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Zamel N, McClean PA, Sandell PR, Siminovitch KA, Slutsky AS.
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.