Sib-pair analysis of 170 individuals from 11 Amish families revealed evidence for linkage of five markers in chromosome 5q31.1 with a gene controlling total serum immunoglobulin E (IgE) concentration. No linkage was found between these markers and specific IgE antibody concentrations. Analysis of total IgE within a subset of 128 IgE antibody-negative sib pairs confirmed evidence for linkage to 5q31.1, especially to the interleukin-4 gene (IL4). A combination of segregation and maximum likelihood analyses provided further evidence for this linkage. These analyses suggest that IL4 or a nearby gene in 5q31.1 regulates IgE production in a nonantigen-specific (noncognate) fashion.

Up-regulation of C-C chemokine expression characterizes allergic inflammation and atopic diseases. A functional mutation in the proximal promoter of the RANTES gene has been identified, which results in a new consensus binding site for the GATA transcription factor family. A higher frequency of this allele was observed in individuals of African descent compared with Caucasian subjects (p < 0.00001). The mutant allele was associated with atopic dermatitis in children of the German Multicenter Allergy Study (MAS-90; p < 0.037), but not with asthma. Transient transfections of the human mast cell line HMC-1 and the T cell line Jurkat with reporter vectors driven by either the mutant or wild-type RANTES promoter showed an up to 8-fold higher constitutive transcriptional activity of the mutant promoter. This is the first report to our knowledge of a functional mutation in a chemokine gene promoter. Our findings suggest that the mutation contributes to the development of atopic dermatitis. Its potential role in other inflammatory and infectious disorders, particularly among individuals of African ancestry, remains to be determined.

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We previously emphasized (1, 2) the usefulness of atopic allergy as a model for studying the genetics of human immune response. A particular advantage is that most allergies result from exposure to minute, immunogenically limiting doses of environmental antigens (allergens), usually <1 ptg/yr (3). Short ragweed pollen component Ra5 (5,000 tool wt) (4, 5) offers a particularly useful tool for studying specific immune response because of its relatively simple structure and low proportion in the pollen (3). In several studies (2, 6-8), immunoglobulin E (IgE)-mediated skin test response to Ra5 was significantly associated with HLA-B7 and the B7 cross-reacting group (Creg). x Further preliminary evidence suggested that the primary association might be with Dw2 (2).Analysis of the Ra5 preparations used in previous studies by crossed immunoelectrophoresis (CIE) indicated the presence of very low (but detectable) levels of impurities that might interfere with genetic analysis. Hence, further purification of Ra5 to -->99.9% purity was performed for the present studies, and highly sensitive assays for IgE and IgG antibodies (Ab) to Ra5 were developed.After studying responses to ultra-pure Ra5 in 447 Caucasians that were naturally exposed to ragweed pollen, we now find that Dw2 is almost a perfect marker for IgE and IgG responses to Ra5. The immune response association with HLA-B7 is secondary to Dw2 and presumably arises from the well-documented linkage disequilibrium between the alleles coding for these two specificities. Analysis of HLA-DR typing data in a portion of the study subjects suggests a weaker association between response to Ra5 with DR2 than with Dw2.

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