Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients.
Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients.
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全基因组关联研究确定了与哮喘患者肺功能相关的 TH1 通路基因。
DOI：
10.1016/j.jaci.2013.01.051
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发表时间：
2013-08
影响因子：
14.2
通讯作者：
Bleecker, Eugene R.
中科院分区：
文献类型：
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作者：
Li, Xingnan;Hawkins, Gregory A.;Ampleford, Elizabeth J.;Moore, Wendy C.;Li, Huashi;Hastie, Annette T.;Howard, Timothy D.;Boushey, Homer A.;Busse, William W.;Calhoun, William J.;Castro, Mario;Erzurum, Serpil C.;Israel, Elliot;Lemanske, Robert F., Jr.;Szefler, Stanley J.;Wasserman, Stephen I.;Wenzel, Sally E.;Peters, Stephen P.;Meyers, Deborah A.;Bleecker, Eugene R.
最近对欧洲血统的一般人群的全基因组关联研究的荟萃分析已经确定了28个肺功能位点。我们试图确定新的肺功能基因位点，特别是哮喘和确认肺功能基因位点确定在一般人群中。在4个欧洲血统的白色人群（n = 1544）中进行肺功能的全基因组关联研究（预测FEV 1百分比[ppFEV 1]、预测用力肺活量百分比和FEV 1/用力肺活量比），随后进行荟萃分析。在普通人群中发现的28个肺功能基因座中，有7个（HHIP、FAM 13 A、THSD 4、GSTCD、NOTCH 4-AGER、RARB和ZNF 323）在单核苷酸多态性（SNP）水平得到证实（P < .05）。与ppFEV 1相关的32个位点中的4个（IL 12 A、IL 12 RB 1、STAT 4和IRF 2）（P < 10−4）属于TH 1或IL-12细胞因子家族通路。通过使用线性加性模型，这4个TH 1途径SNP累积解释了4个人群ppFEV 1值方差的2.9%至7.8%（P = 3 × 10−11）。在重度哮喘研究项目人群中，这4个SNP的遗传评分与ppFEV 1值（P = 2 × 10−7）和美国胸科学会重度哮喘分类（P = .005）相关。TH 2通路基因（IL 13、TSLP、IL 33和IL 1 RL 1）赋予哮喘易感性与肺功能无关。参与气道结构/重塑的基因与普通人群和哮喘受试者的肺功能相关。参与抗病毒/细菌感染和炎症的TH 1途径基因改变哮喘受试者的肺功能。可能影响哮喘严重程度的与肺功能相关的基因不同于与哮喘易感性相关的基因。
Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function. We sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations. Genome-wide association studies of lung function (percent predicted FEV1 [ppFEV1], percent predicted forced vital capacity, and FEV1/forced vital capacity ratio) were performed in 4 white populations of European descent (n = 1544), followed by meta-analyses. Seven of 28 previously identified lung function loci (HHIP, FAM13A, THSD4, GSTCD, NOTCH4-AGER, RARB, and ZNF323) identified in general populations were confirmed at single nucleotide polymorphism (SNP) levels (P < .05). Four of 32 loci (IL12A, IL12RB1, STAT4, and IRF2) associated with ppFEV1 (P < 10−4) belong to the TH1 or IL-12 cytokine family pathway. By using a linear additive model, these 4 TH1 pathway SNPs cumulatively explained 2.9% to 7.8% of the variance in ppFEV1 values in 4 populations (P = 3 × 10−11). Genetic scores of these 4 SNPs were associated with ppFEV1 values (P = 2 × 10−7) and the American Thoracic Society severe asthma classification (P = .005) in the Severe Asthma Research Program population. TH2 pathway genes (IL13, TSLP, IL33, and IL1RL1) conferring asthma susceptibility were not associated with lung function. Genes involved in airway structure/remodeling are associated with lung function in both general populations and asthmatic subjects. TH1 pathway genes involved in anti-virus/bacterial infection and inflammation modify lung function in asthmatic subjects. Genes associated with lung function that might affect asthma severity are distinct from those genes associated with asthma susceptibility.
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