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Polymorphisms in the beta chain of the high affinity receptor for IgE (Fc epsilon RI-beta, MS4A2) are consistently associated with traits underlying asthma and atopy (immunoglobulin E-mediated allergy). However, the causal variants and haplotypes underlying disease have not yet been identified. Maternal effects, with association confined to maternally derived alleles, have been shown in some studies but not in others. We have therefore extended the known sequence and systematically detected polymorphisms across an 18.1 Kb genomic region that includes Fc epsilon RI-beta. Association testing in two panels of subjects showed the presence of single-nucleotide polymorphisms (SNPs) affecting prick skin tests and specific IgE responses in several clusters. Stepwise analyses indicated that the clusters represent independent effects. Interferon regulatory factor 2 (IRF-2) sites were altered by significantly associated SNPs in two regions. Strong association to maternally derived alleles was seen in one panel of subjects and not in the other. Maternal and non-maternally derived associations tended to share the same SNP clusters, but associations were stronger in the presence of maternal effects. Two regions of increased CpG concentration were identified in Fc epsilon RI-beta. One of these approximated a SNP cluster that showed strong association and maternal effects, providing a potential substrate for epigenetic effects.

The Class II genes of the MHC represent a major locus with quantified effects on atopic (allergic) phenotypes in many studies of westernized Caucasians. Although asthma is considered a disease of western societies, typical components of the asthma phenotype, such as elevations of the IgE, are seen with parasitic infestation. We have therefore investigated the effects of the HLA-DRB1 locus on asthma and its intermediate phenotypes in Aboriginal people from the Kimberly region of Australia who were suffering from endemic hookworm infection. Recognizable correlates of allergic asthma were present in the subjects, including skin test positivity to house dust mite (HDM), specific IgE responses to HDM, and the total serum IgE. HLA-DRB1 alleles did not predict the presence of asthma, but multi-allelic tests of association showed the locus accounted for approximately 33% of the variance of the total serum IgE concentration and 17% of the variance of the specific IgE titres to HDM. Genetic admixture was excluded as a cause of the results. These effects of the MHC on IgE levels were an order of magnitude greater than that seen in Caucasians, consistent with the hypothesis that the genetic predisposition to allergic disease may be driven by adaptation to helminth infection. The results further suggest that parasitism per se is not protective against asthma.