Hawkins Gregory A, Lazarus Ross, Smith Richard S, Tantisira Kelan G, Meyers Deborah A, Peters Stephen P, Weiss Scott T, Bleecker Eugene R
Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases, Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
J Allergy Clin Immunol. 2009 Jun;123(6):1376-83.e7. doi: 10.1016/j.jaci.2009.01.049. Epub 2009 Feb 28.
Corticosteroids exert their anti-inflammatory action by binding and activating the intracellular glucocorticoid receptor heterocomplex.
We sought to evaluate the genes HSPCB, HSPCA, STIP1, HSPA8, DNAJB1, PTGES3, FKBP5, and FKBP4 on corticosteroid response.
White asthmatic subjects (n = 382) randomized to once-daily flunisolide or conventional inhaled corticosteroid therapy were genotyped. Outcome measures were baseline FEV1, percent predicted FEV1, and percent change in FEV1 after corticosteroid treatment. Multivariable analyses adjusted for age, sex, and height were performed, fitting the most appropriate genetic model based on the quantitative mean derived from ANOVA models to determine whether there was an independent effect of polymorphisms on change in FEV1 independent of baseline level.
Positive recessive model correlations for STIP1 single nucleotide polymorphisms were observed for baseline FEV1 (rs4980524, P = .009; rs6591838, P = .0045; rs2236647, P = .002; and rs2236648; P = .013), baseline percent predicted FEV1 (rs4980524, P = .002; rs6591838, P = .017; rs2236647, P = .003; and rs2236648, P = .008), and percent change in FEV1 at 4 weeks (rs4980524, P = .044; rs6591838, P = .016; and rs2236647, P = .01) and 8 weeks (rs4980524, P = .044; rs6591838, P = .016; and rs2236647; P = .01) or therapy. Haplotypic associations were observed for baseline FEV1 and percent change in FEV1 at 4 weeks of therapy (P = .05 and P = .01, respectively). Significant trends toward association were observed for baseline percent predicted FEV1 and percent change in FEV1 at 8 weeks of therapy. Positive correlations between haplotypes and percent change in FEV1 were also observed.
STIP1 genetic variations might play a role in regulating corticosteroid response in asthmatic subjects with reduced lung function. Replication in a second asthmatic population is required to confirm these observations.
皮质类固醇通过结合并激活细胞内糖皮质激素受体异源复合物发挥其抗炎作用。
我们试图评估基因HSPCB、HSPCA、STIP1、HSPA8、DNAJB1、PTGES3、FKBP5和FKBP4对皮质类固醇反应的影响。
对随机接受每日一次氟尼缩松或传统吸入性皮质类固醇治疗的白人哮喘患者（n = 382）进行基因分型。观察指标为基线第1秒用力呼气容积（FEV1）、预计FEV1百分比以及皮质类固醇治疗后FEV1的变化百分比。进行了针对年龄、性别和身高的多变量分析，并根据方差分析模型得出的定量均值拟合最合适的遗传模型，以确定多态性对FEV1变化是否存在独立于基线水平的影响。
观察到STIP1单核苷酸多态性与基线FEV1（rs4980524，P = 0.009；rs6591838，P = 0.0045；rs2236647，P = 0.002；rs2236648，P = 0.013）、基线预计FEV1百分比（rs4980524，P = 0.002；rs6591838，P = 0.017；rs2236647，P = 0.003；rs2236648，P = 0.008）以及治疗4周（rs4980524，P = 0.044；rs6591838，P = 0.016；rs2236647，P = 0.01）和8周（rs4980524，P = 0.044；rs6591838，P = 0.016；rs2236647，P = 0.01）时FEV1变化百分比或治疗之间存在正隐性模型相关性。观察到治疗4周时基线FEV1与FEV1变化百分比之间存在单倍型关联（分别为P = 0.05和P = 0.01）。观察到治疗8周时基线预计FEV1百分比与FEV1变化百分比之间存在显著的关联趋势。还观察到单倍型与FEV1变化百分比之间存在正相关。
STIP1基因变异可能在调节肺功能降低的哮喘患者的皮质类固醇反应中起作用。需要在另一组哮喘人群中进行重复研究以证实这些观察结果。
