Document Detail


Different patterns of associations with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in the extended major histocompatibility complex region.
MedLine Citation:
PMID:  19116921     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: To identify additional variants in the major histocompatibility complex (MHC) region that independently contribute to risk in 2 disease subsets of rheumatoid arthritis (RA) defined according to the presence or absence of antibodies to citrullinated protein antigens (ACPAs).
METHODS: In a multistep analytical strategy using unmatched as well as matched analyses to adjust for HLA-DRB1 genotype, we analyzed 2,221 single-nucleotide polymorphisms (SNPs) spanning 10.7 Mb, from 6p22.2 to 6p21.31, across the MHC. For ACPA-positive RA, we analyzed samples from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) and the North American Rheumatoid Arthritis Consortium (NARAC) studies (totaling 1,255 cases and 1,719 controls). For ACPA-negative RA, we used samples from the EIRA study (640 cases and 670 controls). Plink and SAS statistical packages were used to conduct all statistical analyses.
RESULTS: A total of 299 SNPs reached locus-wide significance (P<2.3x10(-5)) for ACPA-positive RA, whereas surprisingly, no SNPs reached this significance for ACPA-negative RA. For ACPA-positive RA, we adjusted for known DRB1 risk alleles and identified additional independent associations with SNPs near HLA-DPB1 (rs3117213; odds ratio 1.42 [95% confidence interval 1.17-1.73], Pcombined=0.0003 for the strongest association).
CONCLUSION: There are distinct genetic patterns of MHC associations in the 2 disease subsets of RA defined according to ACPA status. HLA-DPB1 is an independent risk locus for ACPA-positive RA. We did not identify any associations with SNPs within the MHC for ACPA-negative RA.
Authors:
Bo Ding; Leonid Padyukov; Emeli Lundström; Mark Seielstad; Robert M Plenge; Jorge R Oksenberg; Peter K Gregersen; Lars Alfredsson; Lars Klareskog
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  60     ISSN:  0004-3591     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2009-01-12     Completed Date:  2009-03-05     Revised Date:  2014-09-11    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  30-8     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Antibody Specificity
Arthritis, Rheumatoid / epidemiology,  genetics*,  immunology*
Autoantibodies / blood*
Citrulline
Genetic Predisposition to Disease / epidemiology
Genotype
HLA-DR Antigens / genetics*
HLA-DRB1 Chains
Humans
Linkage Disequilibrium
Peptides, Cyclic / immunology*
Polymorphism, Single Nucleotide
Risk Factors
Grant Support
ID/Acronym/Agency:
K08-AI-55314-3/AI/NIAID NIH HHS; R01 AR044422/AR/NIAMS NIH HHS; R01 AR044422-09A1/AR/NIAMS NIH HHS; R01 AR044422-10/AR/NIAMS NIH HHS; R01-AR-44422/AR/NIAMS NIH HHS; U19-AI-067152/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Autoantibodies; 0/HLA-DR Antigens; 0/HLA-DRB1 Chains; 0/Peptides, Cyclic; 0/cyclic citrullinated peptide; 29VT07BGDA/Citrulline
Comments/Corrections
Erratum In:
Arthritis Rheum. 2009 Apr;60(4):1200

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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