McKone Edward F, Shao Jing, Frangolias Daisy D, Keener Cassie L, Shephard Cynthia A, Farin Federico M, Tonelli Mark R, Pare Peter D, Sandford Andrew J, Aitken Moira L, Kavanagh Terrance J
Department of Environmental and Occupational Health Sciences, University of Washington Mail Box 354695, Seattle, WA 98195, USA.
Am J Respir Crit Care Med. 2006 Aug 15;174(4):415-9. doi: 10.1164/rccm.200508-1281OC. Epub 2006 May 11.
Chronic progressive lung disease is the most serious complication of cystic fibrosis (CF). Glutathione plays an important role in the protection of the CF lung against oxidant-induced lung injury.
We hypothesized that a polymorphism in a novel candidate gene that regulates glutathione synthesis might influence CF lung disease.
In a cross-sectional study, subjects were recruited from CF clinics in Seattle and multiple centers in Canada. We tested for an association between CF lung disease and a functional polymorphism in the glutamate-cysteine ligase catalytic subunit (GCLC) gene. Multiple linear regression was used to test for association between polymorphisms of GCLC and severity of CF lung disease while adjusting for age, Pseudomonas aeruginosa infection, and cystic fibrosis transmembrane conductance regulator (CFTR) genotype. Analysis was repeated for patients with CF stratified by CFTR genotype.
A total of 440 subjects with CF participated in the study (51% male; mean [+/- SD] age, 26 +/- 11 yr; mean FEV(1), 62 +/- 28% predicted). In the total population, there was a trend toward an association between GCLC genotypes and CF lung disease (linear regression coefficient [SEM], 1.68 [1.0]; p = 0.097). In the stratified analysis, there was a highly significant association between GCLC genotype and CF lung function in subjects with a milder CFTR genotype (linear regression coefficient [SEM], 5.5 (1.7); p = 0.001).
In patients with CF with a milder CFTR genotype, there is a strong association between functional polymorphisms of the GCLC gene and CF lung disease severity.
慢性进行性肺病是囊性纤维化（CF）最严重的并发症。谷胱甘肽在保护CF肺免受氧化应激诱导的肺损伤中起重要作用。
我们假设一个调控谷胱甘肽合成的新候选基因中的多态性可能影响CF肺病。
在一项横断面研究中，受试者从西雅图的CF诊所和加拿大的多个中心招募。我们检测了CF肺病与谷氨酸-半胱氨酸连接酶催化亚基（GCLC）基因功能性多态性之间的关联。在调整年龄、铜绿假单胞菌感染和囊性纤维化跨膜传导调节因子（CFTR）基因型的同时，使用多元线性回归检测GCLC多态性与CF肺病严重程度之间的关联。对按CFTR基因型分层的CF患者重复进行分析。
共有440例CF患者参与了研究（51%为男性；平均[±标准差]年龄，26±11岁；平均第一秒用力呼气容积[FEV(1)]，为预测值的62±28%）。在总体人群中，GCLC基因型与CF肺病之间存在关联趋势（线性回归系数[标准误]，1.68[1.0]；p = 0.097）。在分层分析中，CFTR基因型较轻的受试者中，GCLC基因型与CF肺功能之间存在高度显著的关联（线性回归系数[标准误]，5.5（1.7）；p = 0.001）。
在CFTR基因型较轻的CF患者中，GCLC基因的功能性多态性与CF肺病严重程度之间存在强关联。
