title: A genetic variant in granzyme B is associated with progression of joint destruction in rheumatoid arthritis.
abstract: OBJECTIVE
  Genetic factors account for an estimated 45-58% 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 × 10(-4)). Expression QTL of GZMB identified higher expression in the presence of the minor allele of rs8192916 (P = 2.27 × 10(-5)).
  
  
  CONCLUSIONS
  SNP rs8192916 located in GZMB is associated with the progression of joint destruction in RA as well as with RNA expression in whole blood.
authors: Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. r.knevel@lumc.nl
authors: R
authors: R
authors: Knevel
authors: A
authors: A
authors: Krabben
authors: A G
authors: AG
authors: Wilson
authors: E
authors: E
authors: Brouwer
authors: M K
authors: MK
authors: Leijsma
authors: E
authors: E
authors: Lindqvist
authors: D P C
authors: DP
authors: de Rooy
authors: N A
authors: NA
authors: Daha
authors: M P M
authors: MP
authors: van der Linden
authors: S
authors: S
authors: Tsonaka
authors: A
authors: A
authors: Zhernakova
authors: H-J
authors: HJ
authors: Westra
authors: L
authors: L
authors: Franke
authors: J J
authors: JJ
authors: Houwing-Duistermaat
authors: R E M
authors: RE
authors: Toes
authors: T W J
authors: TW
authors: Huizinga
authors: T
authors: T
authors: Saxne
authors: A H M
authors: AH
authors: van der Helm-van Mil
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000473:pathology*; D019902:Chondrocytes / Q000473:pathology / Q000502:physiology; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D053804:Granzymes / Q000235:genetics*; D006801:Humans; D007596:Joints / Q000473:pathology; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012720:Severity of Illness Index
chemical_list: D012333:RNA, Messenger; C509213:GZMB protein, human; D053804:Granzymes