Zamel N, McClean P A, Sandell P R, Siminovitch K A, Slutsky A S
Department of Medicine, University of Toronto, Ontario, Canada.
Am J Respir Crit Care Med. 1996 Jun;153(6 Pt 1):1902-6. doi: 10.1164/ajrccm.153.6.8665053.
Although asthma has a significant heritable component, the mode of inheritance remains controversial because of the complexity of the disease and the influence of environmental factors. Isolated, inbred populations serve to reduce variability, thus increasing the probability of gene localization. We studied the inbred population of the remote island of Tristan da Cunha to document asthma prevalence for the purpose of genetic linkage analysis. Medical histories and skin atopy were determined on 282 islanders, representing 97% of the population, and airway responsiveness was measured in 254; 226 by methacholine challenge (tidal breathing method) and 28 by bronchodilator response (400 micrograms salbutamol aerosol). Blood samples were collected from 275 islanders. Participants ranged in age from 3 to 94 yr. Asthma was defined as increased airway responsiveness (AR+: PC20 < 4 mg/ml or > or = 15% increase in FEV1 postbronchodilator) combined with a positive history (Hx+). Fifty-seven percent of the islanders had at least partial evidence of asthma (Hx+ and/or AR+) and 23% had a definitive diagnosis of asthma (AR+ with Hx+). Overall 47% of the population were atopic, atopy was proportionally higher in asthmatics (74%) than nonasthmatics (32%; p < 0.01). Analysis of the methacholine dose-response curves demonstrated that asthmatics were significantly (p < 0.01) more responsive than those with AR+ only, and nonasthmatics (AR-, Hx-) were more responsive than laboratory control subjects (p < 0.05), suggesting that these islanders may also carry an airway hyperresponsiveness gene. A frequency plot of the percent fall in FEV1 for all Hx- subjects compared with control data suggests a bimodal distribution consistent with a major gene mechanism for airway responsiveness. Genealogy mapping revealed that the islanders are direct descendants of the 15 original settlers, and historical records suggest at least two founders may have been asthmatic. The data confirm previous reports of a high asthma prevalence on Tristan and support the postulate that this prevalence is a result of gene enrichment occurring in isolated populations by virtue of extensive inbreeding and a probable founder effect.
尽管哮喘具有显著的遗传成分，但由于该疾病的复杂性和环境因素的影响，其遗传模式仍存在争议。隔离的近亲繁殖群体有助于减少变异性，从而增加基因定位的可能性。我们研究了特里斯坦-达库尼亚偏远岛屿上的近亲繁殖群体，以记录哮喘患病率，用于遗传连锁分析。我们确定了282名岛民（占该群体的97%）的病史和皮肤过敏情况，并对254人进行了气道反应性测量；其中226人采用乙酰甲胆碱激发试验（潮气呼吸法），28人采用支气管扩张剂反应试验（400微克沙丁胺醇气雾剂）。我们从275名岛民中采集了血样。参与者年龄在3岁至94岁之间。哮喘被定义为气道反应性增加（AR+：PC20<4mg/ml或支气管扩张剂使用后FEV1增加≥15%）并伴有阳性病史（Hx+）。57%的岛民至少有部分哮喘证据（Hx+和/或AR+），23%的人被确诊为哮喘（AR+且Hx+）。总体而言，47%的人群有特应性，哮喘患者中的特应性比例（74%）高于非哮喘患者（32%；p<0.01）。对乙酰甲胆碱剂量反应曲线的分析表明，哮喘患者的反应性显著高于仅具有AR+的患者（p<0.01），而非哮喘患者（AR-，Hx-）的反应性高于实验室对照受试者（p<0.05），这表明这些岛民可能也携带气道高反应性基因。所有Hx-受试者的FEV1下降百分比与对照数据的频率图显示出双峰分布，这与气道反应性的主要基因机制一致。系谱图显示这些岛民是15名原始定居者的直系后代，历史记录表明至少有两名奠基者可能患有哮喘。这些数据证实了之前关于特里斯坦岛哮喘患病率高的报道，并支持这样一种假设，即这种高患病率是由于隔离群体中通过广泛近亲繁殖和可能的奠基者效应导致基因富集的结果。
