Mauro Baldini

Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing.

The beta2-adrenergic receptor (beta2AR) agonists are the most widely used agents in the treatment of asthma, but the genetic determinants of responsiveness to these agents are unknown. Two polymorphic loci within the coding region of the beta2AR have been recently described at amino acids 16 and 27. It has been reported that glycine at codon 16 (Gly-16) is associated with increased agonist-promoted downregulation of the beta2AR as compared with arginine-16 (Arg-16). The form of the receptor with glutamic acid at codon 27 (Glu-27), on the other hand, has been shown to be resistant to downregulation when compared with glutamine-27 (Gln-27), but only when coexpressed with Arg-16. To assess if different genotypes of these two polymorphisms would show differential responses to inhaled beta2AR agonists, we genotyped 269 children who were participants in a longitudinal study of asthma. Spirometry was performed before and after administration of 180 microg of albuterol, and a positive response was considered an increase of >15.3% predicted FEV1. There was marked linkage disequilibrium between the two polymorphisms, with 97.8% of all chromosomes that carried Arg-16 also carrying Gln-27. When compared to homozygotes for Gly-16, homozygotes for Arg-16 were 5.3 times (95% confidence interval 1.6-17.7) and heterozygotes for beta2AR-16 were 2.3 times (1.3-4.2) more likely to respond to albuterol, respectively. Similar trends were observed for asthmatic and nonasthmatic children, and results were independent of baseline lung function, ethnic origin, and previous use of antiasthma medication. No association was found between the beta2AR-27 polymorphism and response to albuterol. These results may explain some of the variability in response to therapeutic doses of albuterol in children.

A promoter polymorphism in the CD14 gene is associated with elevated levels of soluble CD14 but not with IgE or atopic diseases

Background:  A polymorphism in the promoter region of the CD14 gene, C‐159T, has been shown to be associated with increased levels of soluble CD14 (sCD14) and decreased serum immunoglobulin E (IgE) and the expression of a more severe atopic phenotype in previous studies.

CD14: an example of gene by environment interaction in allergic disease.

The prevalence of allergic diseases (1, 2) has increased significantly over the last few decades. Drastic environmental modifications have been targeted as the main culprit of this rise. However, both asthma (3) and total serum immunoglobulin (Ig)E levels (4) are known to be genetically determined. Therefore, the dissection of the relative contribution of environmental and genetic factors will provide a deeper understanding of the pathophysiology underlying the trends in allergic diseases. In this paper, we are reviewing a model of interaction between environmental and genetic factors in the expression of IgE-mediated allergy (5). We are discussing the role of bacterial exposure in the development of the mature immune response and its modulation by a polymorphism in CD14, the gene encoding an essential component of the receptor for bacterial lipopolysaccharide (LPS, endotoxin), a key factor in the initiation of the innate immune response to bacterial infections.

The Monocyte/IgE Connection: May Polymorphisms in the CD14 Gene Teach Us about IgE Regulation?

Background: Total IgE levels are known to be under genetic control. Linkage studies have indicated that one or more loci on chromosome 5q may control total IgE, as well as asthma and bronchial hyperresponsiveness to nonspecific stimuli. Our group has undertaken a systematic analysis of chromosome 5q, and has recently characterized five single nucleotide polymorphisms at position –1619, –1359, –1145, –809 and –159 in the promoter of the gene encoding CD14, the myeloid pattern recognition receptor that is critical for efficient innate immune response to lipopolysaccharide (LPS) and bacterial ligands. Methods: Carriers of the major CD14 haplotypes were analyzed for serum levels of IgE and soluble CD14. In vitro IgE synthesis was assessed in peripheral blood mononuclear cells stimulated with IL-4 in the presence or absence of LPS or anti-CD14 monoclonal antibodies. Results: An inverse correlation was found between serum levels of IgE and soluble CD14. On the other hand, in vitro IL-4-dependent IgE synthesis was strongly upregulated by LPS, but suppressed by anti-CD14 monoclonal antibodies. Conclusions: Our results highlight the complex role played by monocytes in IgE regulation.

CD14: A bridge between innate immunity and adaptive IgE responses

Total IgE levels are known to be under genetic control. Linkage studies have indicated that one or more loci on chromosome 5q may control total IgE, as well as asthma and bronchial hyper-responsiveness to non-specific stimuli. Our group has undertaken a systematic analysis of chromosome 5q, and has recently characterized five single nucleotide polymorphisms at position —1619, —1359, —1145, —809, and —159 in the promoter of the gene encoding CD14, the myeloid pattern recognition receptor that is critical for efficient innate immune responses to lipopolysaccharide and bacterial ligands. Individuals homozygous for the three major CD14 haplotypes found in the Children Respiratory Study population (n = 390) were analyzed for serum levels of total IgE and soluble CD14. A strong inverse correlation was found between these two parameters, i.e. carriers of the —1359T/—1145A/—159C haplotype had the highest levels of IgE, and the lowest levels of sCD14. Conversely, carriers of the —1359G/—1145G/—159T haplotype had the highest levels of sCD14 and the lowest IgE values. Our results suggest that genetic variation in CD14, a key gene of innate immunity, may modulate the effects that exposure to bacterial ligands has on the development of Th2 responses.