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

Genetic markers and clinical relevance in rheumatoid arthritis

“…Knevel et al investigated GZMB as a candidate gene accounting for the severity of joint destruction in RA, and found the SNP rs8192916 located in GZMB was associated with the progression of joint destruction. 28 RA patients carrying risk alleles of Dkk-1 had higher serum levels of functional Dkk-1 and more progressive joint destruction over time. 29 The functional LILRA3 appears to confer a higher risk to disease severity in early RA patients.…”

Predicting the severity of joint damage in rheumatoid arthritis; the contribution of genetic factors

“…Notably, rs4810485 in CD40 and rs7607479 in SPAG16 were identified as risk factors for radiologic progression only in ACPA-positive RA. Genotypings in the EAC were done with allele-specific kinetic PCR analysis,15 Illumina Golden Gate platform,3 4 16 17 Illumina Immunochip,5 18 Sequenom iPLEX6 and LightSnp (Roche) 19. Quality control of genotyping was performed as described previously 3–6 15–19.…”

Genetic data: The new challenge of personalized medicine, insights for rheumatoid arthritis patients

“…Therefore, risk factors for this outcome measure may be used to arrive at individualized treatment strategies (van der Helm-van Mil et al, 2010). It has been shown that genetic variants of IL-15 (Knevel et al 2012), IL4R (Krabben et al, 2013), IL2RA (Knevel et al, 2013a), GZMB (Knevel et al, 2013b), Dkk-1 (de Rooy et al, 2013), MMP-9 (de Rooy et al, 2014), MMP-3 (Knevel et al, 2014a), OPG (Knevel et al, 2014b), PTGER4 (Rodriguez-Rodriguez et al, 2015), TRAF1/C5 as well as the rs2833522 SNP (De Rooy et al, 2013) are associated with RA severity as reflected by radiological damage and joint destruction appeared in RA patients. Moreover, it has been reported that RA patients with the Blimp-1 risk allele show more synovial inflammation than those without this allele (Herenius et al, 2011).…”