title: A genetic variant in the region of MMP-9 is associated with serum levels and progression of joint damage in rheumatoid arthritis.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, , Leiden, The Netherlands.
authors.forename: D P C
authors.initials: DP
authors.lastname: de Rooy
authors.forename: A
authors.initials: A
authors.lastname: Zhernakova
authors.forename: R
authors.initials: R
authors.lastname: Tsonaka
authors.forename: A
authors.initials: A
authors.lastname: Willemze
authors.forename: B A S
authors.initials: BA
authors.lastname: Kurreeman
authors.forename: G
authors.initials: G
authors.lastname: Trynka
authors.forename: L
authors.initials: L
authors.lastname: van Toorn
authors.forename: R E M
authors.initials: RE
authors.lastname: Toes
authors.forename: T W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: J J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.forename: P K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: A H M
authors.initials: AH
authors.lastname: van der Helm-van Mil
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D033023:Foot Joints / Q000000981:diagnostic imaging; D020022:Genetic Predisposition to Disease; D005838:Genotype; D050823:Hand Joints / Q000000981:diagnostic imaging; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011859:Radiography; D012720:Severity of Illness Index
chemical_list: C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Arthritis; Gene Polymorphism; Rheumatoid Arthritis