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

被引:100
作者
Ding, Bo [1 ]
Padyukov, Leonid [2 ]
Lundstrom, Emeli [2 ]
Seielstad, Mark [3 ]
Plenge, Robert M. [4 ,5 ]
Oksenberg, Jorge R. [6 ]
Gregersen, Peter K. [7 ]
Alfredsson, Lars
Klareskog, Lars [2 ]
机构
[1] Karolinska Inst, Inst Environm Med, S-17177 Stockholm, Sweden
[2] Karolinska Univ Hosp, Karolinska Inst, Solna, Sweden
[3] Genome Inst Singapore, Singapore, Singapore
[4] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA
[5] Broad Inst MIT & Harvard, Cambridge, MA USA
[6] Univ Calif San Francisco, San Francisco, CA 94143 USA
[7] Feinstein Inst Med Res, Manhasset, NY USA
来源
ARTHRITIS AND RHEUMATISM | 2009年 / 60卷 / 01期
基金
英国医学研究理事会;
关键词
HLA-DRB1 SHARED EPITOPE; PEPTIDE ANTIBODIES; SUSCEPTIBILITY; ALLELES; CLASSIFICATION; GENETICS; SMOKING; GENES; RISK; MHC;
D O I
10.1002/art.24135
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 < 2.3 x 10(-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 1.7-1.73], P(combined) = 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.
引用
收藏
页码:30 / 38
页数:9
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