Genetic Susceptibility to Asthma -- Bronchial Hyperresponsiveness Coinherited with a Major Gene for Atopy

doi:10.1056/NEJM199510053331402

Volume 333:894-900		October 5, 1995		Number 14

Genetic Susceptibility to Asthma — Bronchial Hyperresponsiveness Coinherited with a Major Gene for Atopy

Dirkje S. Postma, M.D., Eugene R. Bleecker, M.D., Pamela J. Amelung, M.D., Kenneth J. Holroyd, M.D., Jianfeng Xu, M.S., Carolien I.M. Panhuysen, M.D., Deborah A. Meyers, Ph.D., and Roy C. Levitt, M.D.

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ABSTRACT

Background Bronchial hyperresponsiveness, a risk factor forasthma, consists of a heightened bronchoconstrictor responseto a variety of stimuli. The condition has a heritable componentand is closely related to serum IgE levels and airway inflammation.The basis for these relations is unknown, as is the mechanismof genetic susceptibility to bronchial hyperresponsiveness.We attempted to define the interrelation between atopy and bronchialhyperresponsiveness and to investigate the chromosomal locationof this component of asthma.

Methods We studied 303 children and grandchildren of 84 probandswith asthma selected from a homogeneous population in the Netherlands.Ventilatory function, bronchial responsiveness to histamine,and serum total IgE were measured. The association between thelast two variables was evaluated. Using analyses involving pairsof siblings, we tested for linkage between bronchial hyperresponsivenessand genetic markers on chromosome 5q31-q33, previously shownto be linked to a genetic locus regulating serum total IgE levels.

Results Serum total IgE levels were strongly correlated (r =0.65, P<0.01) in pairs of siblings concordant for bronchialhyperresponsiveness (defined as a >20 percent decrease inthe forced expiratory volume in one second produced by histamine[threshold dose, <16 mg per milliliter]), suggesting thatthese traits are coinherited. However, bronchial hyperresponsivenesswas not correlated with serum IgE levels (r = 0.04, P>0.10).Analyses of pairs of siblings showed linkage of bronchial hyperresponsivenesswith several genetic markers on chromosome 5q, including D5S436(P<0.001 for a histamine threshold value of $<=$ 16 mg per milliliter).

Conclusions This study demonstrates that a trait for an elevatedlevel of serum total IgE is coinherited with a trait for bronchialhyperresponsiveness and that a gene governing bronchial hyperresponsivenessis located near a major locus that regulates serum IgE levelson chromosome 5q. These findings are consistent with the existenceof one or more genes on chromosome 5q31-q33 causing susceptibilityto asthma.

Source Information

From University Hospital, Groningen, the Netherlands (D.S.P.); the University of Maryland School of Medicine, Baltimore (E.R.B., P.J.A.); the Asthma Center, Beatrixoord, Haren, the Netherlands (C.I.M.P.); and Johns Hopkins University School of Medicine, Baltimore (K.J.H., J.X., D.A.M., R.C.L.).

Address reprint requests to Dr. Levitt at Meyer 8-134, 600 N. Wolfe St., Johns Hopkins Hospital, Baltimore, MD 21287-7834.

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