Identification of KIF3A as a novel candidate gene for childhood asthma using RNA expression and population allelic frequencies differences.
Identification of KIF3A as a novel candidate gene for childhood asthma using RNA expression and population allelic frequencies differences.
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DOI：
10.1371/journal.pone.0023714
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Hershey GK
中科院分区：
文献类型：
--
作者：
Kovacic MB;Myers JM;Wang N;Martin LJ;Lindsey M;Ericksen MB;He H;Patterson TL;Baye TM;Torgerson D;Roth LA;Gupta J;Sivaprasad U;Gibson AM;Tsoras AM;Hu D;Eng C;Chapela R;Rodríguez-Santana JR;Rodríguez-Cintrón W;Avila PC;Beckman K;Seibold MA;Gignoux C;Musaad SM;Chen W;Burchard EG;Hershey GK
哮喘是一种慢性炎症性疾病，具有很强的遗传易感性。哮喘候选基因关联研究的一个主要挑战是生物相关基因的选择。利用上皮RNA表达谱、HapMap等位基因频率变异和文献资料，我们确定了6个可能的儿童哮喘易感基因，包括ADCY2、DNAH5、KIF3A、PDE4B、PLAU、SPRR2B。为了评估这些基因，我们比较了790名哮喘、过敏性和非过敏性儿童中194个主要标记SNPs的基因类型。我们发现，在我们发现的队列中，所有六个基因中的SNP在名义上与哮喘有关(p<；0.05)，在三个独立的队列中，在SNP或基因水平上(p<；0.05)。此外，我们确定我们的选择方法优于随机选择与对照组相比在哮喘患者中差异表达的基因(p = 0.0049)或仅基于文献选择的基因(p = 0.0049)，证实了我们的基因选择方法的有效性。重要的是，我们观察到KIF3A基因中的9个SNP中有7个会使患哮喘的几率增加一倍以上(OR = 2.3，p<；0.0001)，并增加患过敏性疾病的几率(OR = 1.8，p<；0.008)。我们的数据表明，KIF3A rs7737031(T等位基因)具有18.5%的哮喘人群归因风险。KIF3A rs7737031与哮喘的相关性在3个独立的人群中得到了验证，进一步证实了我们基因选择方法的有效性。我们的研究表明，KIF3A是微管相关运动蛋白超家族的成员，在纤毛内蛋白质复合体的运输中起重要作用，是儿童哮喘的一个新的候选基因。KIF3A基因的多态性可能是导致呼吸道粘液和/或过敏原清除不良的部分原因。此外，我们的研究为识别和评估新的候选易感基因提供了一个有前景的框架。
Asthma is a chronic inflammatory disease with a strong genetic predisposition. A major challenge for candidate gene association studies in asthma is the selection of biologically relevant genes. Using epithelial RNA expression arrays, HapMap allele frequency variation, and the literature, we identified six possible candidate susceptibility genes for childhood asthma including ADCY2, DNAH5, KIF3A, PDE4B, PLAU, SPRR2B. To evaluate these genes, we compared the genotypes of 194 predominantly tagging SNPs in 790 asthmatic, allergic and non-allergic children. We found that SNPs in all six genes were nominally associated with asthma (p<0.05) in our discovery cohort and in three independent cohorts at either the SNP or gene level (p<0.05). Further, we determined that our selection approach was superior to random selection of genes either differentially expressed in asthmatics compared to controls (p = 0.0049) or selected based on the literature alone (p = 0.0049), substantiating the validity of our gene selection approach. Importantly, we observed that 7 of 9 SNPs in the KIF3A gene more than doubled the odds of asthma (OR = 2.3, p<0.0001) and increased the odds of allergic disease (OR = 1.8, p<0.008). Our data indicate that KIF3A rs7737031 (T-allele) has an asthma population attributable risk of 18.5%. The association between KIF3A rs7737031 and asthma was validated in 3 independent populations, further substantiating the validity of our gene selection approach. Our study demonstrates that KIF3A, a member of the kinesin superfamily of microtubule associated motors that are important in the transport of protein complexes within cilia, is a novel candidate gene for childhood asthma. Polymorphisms in KIF3A may in part be responsible for poor mucus and/or allergen clearance from the airways. Furthermore, our study provides a promising framework for the identification and evaluation of novel candidate susceptibility genes.
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影响因子：
8
作者：
Akinbami, LJ;Rhodes, JC;Lara, M
通讯作者：
Lara, M
影响因子：
14.9
作者：
LAIRD, PW;ZIJDERVELD, A;BERNS, A
通讯作者：
BERNS, A
DOI：
10.1089/jamp.2007.0659
发表时间：
2008-03-01
影响因子：
3.4
作者：
Mall, Marcus A.
通讯作者：
Mall, Marcus A.
影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
DOI：
10.1164/rccm.200309-1293oc
发表时间：
2004-02-01
影响因子：
24.7
作者：
Burchard, EG;Avila, PC;Silverman, EK
通讯作者：
Silverman, EK