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A genetic variant in the region of MMP-9 is associated with serum levels and progression of joint damage in rheumatoid arthritis
  1. D P C de Rooy1,
  2. A Zhernakova1,2,
  3. R Tsonaka3,
  4. A Willemze1,
  5. B A S Kurreeman1,
  6. G Trynka2,4,5,
  7. L van Toorn1,
  8. R E M Toes1,
  9. T W J Huizinga1,
  10. J J Houwing-Duistermaat3,
  11. P K Gregersen6,
  12. A H M van der Helm-van Mil1
  1. 1Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
  3. 3Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands
  4. 4Division of Genetics and Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  5. 5Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
  6. 6Robert S Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research and North Shore–Long Island Jewish Health System, Manhasset, New York, USA
  1. Correspondence to Dr A H M van der Helm-van Mil, Department of Rheumatology, Leiden University Medical Center, PO Box 9600, Leiden 2300 RC, The Netherlands; AvdHelm{at}lumc.nl.

Abstract

Objectives The severity of joint destruction is highly variable between rheumatoid arthritis (RA) patients. The majority of its heritability is still unexplained. Several autoimmune diseases share genetic risk variants that may also influence disease progression. We aimed to identify genetic risk factors for the severity of joint damage in RA by studying genetic susceptibility loci of several autoimmune diseases.

Methods In phase 1, 3143 sets of x-rays of 646 Dutch RA patients taken over 7 years (Sharp van der Heijde (SHS) scored) were studied. Genotyping was done by Immunochip. Associations of single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) >0.01 and joint destruction were analysed. In phase 2, 686 North American RA patients with 926 SHS-scored x-rays over 15 years of follow-up were evaluated. In both phases multiple testing corrections were done for the number of uncorrelated SNPs; the thresholds for significance were p<1.1×10−6 and p<0.0036. Matrix metalloproteinase 9 (MMP-9) levels were measured with ELISA in baseline serum samples.

Results In phase 1, 109 SNPs associated significantly with joint destruction (p<1.1×10−6). Of these, 76 were located in the HLA region; the 33 non-HLA variants were studied in phase 2. Here two variants were associated with the severity of joint destruction: rs451066 on chromosome 14 (p=0.002, MAF=0.20) and rs11908352 on chromosome 20 (p=0.002, MAF=0.21). Rs11908352 is located near the gene encoding MMP-9. Serum levels of MMP-9 were significantly associated with the rs11908352 genotypes (p=0.007).

Conclusions These data indicate that two loci that confer risk to other autoimmune diseases also affect the severity of joint destruction in RA. Rs11908352 may influence joint destruction via MMP-9 production.

  • Gene Polymorphism
  • Rheumatoid Arthritis
  • Arthritis

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