Genetic susceptibility to asthma – bronchial hyperresponsiveness coinherited with a major gene for atopy

Bronchial hyperresponsiveness, a risk factor for asthma, consists of a heightened bronchoconstrictor response to a variety of stimuli. The condition has a heritable component and is closely related to serum IgE levels and airway inflammation. The basis for these relations is unknown, as is the mechanism of genetic susceptibility to bronchial hyperresponsiveness. We attempted to define the interrelation between atopy and bronchial hyperresponsiveness and to investigate the chromosomal location of this component of asthma. We studied 303 children and grandchildren of 84 probands with asthma selected from a homogeneous population in the Netherlands. Ventilatory function, bronchial 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 bronchial hyperresponsiveness and genetic markers on chromosome 5q31-q33, previously shown to be linked to a genetic locus regulating serum total IgE levels. Serum total IgE levels were strongly correlated (r = 0.65, P<0.01) in pairs of siblings concordant for bronchial hyperresponsiveness (defined as a =20 percent decrease in the forced expiratory volume in one second produced by histamine [threshold dose, <16 mg per milliliter]), suggesting that these traits are coinherited. However, bronchial hyperresponsiveness was not correlated with serum IgE levels (r = 0.04, P=0.10). Analyses of pairs of siblings showed linkage of bronchial hyperresponsiveness with several genetic markers on chromosome 5q, including D5S436 (P<0.001 for a histamine threshold value of ≤16 mg per milliliter). 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 existence of one or more genes on chromosome 5q31-q33 causing susceptibility to asthma. Bronchial hyperresponsiveness is a fundamental characteristic of asthma thought to have a heritable component.¹ Longitudinal studies in children show that bronchial hyperresponsiveness precedes asthma and is a risk factor for the development of asthma.²,³ Studies in both humans and animals have demonstrated a genetic predisposition to bronchial hyperresponsiveness,²–¹⁰ such as greater concordance for this trait among monozygotic twins than among dizygotic twins.⁹,¹⁰ Bronchial hyperresponsiveness to carbachol appears to be inherited as an autosomal dominant trait,⁴ but the bimodal distribution of bronchial responsiveness to methacholine is not controlled by a single gene.⁵ Although these studies confirm a strong.