Linkage analysis of alpha 1-antitrypsin deficiency: lessons for complex diseases.
Linkage analysis of alpha 1-antitrypsin deficiency: lessons for complex diseases.
复制标题
α1-抗胰蛋白酶缺乏症的连锁分析：复杂疾病的教训。
DOI：
10.1159/000053380
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发表时间：
2001
期刊：
影响因子：
1.8
通讯作者：
Campbell,EJ
中科院分区：
文献类型：
--
作者：
Silverman,EK;Mosley,JD;Rao,DC;Palmer,LJ;Province,MA;Elston,RC;Weiss,ST;Campbell,EJ
目的：严重α 1-抗胰蛋白酶（A1 AT）缺乏是慢性阻塞性肺疾病（COPD）的一个已证实的遗传危险因素。在没有A1 AT缺乏的个体中，COPD已被证明具有家族聚集性，但尚未报道COPD的连锁分析。为了探讨COPD连锁分析的最佳表型定义和分析方法，我们检查了一组包含155个个体的28个A1 AT缺陷家族。我们将蛋白酶抑制剂（PI）基因型作为遗传标记而不是疾病基因，并对PI基因型与血清A1 AT水平及肺功能相关表型进行了连锁分析（FEV 1作为预测%），FEV 1与用力肺活量的比率（FEV 1/FVC为%预测值）和血清A1 AT水平，在SOLAR中使用方差分量法，在CAMPAL中使用广义估计方程法，以及LINKAGE中基于模型的经典lod评分法。使用基于模型的方法（LINKAGE）和无模型方法（GENEHUNTER）进行定性A1 AT和肺活量测定表型的连锁分析。调整吸烟的影响进行了调查下each methods.ResultsAll的方法证明联系的PI型血清A1 AT水平。然而，有趣的是，其他定量表型仅提供了PI型与肺部疾病联系的弱证据。更好的证据，肺疾病的联系PI型被发现使用一个温和的或温和的阈值的定义气流obligation.ConclusionsFor连锁分析的肺功能表型在A1 AT缺乏症，定性表型提供了更有力的证据，连锁比定量表型。与定性肺功能测定表型相关的更有力证据的可能贡献者包括PI Z受试者的确定方案和肺功能数据的非正态性。本研究为与A1 AT缺乏无关的COPD遗传学研究提供了指导。
ObjectivesSevere alpha 1-antitrypsin (A1AT) deficiency is the one proven genetic risk factor for chronic obstructive pulmonary disease (COPD). Familial aggregation has been demonstrated for COPD among individuals who do not have A1AT deficiency, but linkage analysis of COPD has not been reported. To investigate the optimal phenotype definitions and analytical methods for the linkage analysis of COPD, we examined a set of 28 A1AT-deficient families containing 155 individuals. We have used the protease inhibitor (PI) type as a genetic marker rather than a disease gene, and we have performed linkage analysis between PI type and serum A1AT level and spirometry-related phenotypes.MethodsLinkage analysis was performed on the quantitative phenotypes forced expiratory volume at 1 s (FEV 1 as% predicted), the ratio of FEV 1 to forced vital capacity (FEV 1/FVC as% predicted), and serum A1AT level using the variance component approach in SOLAR, the generalized estimating equation approach in RELPAL, and the model-based classical lod score method in LINKAGE. Linkage analysis with qualitative A1AT and spirometry phenotypes was performed using a model-based method (LINKAGE) and a model-free method (GENEHUNTER). Adjustments for smoking effects were investigated under each method.ResultsAll of the methods demonstrated linkage of PI type to serum A1AT level. Interestingly, however, the other quantitative phenotypes provided only weak evidence for linkage of PI type to lung disease. Better evidence for linkage of lung disease to PI type was found using a moderate or a mild threshold for the definition of airflow obstruction.ConclusionsFor linkage analysis of spirometry phenotypes in A1AT deficiency, qualitative phenotypes provided stronger evidence for linkage than quantitative phenotypes. Possible contributors to the stronger evidence for linkage to qualitative spirometry phenotypes include the ascertainment scheme and the nonnormality of the pulmonary function data in PI Z subjects. This study provides guidelines for studies of the genetics of COPD unrelated to A1AT deficiency.