Genome wide association (GWA) predictors of anti-TNFalpha therapeutic responsiveness in pediatric inflammatory bowel disease.
Genome wide association (GWA) predictors of anti-TNFalpha therapeutic responsiveness in pediatric inflammatory bowel disease.
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DOI：
10.1002/ibd.21174
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发表时间：
2010-08
影响因子：
4.9
通讯作者：
Rotter, Jerome I.
中科院分区：
文献类型：
--
作者：
Dubinsky, Marla C.;Mei, Ling;Friedman, Madison;Dhere, Tanvi;Haritunians, Talin;Hakonarson, Hakon;Kim, Cecilia;Glessner, Joseph;Targan, Stephan R.;McGovern, Dermot P.;Taylor, Kent D.;Rotter, Jerome I.
抗TNF α治疗反应的个体间差异可通过疾病发病机制或作用机制的遗传变异性来解释。最近的IBD全基因组关联研究（GWAS）增加了我们对IBD遗传易感性的理解。检测已知IBD易感基因座和新型“药物遗传学”GWAS的相关性，确定儿科IBD患者中对抗TNF α治疗原发性无应答的基因座，并开发原发性无应答的预测模型。使用HBI（CD）和部分马约评分（UC）定义原发性无应答。使用Illumina Infinium平台进行基因分型。卡方分析检验了表型和基因型与原发性无应答的相关性。通过检测已知的IBD易感基因座和对原发性无应答进行GWAS来确定遗传相关性。进行逐步多元逻辑回归以建立预测模型。94例受试者中有22例无应答。6个已知的易感基因座与原发性无应答相关（p < 0.05）。只有21q22.2/BRWDI基因座在预测模型中仍具有显著性。最具预测性的模型包括3个新的“药物遗传学”GWAS基因座、先前鉴定的BRWD 1、pANCA和UC诊断（R2 =0.82和AUC = 0.98%）。当风险因素数量从0-2增加到≥ 3时，无应答的相对风险增加15倍。表型和基因型的组合是最能预测儿童IBD中抗TNF α原发性无应答的因素。定义抗TNF α应答的预测因子可能有助于识别无法从此类治疗中获益的患者。
Inter-individual variation in response to anti-TNFα therapy may be explained by genetic variability in disease pathogenesis or mechanism of action. Recent genome wide association studies (GWAS) in IBD have increased our understanding of the genetic susceptibility to IBD. Test associations of known IBD susceptibility loci and novel “pharmacogenetic” GWAS identified loci with primary non-response to anti-TNFα in pediatric IBD patients and develop a predictive model of primary non-response. Primary non response was defined using the HBI for CD and partial Mayo score for UC. Genotyping was performed using the Illumina Infinium platform. Chi square analysis tested associations of phenotype and genotype with primary non-response. Genetic associations were identified by testing known IBD susceptibility loci and by performing a GWAS for primary non-response. Step-wise multiple logistic regression was performed to build predictive models. Non-response occurred in 22 of 94 subjects. Six known susceptibility loci were associated with primary non-response (p < 0.05). Only the 21q22.2/BRWDI loci remained significant in the predictive model. The most predictive model included 3 novel “pharmacogenetic” GWAS loci, the previously identified BRWD1, pANCA and a UC diagnosis (R2 =0.82 and AUC = 0.98%). The relative risk of non-response increased 15 fold when number of risk factors increased from 0–2 to ≥ 3. The combination of phenotype and genotype is most predictive of primary non response to anti-TNFα in pediatric IBD. Defining predictors of response to anti-TNFα may allow the identification of patients who will not benefit from this class of therapy.
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影响因子：
30.8
作者：
Gunderson, KL;Steemers, FJ;Chee, MS
通讯作者：
Chee, MS
溃疡性结肠炎中克罗恩病风险的研究进一步定义了它们的分子关系。
影响因子：
29.4
作者：
Anderson CA;Massey DC;Barrett JC;Prescott NJ;Tremelling M;Fisher SA;Gwilliam R;Jacob J;Nimmo ER;Drummond H;Lees CW;Onnie CM;Hanson C;Blaszczyk K;Ravindrarajah R;Hunt S;Varma D;Hammond N;Lewis G;Attlesey H;Watkins N;Ouwehand W;Strachan D;McArdle W;Lewis CM;Wellcome Trust Case Control Consortium;Lobo A;Sanderson J;Jewell DP;Deloukas P;Mansfield JC;Mathew CG;Satsangi J;Parkes M
通讯作者：
Parkes M
DOI：
10.1016/j.cgh.2008.04.032
发表时间：
2008-10
期刊：
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
影响因子：
--
作者：
Dubinsky MC;Kugathasan S;Mei L;Picornell Y;Nebel J;Wrobel I;Quiros A;Silber G;Wahbeh G;Katzir L;Vasiliauskas E;Bahar R;Otley A;Mack D;Evans J;Rosh J;Hemker MO;Leleiko N;Crandall W;Langton C;Landers C;Taylor KD;Targan SR;Rotter JI;Markowitz J;Hyams J;Western Regional Pediatric IBD Research Alliance;Pediatric IBD Collaborative Research Group;Wisconsin Pediatric IBD Alliance
通讯作者：
Wisconsin Pediatric IBD Alliance
影响因子：
30.8
作者：
Fisher, Sheila A.;Tremelling, Mark;Anderson, Carl A.;Gwilliam, Rhian;Bumpstead, Suzannah;Prescott, Natalie J.;Nimmo, Elaine R.;Massey, Dunecan;Berzuini, Carlo;Johnson, Christopher;Barrett, Jeffrey C.;Cummings, Fraser R.;Drummond, Hazel;Lees, Charlie W.;Onnie, Clive M.;Hanson, Catherine E.;Blaszczyk, Katarzyna;Inouye, Mike;Ewels, Philip;Ravindrarajah, Radhi;Keniry, Andrew;Hunt, Sarah;Carter, Martyn;Watkins, Nick;Ouwehand, Willem;Lewis, Cathryn M.;Cardon, Lon;Lobo, Alan;Forbes, Alastair;Sanderson, Jeremy;Jewell, Derek P.;Mansfield, John C.;Deloukas, Panos;Mathew, Christopher G.;Parkes, Miles;Satsangi, Jack
通讯作者：
Satsangi, Jack
影响因子：
30.8
作者：
Kugathasan, Subra;Baldassano, Robert N.;Bradfield, Jonathan P.;Sleiman, Patrick M. A.;Imielinski, Marcin;Guthery, Stephen L.;Cucchiara, Salvatore;Kim, Cecilia E.;Frackelton, Edward C.;Annaiah, Kiran;Glessner, Joseph T.;Santa, Erin;Willson, Tara;Eckert, Andrew W.;Bonkowski, Erin;Shaner, Julie L.;Smith, Ryan M.;Otieno, F. George;Peterson, Nicholas;Abrams, Debra J.;Chiavacci, Rosetta M.;Grundmeier, Robert;Mamula, Petar;Tomer, Gitit;Piccoli, David A.;Monos, Dimitri S.;Annese, Vito;Denson, Lee A.;Grant, Struan F. A.;Hakonarson, Hakon
通讯作者：
Hakonarson, Hakon