GENETIC SUSCEPTIBILITY TO ASTHMA - BRONCHIAL, HYPERRESPONSIVENESS COINHERITED WITH A MAJOR GENE FOR ATOPY

Background. Bronchial hyperresponsiveness, a risk factor for asthma, c onsists of a heightened bronchoconstrictor response to a variety of st imuli. The condition has a heritable component and is closely related to serum IgE levels and airway inflammation. The basis for these relat ions is unknown, as is the mechanism of genetic susceptibility to bron chial hyperresponsiveness. We attempted to define the interrelation be tween atopy and bronchial hyperresponsiveness and to investigate the c hromosomal location of this component of asthma. Methods. We studied 3 03 children and grandchildren of 84 probands with asthma selected from a homogeneous population in the Netherlands. Ventilatory function, br onchial responsiveness to histamine, and serum total IgE were measured . The association between the last two variables was evaluated. Using analyses involving pairs of siblings, we tested for linkage between br onchial hyperresponsiveness and genetic markers on chromosome 5q31-q33 , previously shown to be linked to a genetic locus regulating serum to tal IgE levels. Results. Serum total IgE levels were strongly correlat ed (r=0.65, P<0.01) in pairs of siblings concordant for bronchial hype rresponsiveness (defined as a greater than or equal to 20 percent decr ease in the forced expiratory volume in one second produced by histami ne [threshold dose, less than or equal to 16 mg per milliliter]), sugg esting that these traits are coinherited. However, bronchial hyperresp onsiveness was not correlated with serum IgE levels (r=0.04, P>0.10). Analyses of pairs of siblings showed linkage of bronchial hyperrespons iveness with several genetic markers on chromosome 5q, including D5S43 6 (P<0.001 for a histamine threshold value of less than or equal to 16 mg per milliliter). Conclusions. This study demonstrates that a trait for an elevated level of serum total IgE is coinherited with a trait for bronchial hyperresponsiveness and that a gene governing bronchial hyperresponsiveness is located near a major locus that regulates serum IgE levels on chromosome 5q. These findings are consistent with the e xistence of one or more genes on chromosome 5q31-q33 causing susceptib ility to asthma.