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Background: Familial aggregation of specific response to allergens and asthma adjusted for age and sensitization to multiple allergens was assessed in two large population cohorts. Methods: Allergen skin prick tests (SPTs) were administered to 1151 families in the Tucson Childrens Respiratory Study (CRS) and 435 families in the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD). Sensitization was defined by wheal size =3 mm; physician-diagnosed asthma at age =8 yr was based on questionnaires. Using s.a.g.e. 6.1 software assoc and fcor, familial correlations of crude and adjusted phenotypes were evaluated. Results: Crude estimates of parentoffspring (PO) and sibling correlations were statistically significant for most allergens, ranging from 0.03 to 0.29. After adjusting for age of assessment and other atopy (SPT-positive response to additional allergens), correlations were reduced by 1471%. Sibling correlations for specific response to allergens were consistently higher than PO correlations, but this difference was significant only for dust mite and weed mix in the TESAOD population. Familial correlation for atopic status (any positive SPTs vs. none) tended to be higher than for specific allergens. Asthma, with and without adjustment, showed greater familial correlation than either specific or general SPT response and significantly higher sibling correlation in TESAOD than in CRS, probably due to the older age of the siblings and the longer period of ascertainment. Conclusions: Significant familial aggregation of specific response to allergen after adjustment for other atopy appears to reflect a genetic propensity toward atopy, dependent on shared familial exposures. Results also suggest that inheritance of asthma is independent of atopic sensitization.