Asthma is an inflammatory airways disease associated with intermittent respiratory symptoms, bronchial hyper-responsiveness (BHR) and reversible airflow obstruction and is phenotypically heterogeneous. Patterns of clustering and segregation analyses in asthma families have suggested a genetic component to asthma. Previous studies reported linkage of BHR and atopy to chromosomes 5q (refs 7-9), 6p (refs 10-12), 11q (refs 13-15), 14q (ref. 16), and 12q (ref. 17) using candidate gene approaches. However, the relative roles of these genes in the pathogenesis of asthma or atopy are difficult to assess outside of the context of a genome-wide search. One genome-wide search in atopic sib pairs has been reported, however, only 12% of their subjects had asthma. We conducted a genome-wide search in 140 families with > or = 2 asthmatic sibs, from three racial groups and report evidence for linkage to six novel regions: 5p15 (P = 0.0008) and 17p11.1-q11.2 (P = 0.0015) in African Americans; 11p15 (P = 0.0089) and 19q13 (P = 0.0013) in Caucasians; 2q33 (P = 0.0005) and 21q21 (P = 0.0040) in Hispanics. Evidence for linkage was also detected in five regions previously reported to be linked to asthma-associated phenotypes: 5q23-31 (P = 0.0187), 6p21.3-23 (P = 0.0129), 12q14-24.2 (P = 0.0042), 13q21.3-qter (P = 0.0014), and 14q11.2-13 (P = 0.0062) in Caucasians and 12q14-24.2 (P = 0.0260) in Hispanics.
We evaluated atopy-associated parameters in 1,099 people (aged 6-84 years) from families with history for atopy. All were tested for serum total immunoglobulin E (IgE) and allergen sensitivity by skin prick test. Specific IgE tests were done in randomly selected families. There was a decline with age in serum total IgE values, and relative atopy "incidence rates" were slightly lower among those older than 60 years. However, there was no change with age in sensitivity or severity of atopy. Among those sensitized to ragweed (Ambrosia artemisilfolia), there was no age-associated change in IgE levels specific to Amb a 1, a major allergen extracted from ragweed, and no change in the binding affinity of IgE for the Amb a 1 allergen. Among families with atopic histories, the underlying atopic mechanisms are particularly robust, and the atopic propensity remains into advanced age. In addition, established atopic responses may be focused in an immune system compartment either independent of or minimally influenced by T-cell activity.
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