linden, M. P. M. and Tsonaka, S. and Zhernakova, A. and Westra, H. -J. and Franke, L. and Houwing-Duistermaat, J. J. and Toes, R. E. M. and Huizinga, T. W. J. and Saxne, Tore and van der Helm-van Mil, A. H. M.}},
  issn         = {{1529-0131}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{582--589}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Arthritis and Rheumatism}},
  title        = {{A genetic variant in granzyme B is associated with progression of joint destruction in rheumatoid arthritis}},
  url          = {{http://dx.doi.org/10.1002/art.37808}},
  doi          = {{10.1002/art.37808}},
  volume       = {{65}},
  year         = {{2013}},
}