The FoxP1 gene regulates lung function, production of matrix metalloproteinases and inflammatory mediators, and viability of lung epithelia.
The FoxP1 gene regulates lung function, production of matrix metalloproteinases and inflammatory mediators, and viability of lung epithelia.
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DOI：
10.1186/s12931-022-02213-4
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发表时间：
2022-10-11
影响因子：
5.8
通讯作者：
中科院分区：
文献类型：
--
作者：
参与肺发育的基因在成人生活中可能会变得失调，并参与肺部疾病的发病。多个基因调控肺发育，包括叉头盒蛋白P1-4(FoxP1-4)。我们研究了FoxP1-4基因变异与肺功能之间的关系，使用的数据来自GWA，其中包括近40万个个体和2000万个SNPs。FoxP1基因中的100多个变异与肺功能有关，但FoxP2-4基因中没有一个变异。与FEV1相关的FoxP1基因的前哨变异为rs1499894(C >； T)，与FVC相关的FoxP1基因的前哨变异为rs35480566(A >； G)。Rs1499894的T等位基因取代C等位基因，或rs35480566的G等位基因取代A等位基因的患者，转录数据中FoxP1基因表达水平升高，FEV1和FVC升高，被诊断为特发性肺纤维化的几率降低。此外，通过RNA干扰抑制肺上皮细胞中的FoxP1导致基质金属蛋白酶1、2、3以及促炎细胞因子IL-6和IL-8的mRNA水平增加，以及暴露于香烟烟雾后细胞活力下降-所有这些过程都与COPD和IPF的发病有关。我们的结果表明，FoxP1基因编码的蛋白可能对COPD和IPF的发展具有保护作用。FoxP1在COPD和IPF发病机制中的因果作用值得进一步研究，FoxP1可能成为治疗这些肺部疾病的新靶点。网上版载有补充材料，可在10.1186/s12931-022-02213-4查阅。
Genes involved in lung development may become dysregulated in adult life and contribute to the pathogenesis of lung diseases. Multiple genes regulate lung development, including Forkhead box protein P1-4 (FoxP1-4). We examined the association between variants in the FoxP1-4 genes and lung function using data from a GWAS that included close to 400,000 individuals and 20 million SNPs. More than 100 variants in the FoxP1 gene, but none in the FoxP2-4 genes, are associated with lung function. The sentinel variant in the FoxP1 gene associated with FEV1 was rs1499894 (C > T), while the sentinel variant in the FoxP1 gene associated with FVC was rs35480566 (A > G). Those with the T allele instead of the C allele for rs1499894, or the G allele instead of the A allele for rs35480566 had increased FoxP1 mRNA levels in transcriptomic data, higher FEV1 and FVC, and reduced odds of being diagnosed with idiopathic pulmonary fibrosis. Further, knockdown of FoxP1 in lung epithelial cells by RNA interference led to increased mRNA levels for matrix metalloproteinases 1, 2, 3 and pro-inflammatory cytokines IL-6 & IL-8, as well as reduced cell viability after exposure to cigarette smoke—all processes implicated in the pathogenesis of COPD and IPF. Our results suggest that the protein encoded by the FoxP1 gene may protect against the development of COPD and IPF. A causal role for FoxP1 in the pathogenesis of COPD and IPF may warrant further investigation, and FoxP1 may be a novel therapeutic target for these lung disorders. The online version contains supplementary material available at 10.1186/s12931-022-02213-4.
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DOI：
10.1007/s00018-021-03938-z
发表时间：
2021-11
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Romagnoli A;D'Agostino M;Ardiccioni C;Maracci C;Motta S;La Teana A;Di Marino D
通讯作者：
Di Marino D
影响因子：
6.9
作者：
Houghton, A. McGarry
通讯作者：
Houghton, A. McGarry
影响因子：
9.8
作者：
Brynedal, Boel;Choi, JinMyung;Cotsapas, Chris
通讯作者：
Cotsapas, Chris
影响因子：
30.8
作者：
Hobbs BD;de Jong K;Lamontagne M;Bossé Y;Shrine N;Artigas MS;Wain LV;Hall IP;Jackson VE;Wyss AB;London SJ;North KE;Franceschini N;Strachan DP;Beaty TH;Hokanson JE;Crapo JD;Castaldi PJ;Chase RP;Bartz TM;Heckbert SR;Psaty BM;Gharib SA;Zanen P;Lammers JW;Oudkerk M;Groen HJ;Locantore N;Tal-Singer R;Rennard SI;Vestbo J;Timens W;Paré PD;Latourelle JC;Dupuis J;O'Connor GT;Wilk JB;Kim WJ;Lee MK;Oh YM;Vonk JM;de Koning HJ;Leng S;Belinsky SA;Tesfaigzi Y;Manichaikul A;Wang XQ;Rich SS;Barr RG;Sparrow D;Litonjua AA;Bakke P;Gulsvik A;Lahousse L;Brusselle GG;Stricker BH;Uitterlinden AG;Ampleford EJ;Bleecker ER;Woodruff PG;Meyers DA;Qiao D;Lomas DA;Yim JJ;Kim DK;Hawrylkiewicz I;Sliwinski P;Hardin M;Fingerlin TE;Schwartz DA;Postma DS;MacNee W;Tobin MD;Silverman EK;Boezen HM;Cho MH;COPDGene Investigators;ECLIPSE Investigators;LifeLines Investigators;SPIROMICS Research Group;International COPD Genetics Network Investigators;UK BiLEVE Investigators;International COPD Genetics Consortium
通讯作者：
International COPD Genetics Consortium
影响因子：
4.8
作者：
Yang X;Zhong W;Cao R
通讯作者：
Cao R