DeMeo D L, Campbell E J, Brantly M L, Barker A F, Eden E, McElvaney N G, Rennard S I, Stocks J M, Stoller J K, Strange C, Turino G, Sandhaus R A, Silverman E K
Channing Laboratory and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.
Hum Hered. 2009;67(1):38-45. doi: 10.1159/000164397. Epub 2008 Oct 17.
Severe alpha-1 antitrypsin (AAT) deficiency is a proven genetic risk factor for COPD, but there is marked variation in the development of COPD among AAT deficient subjects. To investigate familial aggregation of lung function in subjects with AAT deficiency, we estimated heritability for forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) in 378 AAT deficient subjects from 167 families in the AAT Genetic Modifiers Study; all subjects were verified homozygous for the Z AAT deficiency allele. Heritability was evaluated for models that included and excluded an ascertainment correction, as well as for models that excluded, included and were stratified by a cigarette smoking covariate. In models without an ascertainment correction, and in all models without a covariate for smoking, no evidence for familial aggregation of lung function was observed. In models conditioned on the index proband with covariates for smoking, post-bronchodilator FEV1/FVC demonstrated significant heritability (0.26 +/- 0.14, p = 0.03). When we limited the analysis to subjects with a smoking history, post-bronchodilator FEV1 demonstrated significant heritability (0.47 +/- 0.21, p = 0.02). Severity rate phenotypes were also assessed as potential phenotypes for genetic modifier studies. Significant heritability was found with all age-of-onset threshold models that included smoking and ascertainment adjustments. Using the t-distribution, the heritability estimates ranged from 0.43 to 0.64, depending on the age-of-onset of FEV1 decline used for the severity rate calculation. Correction for ascertainment and consideration of gene-by-smoking interactions will be crucial for the identification of genes that may modify susceptibility for COPD in families with AAT deficiency.
严重的α1抗胰蛋白酶（AAT）缺乏是慢性阻塞性肺疾病（COPD）已被证实的遗传危险因素，但在AAT缺乏的受试者中，COPD的发病情况存在显著差异。为了研究AAT缺乏受试者肺功能的家族聚集性，我们在AAT基因修饰研究中，对来自167个家庭的378名AAT缺乏受试者的1秒用力呼气容积（FEV1）和FEV1/用力肺活量（FVC）的遗传力进行了估计；所有受试者均被证实为Z型AAT缺乏等位基因的纯合子。对包括和排除确定校正的模型，以及排除、包括吸烟协变量并按其分层的模型进行了遗传力评估。在没有确定校正的模型中，以及在所有没有吸烟协变量的模型中，未观察到肺功能家族聚集的证据。在以吸烟协变量为条件的先证者模型中，支气管扩张剂后FEV1/FVC显示出显著的遗传力（0.26±0.14，p = 0.03）。当我们将分析限于有吸烟史的受试者时，支气管扩张剂后FEV1显示出显著的遗传力（0.47±0.21，p = 0.02）。严重程度率表型也被评估为基因修饰研究的潜在表型。在所有包括吸烟和确定校正的发病年龄阈值模型中均发现了显著的遗传力。根据用于严重程度率计算的FEV1下降的发病年龄，使用t分布，遗传力估计值范围为0.43至0.64。确定校正以及基因与吸烟相互作用的考虑对于识别可能改变AAT缺乏家族中COPD易感性的基因至关重要。
