Genetic predictors of response to anti-TNF therapy in rheumatoid arthritis

类风湿性关节炎抗 TNF 治疗反应的遗传预测因素

• 批准号: 8691893
• 负责人: Michael B. Brenner
• 金额: $ 140.02万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8691893
• 关键词: Alleles; Anti-Tumor Necrosis Factor Therapy; Antirheumatic Agents; Biological; Biological Markers; Cells; Clinical; Collaborations; Computerized Medical Record; DNA; Data; Disease; Disease remission; Disease-Modifying Second-Line Drugs; Genetic; Genetic Markers; Goals; Healthcare; Human; Immune; Individual; Inflammation; Inflammatory; Informatics; Methods; Onset of illness; Outcome; Patient Care; Patients; Pharmaceutical Preparations; Principal Investigator; Rheumatoid Arthritis; Sampling; Single Nucleotide Polymorphism; Statistical Methods; TNF gene; Testing; Tumor Necrosis Factor-alpha; Variant; base; bone; cytokine; genetic variant; genome wide association study; human TNF protein; improved; novel; public health relevance; response; theories; treatment response

DESCRIPTION (provided by applicant): Long-term outcome in patients with rheumatoid arthritis (RA) is highly dependent upon aggressive pharmacological control of inflammation early in the disease course. Despite the importance of selecting the optimal medication soon after disease onset, there is no clinical or biomarker predictor of drug treatment response. A genetic biomarker would be particularly useful for drugs that block the inflammatory cytokine TNF-alpha (TNF), as these drugs are first-line biological disease modifying anti-rheumatic drugs DMARDs, yet induce remission in only ~30% of patients. In this application, our central hypothesis is that common genetic variants of modest effect size predict response to anti-TNF therapy. To test this hypothesis, we propose to expand upon our established multi-center collaboration and available GWAS data to develop (i) new statistical methods for conducting GWAS (estimating variance explained by common single nucleotide polymorphisms, SNPs), (ii) new informatics methods for defining treatment response in the EMR (which will allow us to collect many more samples for GWAS), and (iii) a novel framework for testing mechanism directly in human immune cells. Aim 1: Analyze GWAS data on ~1,200 RA patients to search for common variants that predict response to anti-TNF therapy. Aim 2: Use electronic medical records (EMR) at Partners HealthCare, Vanderbilt and Northwestern to define treatment response, and conduct a GWAS on ~1,200 additional RA patients treated with anti-TNF therapy. Aim 3: Test mechanism of action of alleles that predict treatment response to anti-TNF therapy in human immune cells.

描述（由申请人提供）：

项目成果

Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study.

• DOI: 10.1016/s1470-2045(16)30148-6
• 发表时间: 2016-09
• 期刊: The Lancet. Oncology
• 作者: Li Z;Xia Y;Feng LN;Chen JR;Li HM;Cui J;Cai QQ;Sim KS;Nairismägi ML;Laurensia Y;Meah WY;Liu WS;Guo YM;Chen LZ;Feng QS;Pang CP;Chen LJ;Chew SH;Ebstein RP;Foo JN;Liu J;Ha J;Khoo LP;Chin ST;Zeng YX;Aung T;Chowbay B;Diong CP;Zhang F;Liu YH;Tang T;Tao M;Quek R;Mohamad F;Tan SY;Teh BT;Ng SB;Chng WJ;Ong CK;Okada Y;Raychaudhuri S;Lim ST;Tan W;Peng RJ;Khor CC;Bei JX
• 通讯作者: Bei JX

Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response.

• DOI: 10.1001/jama.2015.3435
• 发表时间: 2015-04-28
• 期刊: JAMA
• 作者: Viatte S;Plant D;Han B;Fu B;Yarwood A;Thomson W;Symmons DP;Worthington J;Young A;Hyrich KL;Morgan AW;Wilson AG;Isaacs JD;Raychaudhuri S;Barton A
• 通讯作者: Barton A

Association of valine and leucine at HLA-DRB1 position 11 with radiographic progression in rheumatoid arthritis, independent of the shared epitope alleles but not independent of anti-citrullinated protein antibodies.

HLA-DRB1 位点 11 的缬氨酸和亮氨酸与类风湿性关节炎的放射学进展相关，独立于共享表位等位基因，但不独立于抗瓜氨酸蛋白抗体。

• DOI: 10.1002/art.39018
• 发表时间: 2015
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: vanSteenbergen,HW;Raychaudhuri,S;Rodríguez-Rodríguez,L;Rantapää-Dahlqvist,S;Berglin,E;Toes,REM;Huizinga,TWJ;Fernández-Gutiérrez,B;Gregersen,PK;vanderHelm-vanMil,AHM
• 通讯作者: vanderHelm-vanMil,AHM