A large-scale rheumatoid arthritis genetic study identifies association at chromosome 9q33.2.
A large-scale rheumatoid arthritis genetic study identifies association at chromosome 9q33.2.
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DOI：
10.1371/journal.pgen.1000107
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发表时间：
2008-06-27
期刊：
影响因子：
4.5
通讯作者：
Begovich AB
中科院分区：
文献类型：
--
作者：
Chang M;Rowland CM;Garcia VE;Schrodi SJ;Catanese JJ;van der Helm-van Mil AH;Ardlie KG;Amos CI;Criswell LA;Kastner DL;Gregersen PK;Kurreeman FA;Toes RE;Huizinga TW;Seldin MF;Begovich AB
类风湿性关节炎（RA）是一种影响关节和关节外组织的慢性系统性自身免疫性疾病。虽然一些RA的遗传风险因素已经确定，最显著的是HLA-DRB1和PTPN22，但这些标记并不能完全解释观察到的遗传力。为了确定其他易感位点，我们进行了一项多层病例对照关联研究，对475名北美白人RA患者和475名匹配对照进行了25,966个假定的功能snp基因分型。在另外两个独立的白色病例对照样本组（北美661例/1322例对照和荷兰596例/705例对照）中进行显著标记基因分型，发现染色体9q33.2上的SNP rs1953126与RA显著相关（ORcommon = 1.28，趋势Pcomb = 1.45E-06）。通过全面的精细定位snp选择程序，在9q33.2上从MEGF9到STOM的668 kb区域中选择了137个额外的snp，以分阶段方法进行后续基因分型。单标记结果显著（Pcomb<0.01），覆盖了从FBXW2到GSN的525 kb区域。然而，各种分析发现，从PHF19的第三个内含子穿过TRAF1延伸到TRAF1-C5基因间区，但不包括C5编码区，70 kb区域的snp是最有趣的（趋势Pcomb: 1.45E-06→5.41E-09）。观察到的这些snp的关联模式具有更高的统计学意义和更高程度的跨样本集的一致性。此外，与其他snp相比，这些snp的等位基因频率在对照组之间表现出较少的变异性。最后，结合其他两个已知的遗传风险因素，HLA-DRB1和PTPN22，这里报告的变异产生了超过45倍的ra风险差异。类风湿关节炎（RA）是一种影响约1%人口的慢性自身免疫性疾病，其特征是免疫细胞介导的关节结构破坏。基因-环境相互作用被认为是类风湿关节炎病因学的基础。HLA-DRB1和造血特异性磷酸酶PTPN22内的变异是确定的ra易感性位点，尽管已经确定了其他标记，但它们并不能完全解释该疾病的遗传性。为了确定其他易感等位基因，我们进行了一项多层病例对照关联研究，对25000个假定的功能snp进行了基因分型；在这里，我们报告了我们在染色体9q33.2上发现的ra相关变异。结合HapMap信息对该区域进行了详细的遗传分析，将ra易感性效应定位在一个70 kb的区域，该区域包括部分PHF19、全部TRAF1和大部分TRAF1-C5基因间区，但不包括C5编码区。除了为疾病的潜在机制提供新的见解和提出新的治疗靶点外，这些数据还为遗传标记提供了基础，可以预测患RA风险增加的个体。事实上，对三种已知遗传风险因素（HLA、PTPN22和9q33.2染色体变异）的初步分析表明，根据个体的三位点基因型，RA的风险差异高达45倍。
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting both joints and extra-articular tissues. Although some genetic risk factors for RA are well-established, most notably HLA-DRB1 and PTPN22, these markers do not fully account for the observed heritability. To identify additional susceptibility loci, we carried out a multi-tiered, case-control association study, genotyping 25,966 putative functional SNPs in 475 white North American RA patients and 475 matched controls. Significant markers were genotyped in two additional, independent, white case-control sample sets (661 cases/1322 controls from North America and 596 cases/705 controls from The Netherlands) identifying a SNP, rs1953126, on chromosome 9q33.2 that was significantly associated with RA (ORcommon = 1.28, trend Pcomb = 1.45E-06). Through a comprehensive fine-scale-mapping SNP-selection procedure, 137 additional SNPs in a 668 kb region from MEGF9 to STOM on 9q33.2 were chosen for follow-up genotyping in a staged-approach. Significant single marker results (Pcomb<0.01) spanned a large 525 kb region from FBXW2 to GSN. However, a variety of analyses identified SNPs in a 70 kb region extending from the third intron of PHF19 across TRAF1 into the TRAF1-C5 intergenic region, but excluding the C5 coding region, as the most interesting (trend Pcomb: 1.45E-06 → 5.41E-09). The observed association patterns for these SNPs had heightened statistical significance and a higher degree of consistency across sample sets. In addition, the allele frequencies for these SNPs displayed reduced variability between control groups when compared to other SNPs. Lastly, in combination with the other two known genetic risk factors, HLA-DRB1 and PTPN22, the variants reported here generate more than a 45-fold RA-risk differential. Rheumatoid arthritis (RA), a chronic autoimmune disorder affecting ∼1% of the population, is characterized by immune-cell–mediated destruction of the joint architecture. Gene–environment interactions are thought to underlie RA etiology. Variants within HLA-DRB1 and the hematopoietic-specific phosphatase, PTPN22, are well established RA-susceptibility loci, and although other markers have been identified, they do not fully account for the disease heritability. To identify additional susceptibility alleles, we carried out a multi-tiered, case-control association study genotyping >25,000 putative functional SNPs; here we report our finding of RA-associated variants in chromosome 9q33.2. A detailed genetic analysis of this region, incorporating HapMap information, localizes the RA-susceptibility effects to a 70 kb region that includes a portion of PHF19, all of TRAF1, and the majority of the TRAF1-C5 intergenic region, but excludes the C5 coding region. In addition to providing new insights into underlying mechanism(s) of disease and suggesting novel therapeutic targets, these data provide the underpinnings of a genetic signature that may predict individuals at increased risk for developing RA. Indeed, initial analyses of three known genetic risk factors, HLA, PTPN22, and the chromosome 9q33.2 variants described here, suggest a >45-fold difference in RA risk depending on an individual's three-locus genotype.
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