Choi Eun Hwa, Ehrmantraut Mary, Foster Charles B, Moss Joel, Chanock Stephen J
Section on Genomic Variation, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4065, USA.
Pediatr Pulmonol. 2006 Mar;41(3):255-62. doi: 10.1002/ppul.20361.
Most individual cystic fibrosis transmembrane conductance regulator (CFTR) mutations appear not to correlate directly with severity of lung damage in cystic fibrosis (CF). Components of innate immunity, namely, mannose-binding lectin (MBL2), and surfactant protein A1 and A2 genes (SFTPA1 and SFTPA2), were shown to be critical in pulmonary host defenses. A pilot association study was conducted to identify genetic modifiers of lung disease in adult patients with CF. The structural and promoter (-221x/y) variants of MBL2, variants at codons 19, 50, 62, and 219 of SFTPA1, and at codons 9, 91, and 223 for SFTPA2, were studied in 135 adults with CF and compared to their forced expired volume in 1 sec (FEV1), diffusion of CO (DLCO), and other pulmonary scores. Predicted FEV1 was significantly lower in adults with the SFTPA1 6A3 allele and SFTPA2 1A1) allele (P = 0.01 and 0.009, respectively). The extended haplotype 6A3/1A1, which includes SFTPA1 and SFTPA2, was associated with lower pulmonary function, using FEV1 (P = 0.005) and poor pulmonary scores which were determined by American Medical Association, American Thoracic Society, and modified Shwachman-Kulczycki scores. Lower FEV1 and DLCO values were associated with MBL2 coding variants in those who had the DeltaF508 CFTR mutation (P = 0.03 and 0.004, respectively). These results support the current hypothesis that variants in pulmonary host defense molecules are potentially genetic modifiers of pulmonary disease in CF. Further work in larger populations is required to provide important new insights into the pathogenesis of CF.
大多数个体囊性纤维化跨膜传导调节因子（CFTR）突变似乎与囊性纤维化（CF）患者肺部损伤的严重程度没有直接关联。先天免疫成分，即甘露糖结合凝集素（MBL2）以及表面活性蛋白A1和A2基因（SFTPA1和SFTPA2），已被证明在肺部宿主防御中至关重要。开展了一项初步关联研究，以确定成年CF患者肺部疾病的基因修饰因子。在135名成年CF患者中研究了MBL2的结构和启动子（-221x/y）变体、SFTPA1第19、50、62和219密码子处的变体以及SFTPA2第9、91和223密码子处的变体，并将其与他们的一秒用力呼气容积（FEV1）、一氧化碳弥散量（DLCO）及其他肺部评分进行比较。携带SFTPA1 6A3等位基因和SFTPA2 1A1等位基因的成年患者预测FEV1显著更低（分别为P = 0.01和0.009）。包含SFTPA1和SFTPA2的扩展单倍型6A3/1A1与较低的肺功能相关，采用FEV1衡量时（P = 0.005），并且与美国医学协会、美国胸科学会和改良的施瓦赫曼-库尔奇茨基评分所确定的较差肺部评分相关。对于携带ΔF508 CFTR突变的患者，较低的FEV1和DLCO值与MBL2编码变体相关（分别为P = 0.03和0.004）。这些结果支持了当前的假说，即肺部宿主防御分子中的变体可能是CF患者肺部疾病的基因修饰因子。需要在更大规模人群中开展进一步研究，以深入了解CF的发病机制。
