N Zamel, PA McClean, PR Sandell, KA Siminovitch and AS Slutsky
Department of Medicine, University of Toronto, Ontario, Canada.

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.

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