Epistasis between serine protease inhibitor Kazal-type 5 (SPINK5) and thymic stromal lymphopoietin (TSLP) genes contributes to childhood asthma.
Epistasis between serine protease inhibitor Kazal-type 5 (SPINK5) and thymic stromal lymphopoietin (TSLP) genes contributes to childhood asthma.
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DOI：
10.1016/j.jaci.2014.03.037
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发表时间：
2014-10
影响因子：
14.2
通讯作者：
Hershey, Gurjit K. Khurana
中科院分区：
文献类型：
--
作者：
Myers, Jocelyn M. Biagini;Martin, Lisa J.;Kovacic, Melinda Butsch;Mersha, Tesfaye B.;He, Hua;Pilipenko, Valentina;Lindsey, Mark A.;Ericksen, Mark B.;Bernstein, David I.;LeMasters, Grace K.;Lockey, James E.;Hershey, Gurjit K. Khurana
上皮基因以前曾与哮喘有关，但只能解释一小部分遗传性。在某种程度上，这可能是由于上位性，往往不考虑。确定FLG、SPINK 5和TSLP基因变异体与儿童哮喘之间的独立和上位关联。使用候选基因的方法，我们在哮喘，过敏，非过敏-非哮喘白色和黑人儿童参与了良好的表型大辛辛那提儿科诊所储存库（GCPCR）的FLG，SPINK 5和TSLP的29个变异体的基因分型。与哮喘的关联也在6个重复人群中进行了评估。我们观察到SPINK 5（p=0.003）和TSLP（p=0.006）变异与儿童哮喘的独立关联; SPINK 5 SNP被复制。在具有一个或多个SPINK 5风险等位基因的受试者中，TSLP保护性次要等位基因的缺失与哮喘的显著增加相关（67% vs. 53%，p=0.0017）。相反，TSLP次要等位基因的存在或不存在并不影响无SPINK 5风险等位基因的受试者的哮喘风险。SPINK 5和TSLP上位性在黑人群体中复制（p=0.036），其未显示与这些基因中的变体的独立关联。我们的研究结果支持SPINK 5和TSLP之间的上位性，这有助于儿童哮喘。这些发现强调了利用生物学为分析提供信息以确定复杂疾病的遗传易感性的重要性。我们的研究结果具有临床相关性，并支持哮喘患者抗TSLP治疗的治疗效果可能取决于SPINK 5基因型。
Epithelial genes have previously been associated with asthma, but only explain a small fraction of heritability. In part, this may be due to epistasis that is often not considered. To determine independent and epistatic associations between FLG, SPINK5 and TSLP gene variants and childhood asthma. Using a candidate gene approach, we genotyped 29 variants in FLG, SPINK5 and TSLP in asthmatic, allergic, and non-allergic-non-asthmatic white and black children participating in the well-phenotyped Greater Cincinnati Pediatric Clinic Repository (GCPCR). Associations with asthma were also assessed in six replication populations. We observed independent associations of variants in SPINK5 (p=0.003) and TSLP (p=0.006) with childhood asthma; a SPINK5 SNP was replicated. In subjects with one or more SPINK5 risk alleles, the absence of the TSLP protective minor alleles was associated with a significant increase in asthma (67% vs. 53%, p=0.0017). In contrast, the presence or absence of TSLP minor alleles did not affect asthma risk in subjects without the SPINK5 risk alleles. The SPINK5 and TSLP epistasis was replicated in a black population (p=0.036) that did not display independent association with variants in these genes. Our results support epistasis between SPINK5 and TSLP which contributes to childhood asthma. These findings emphasize the importance of utilizing biology to inform analyses to identify genetic susceptibility to complex diseases. The results from our study have clinical relevance and support that the therapeutic effects of anti-TSLP therapy in asthmatics may be dependent on SPINK5 genotype.
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影响因子：
3.7
作者：
Baye TM;Butsch Kovacic M;Biagini Myers JM;Martin LJ;Lindsey M;Patterson TL;He H;Ericksen MB;Gupta J;Tsoras AM;Lindsley A;Rothenberg ME;Wills-Karp M;Eissa NT;Borish L;Khurana Hershey GK
通讯作者：
Khurana Hershey GK
DOI：
10.1084/jem.20082242
发表时间：
2009-05-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Briot A;Deraison C;Lacroix M;Bonnart C;Robin A;Besson C;Dubus P;Hovnanian A
通讯作者：
Hovnanian A
影响因子：
3.7
作者：
Chen ZG;Zhang TT;Li HT;Chen FH;Zou XL;Ji JZ;Chen H
通讯作者：
Chen H
影响因子：
3.9
作者：
Kosoy, Roman;Nassir, Rami;Tian, Chao;White, Phoebe A.;Butler, Lesley M.;Silva, Gabriel;Kittles, Rick;Alarcon-Riquelme, Marta E.;Gregersen, Peter K.;Belmont, John W.;De La Vega, Francisco M.;Seldin, Michael F.
通讯作者：
Seldin, Michael F.
影响因子：
3.7
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
通讯作者：
Hershey GK