文章題目：Genetics of rheumatoid arthritis contributes to biology and drug discovery
作者：Robert M.
單位：Division of Rheumatology, Immunology, and Allergy
發表時間：2013 Dec 25
雜誌：Meta-Analysis
影響因子：42.778
分區：2
1. 核心亮點：We found that approximately two-thirds of RA risk loci demonstrated pleiotropy with other human phenotypes，including immune-related diseases (for example,vitiligo,primary biliary cirrhosis), inflammation-related or haematological biomarkers (for example, fibrinogen, neutrophil counts) and other complex traits. 我們發現，大約三分之二的RA風險位點與其他人類表型表現出多向同性，包括免疫相關疾病（例如白癜風、原發性膽汁性肝硬化)、炎症相關或血液學生物標誌物 (例如纖維蛋白原,中性粒細胞計數)和其他複雜性狀。
2. 思路與方法：
Our study included 29,880 RA cases (88.1% seropositive and 9.3%seronegative for anti-citrullinated peptide antibody (ACPA) or rheumatoid factor (RF), and 2.6% who had unknown autoantibody status) and 73,758 controls. All RA cases fulfilled the 1987 criteria of the American College of Rheumatology for RA diagnosis24, or were diagnosed with RA by a professional rheumatologist. The 19,234 RA cases and 61,565 controls enrolled in the stage 1 trans-ethnic GWAS meta-analysis were obtained from 22 studies on people with European and Asian ancestries (14,361 RA cases and 43,923 controls from 18 studies of Europeans and 4,873 RA cases and 17,642 controls from 4 studies of Asians):BRASS2,CANADA2,EIRA2,NARAC12,NARAC22,WTCCC2 , Rheumatoid Arthritis Consortium International for Immunochip (RACI)-UK4 , RACI-US4 ,RACI-SE-E4,RACI-SE-U4,RACI-NL4,RACI
ES4,RACI-i2b2,ReAct,Dutch(including AMC,BeSt, LUMC and DREAM), anti-TNF response to therapy collection (ACR-REF: BRAGGSS, BRAGGSS2, ERA, KI and TEAR), CORRONA, Vanderbilt, three studies from the GARNET consortium (BioBank Japan Project3 , Kyoto University3 and IORRA3 ), and Korea. 我們的研究包括29，880例RA病例 (88.1%血清陽性，9.3%血清陽性，用於抗瓜氨酸肽抗體 (ACPA)或類風溼因子 (RF)，2.6%的自身抗體狀態不明)和73758例對照組。所有RA病例均符合1987年美國風溼病學院RA診斷標準24，或由專業風溼病學家診斷為RA。在第一階段跨種族GWAS元分析中登記的19,234例RA病例和61,565例對照來自22項關於歐洲和亞洲祖先的研究(14,361例RA病例和43,923例對照來自18項歐洲研究和4,873例RA病例和17,642例亞洲人研究)：BRASS2、CANADA2、EIRA2、NARAC12、NARAC22、WTCCC2、類風溼關節炎國際免疫聯盟(RACI)-UK4、RACI-US4、RACI-SE-E4、RACI-SE-U4、RACI-NL4、RACI-NL4、RACI-ES4、RACI-I2b2、ReAct、荷蘭(包括AMC、Be St、LUMC和DREAM)、抗TNF對治療收集的反應(ACR-REF：BRAGSS2、BRAGSS2、ERA、GGSS4、ERA、RACI-ES4、RACI-I-I2B2B2、RACKI和TEAR)、CORRONA、Vanderbilt、GARNET財團(Bio Bank Japan Project3、京都大學3和IORRA3)和韓國的三項研究。
3. 摘要：
OBJECTIVE
A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA).Here we performed a genome-wide association study meta-analysis in a total of.100,000subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2–4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation，cis-acting expression quantitative trait loci6 and pathway analyses as well as novelmethods based ongenetic overlapwith human primaryimmuno deficiency, haematological cancer somatic mutations and knockout mouse phenotypes to identify 98 biological candidate genes at these 101 riskloci.We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery. 人類遺傳學的一個主要挑戰是設計一種系統的策略，將疾病相關變異與不同的基因組和生物數據集結合起來，以提供對疾病發病機制的洞察，並指導類風溼關節炎 (RA)1等複雜性狀的藥物發現。在這裡，我們進行了一個全基因組關聯研究，共進行了元分析。通過評估1000萬個單核苷酸多態性，100000名歐洲和亞洲祖先 (29，880例RA病例和73758例對照組。我們在基因組範圍內發現了42個新的RA風險位點，使總數達到101個。我們設計了一種基於功能注釋5順式作用表達數量性狀位點6和通路分析7-9的生物信息學方法，以及基於人類原發性免疫缺陷、血癌體細胞突變和敲除小鼠表型的遺傳重疊的新方法，以鑑定這101個風險基因中的98個生物候選基因。我們證明這些基因是批准治療RA的靶點，並進一步表明，批准用於其他適應症的藥物可能被重新用於治療RA。這一綜合遺傳學研究共同揭示了導致RA發病的基本基因、途徑和細胞類型，並提供了經驗證據，表明RA的遺傳學可以為藥物發現提供重要信息。
4. 圖表：