期刊
ARTHRITIS AND RHEUMATISM
卷 60, 期 12, 页码 3582-3590出版社
WILEY
DOI: 10.1002/art.24939
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资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Center for Genomic Medicine of the Institute of Physical and Chemical Research
- Ministry of Health, Labor, and Welfare of Japan
Objective. To examine the risk of anti-cyclic citrullinated peptide (anti-CCP) antibody positivity in rheumatoid arthritis (RA) patients carrying certain haplotypes in the HLA region. Methods. A total of 1,389 Japanese patients with RA were genotyped for 30 single-nucleotide polymorphisms (SNPs) in the HLA region using commercial oligonucleotide arrays (from Perlegen or Affymetrix) as well as for HLA-DRB1 alleles using a sequence-specific polymerase chain reaction method. Stepwise logistic regression was used to select from among the 30 SNPs the ones that represented a risk of anti-CCP antibody positivity. Haplotypes of the selected SNPs were inferred using an expectation-maximization algorithm. Associations of individual SNPs were evaluated with the Cochran-Armitage test for trend. DRB1 alleles and haplotypes were evaluated with the chi-square test. Heterogeneities of risks among the shared epitope (SE) and non-SE HLA-DRB1 alleles were examined using the exact test. Haplotype associations that were independent of individual HLA-DRB1 alleles were evaluated using the likelihood ratio test. Results. Significant associations were found for 9 SNPs (smallest P value being 2.4 x 10(-8)) and in 4 HLA-DRB1 alleles (smallest P value being 2.0 x 10(-10) in DRB1*0405). Stepwise logistic regression selected 4 SNPs (rs9262638, rs7775228, rs4713580, and rs9277359). Among the 16 inferred haplotypes of these 4 SNPs, 6 indicated significant associations (smallest P value being 1.9 x 10(-11)). Risks among SE and non-SE alleles were significantly heterogeneous (P = 0.0095 and P = 9.8 x 10(-9), respectively), indicating the importance of stratification with individual DRB1 alleles rather than SE alleles. Conditional analysis of the risk associated with individual DRB1 alleles identified a risk haplotype that was independent of DRB1 (odds ratio 2.00 [95% confidence interval 1.44-2.79], P = 2.6 x 10(-5)). Conclusion. Heterogeneous risks of anti-CCP antibody positivity were confirmed among SE and non-SE alleles in our patient population. A risk haplotype in the HLA region that is independent of HLA-DRB1 was confirmed.
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