The HLA-DRB1 shared epitope is associated with susceptibility, to rheumatoid arthritis in African Americans through European genetic admixture
The HLA-DRB1 shared epitope is associated with susceptibility, to rheumatoid arthritis in African Americans through European genetic admixture
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DOI：
10.1002/art.23166
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发表时间：
2008-02-01
影响因子：
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通讯作者：
Bridges, S. Louis, Jr.
中科院分区：
文献类型：
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作者：
Hughes, Laura B.;Morrison, Dahliann;Bridges, S. Louis, Jr.
Objective.为了确定是否共享表位（SE）的HLA-DRB 1等位基因与类风湿性关节炎（RA）在非洲裔美国人和他们的存在是否与较高程度的全球（全基因组）遗传混合物从欧洲人口。在这项多中心队列研究中，分析了患有早期RA的非洲裔美国人和匹配的对照受试者。除了测量血清抗环瓜氨酸肽（抗CCP）抗体和HLA-DRB 1基因分型外，还分析了RA患者和对照组中一组超过1,200个祖先信息标记，以估计欧洲血统的比例。非裔美国人RA患者中含SE的HLA-DRB 1等位基因频率为25.2%，对照组为13.6%（P = 0.00005）。在321例RA患者中，42.1%的患者至少有1个含SE等位基因，而166例对照组中为25.3%（P = 0.0004）。在非裔美国人中，无论疾病状态（RA或对照）如何，欧洲血统的平均估计百分比与含SE的HLA-DRB 1等位基因相关。据报道，在欧洲血统的RA患者中，SE与抗CCP抗体的存在显著相关：176例抗CCP抗体阳性的RA患者中有86例（48.9%）至少有1个SE等位基因，而110例抗CCP抗体阴性的RA患者中有36例（32.7%）至少有1个SE等位基因（χ 2检验，P = 0.01）。含有SE的HLA-DRB 1等位基因与非裔美国人RA易感性密切相关。绝对贡献低于欧洲血统人群中RA的报告，其中约50-70%的患者至少有1个SE等位基因。与欧洲RA患者一样，SE与抗CCP抗体的非裔美国人患者亚组的相关性最强。在具有SE等位基因的非裔美国人中发现更高程度的欧洲血统表明，RA的遗传风险因素通过混合物引入非裔美国人人群，从而使这些个体更容易受到随后引发疾病的环境或未知因素的影响。
Objective. To determine whether shared epitope (SE)-containing HLA-DRB1 alleles are associated with rheumatoid arthritis (RA) in African Americans and whether their presence is associated with higher degrees of global (genome-wide) genetic admixture from the European population.Methods. In this multicenter cohort study, African Americans with early RA and matched control subjects were analyzed. In addition to measurement of serum anti-cyclic citrullinated peptide (anti-CCP) antibodies and HLA-DRB1 genotyping, a panel of > 1,200 ancestry-informative markers was analyzed in patients with RA and control subjects, to estimate the proportion of European ancestry.Results. The frequency of SE-containing HLA-DRB1 alleles was 25.2% in African American patients with RA versus 13.6% in control subjects (P = 0.00005). Of 321 patients with RA, 42.1% had at least 1 SE-containing allele, compared with 25.3% of 166 control subjects (P = 0.0004). The mean estimated percent European ancestry was associated with SE-containing HLA-DRB1 alleles in African Americans, regardless of disease status (RA or control). As reported in RA patients of European ancestry, there was a significant association of the SE with the presence of the anti-CCP antibody: 86 (48.9%) of 176 patients with anti-CCP antibody positive RA had at least 1 SE allele, compared with 36 (32.7%) of 110 patients with anti-CCP antibody-negative RA (P = 0.01, by chi-square test).Conclusion. HLA-DRB1 alleles containing the SE are strongly associated with susceptibility to RA in African Americans. The absolute contribution is less than that reported in RA among populations of European ancestry, in which similar to 50-70% of patients have at least 1 SE allele. As in Europeans with RA, the SE association was strongest in the subset of African American patients with anti-CCP antibodies. The finding of a higher degree of European ancestry among African Americans with SE alleles suggests that a genetic risk factor for RA was introduced into the African American population through admixture, thus making these individuals more susceptible to subsequent environmental or unknown factors that trigger the disease.