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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.

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.

journal_name

Ann Rheum Dis

journal_title

Annals of the rheumatic diseases

authors

de Rooy DP,Zhernakova A,Tsonaka R,Willemze A,Kurreeman BA,Trynka G,van Toorn L,Toes RE,Huizinga TW,Houwing-Duistermaat JJ,Gregersen PK,van der Helm-van Mil AH

doi

10.1136/annrheumdis-2013-203375

subject

Has Abstract

pub_date

2014-06-01 00:00:00

pages

1163-9

issue

eissn

0003-4967

issn

1468-2060

pii

annrheumdis-2013-203375

journal_volume

pub_type

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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.