Association of a specific haplotype across the genes <Emphasis Type="Italic">MMP1</Emphasis> and <Emphasis Type="Italic">MMP3</Emphasis> with radiographic joint destruction in rheumatoid arthritis |
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Authors: | Sylvia?D?rr Nadine?Lechtenb?hmer Rolf?Rau Gertraud?Herborn Ulf?Wagner Bertram?Müller-Myhsok Ingo?Hansmann Email author" target="_blank">Gernot?KeyszerEmail author |
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Institution: | (1) Institute of Human Genetics, University of Halle/Saale, Germany;(2) Evangelisches Fachkrankenhaus, Ratingen, Germany;(3) Rheumazentrum, University of Leipzig, Leipzig, Germany;(4) Bernhard-Nocht-Institute, Hamburg, Germany;(5) Department of Internal Medicine I, University of Halle/Saale, Germany; |
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Abstract: | The genetic background of rheumatoid arthritis (RA) is only partly understood, and several genes seem to be involved. The
matrix metalloproteinases MMP1 (interstitial collagenase) and MMP3 (stromelysin 1) are thought to be important in destructive joint changes seen in RA. In the present study, functional relevant
promoter polymorphisms of MMP1 and MMP3 were genotyped in 308 patients and in 110 controls, to test whether the polymorphisms contribute to the severity of the disease
measured by radiographic progression of joint destruction. For comparison, the shared epitope of HLA DR4 and DR1 (SE) was
determined by polymerase chain reaction. There was no association of MMP polymorphisms with susceptibility to RA. However,
a strong linkage disequilibrium was observed between the 1G/2G (MMP1) and the 5A/6A (MMP3) polymorphisms (P << 10-6; linkage disequilibrium index D' = 0.46). In factorial regression, the degree of radiographic joint destruction correlated significantly with the 1G-5A haplotype
(P = 0.0001) and the interaction term 'estimated number of 1G-5A haplotypes × duration of disease' (P = 0.0007). This association was phasic, indicating that possession of the 1G-5A haplotype has a protective effect over a
period of about 15 years of RA, but might be associated with a more pronounced radiographic progression later on. Similar
results were also found with the 1G allele of MMP1 alone (P = 0.015) and with the interaction term 'estimated number of 1G alleles × duration of disease' (P = 0.014). The correlation of SE with the Ratingen score was comparable (0.044). The regression model of MMP haplotypes explained 35% of the variance of the radiographic score, whereas the SE explained 29%. The 1G-5A haplotype across
the closely linked MMP1 and MMP3 gene loci is a newly described genetic factor strongly associated with the progression of joint damage in RA. Our findings
suggest that there are haplotypes in a MMP cluster region that modify the joint destruction in RA in a phasic manner. |
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