© 2004 American Thoracic Society
New Thoughts Regarding the Genetics of AtopyUniversity of Minnesota Minneapolis, Minnesota Atopy is a term proposed by Coca and Cooke in 1923 to identify clinical allergies involving allergen-specific immunoglobulin E (IgE) that were subjected to hereditary influences (1). It is involved in development of many cases of asthma, particularly those in early life (2). Understanding of the pathogenesis of atopy is dependent on knowledge of the phenotype as well as the genome environmental interactions. In a report in this issue of the Journal (pp. 615–622), O'Donnell and coworkers use CD14 as a model to investigate gene–environmental interaction (3). Atopy, as pointed out by O'Donnell and coworkers, involves an adaptive response that is a T lymphocyte–dependent generation of allergen-specific antibody (3). Some, but not all, of the antibodies are IgE. Two distinct types of IgE appear to exist in humans. One is a basal IgE distribution that appears to be unrelated to atopy or any other disorder (a noncognate IgE fraction). The other is allergen-specific and related to atopic disease (a cognate IgE fraction). We have demonstrated that the differences in allergen-specific immunoglobulin production by atopics and nonatopics are not too great. Although atopics produce allergen-specific IgE, the relative proportionate amounts of the allergen-specific immunoglobulin A and immunoglobulin G subclasses are comparable in both groups. The distinction between the two groups is that atopics produce extremely high binding affinity specific IgE and lower affinity specific immunoglobulin G1 while nonatopics mount an equally vigorous humoral response to allergens in the form of high binding affinity specific immunoglobulin G1. Quantitatively, atopics tend to produce more of certain isotypes (specific IgE) than nonatopics, and nonatopics tend to produce more of certain isotypes than atopics (specific immunoglobulin G1) (4, 5). Atopy may be an error in immunoglobulin isotype class switching during a normal process of antigen recognition and generation of a humoral antibody response. It does not involve tolerance.
Of the many candidate genes that may be involved with total and allergen-specific IgE production, O'Donnell and coworkers focused on one encoding for CD14, the so-called endotoxin receptor (2, 6). Three polymorphisms for this gene have been reported on chromosome 5q31.1, identified in a C-to-T transition located at base pair -159 designated CC, TC, and TT. The TT homozygotes at base pair -159 have been noted by some to be associated with a significantly higher serum level of soluble CD14 and lower levels of IgE than carriers of other genotypes (7, 8). It is suggested that T helper cell type 1 favored helper T cell differentiation, which is enhanced by complexes of CD14 and bacterial cell wall components, may be augmented by higher expression of CD14 (7). They noted that there is a negative correlation between the levels of soluble CD14 and IgE. In 11-year-old white children who were skin prick test positive to one or more allergens, the CC genotype was associated with a higher serum total IgE level compared with those who were CT or TT. Also, the CC children had a higher average number of skin test responses. In these studies, the effect of CD14 on serum total IgE values only appeared among those who were sensitized to allergen (any skin test reactivity results). There was no apparent influence on IgE values for those who were skin prick test negative, suggesting that that CD14 is implicated in the predisposition to allergen sensitization rather than regulation of IgE production. Others have not been able to find evidence supporting this association (9–12). Soluble CD14 may have a dual effect, i.e., inhibition of IgE production before and aggravation of allergic inflammation after the onset of allergic diseases. As a result, there may be a negative correlation between soluble CD14 and IgE in early infancy, the time before the onset of allergic inflammation. To further complicate the picture, CD14 may actually be a suppressor of IgE production rather than a promoter. Soluble CD14 appears to play a specific functional role on T lymphocytes. In general, it acts as a time-dependent suppressor of T cell function as it induces the progressive accumulation of an inhibitor protein (I It has become apparent that to further our knowledge regarding the development of atopy with regard to the involved genetic as well as nongenetic factors, different phenotyping, genotyping and statistical methods are needed. The study by O'Donnell and coworkers utilizes longitudinal studies in genetic analysis to evaluate the relationship of genetic architecture to standard phenotypes such as atopy, airway hyperresponsiveness, presence of wheezing, and total serum IgE levels (3). They demonstrated that CD14 C 159T is associated with early onset of atopy using models that incorporate repeated measures over a period of time. These longitudinal analyses appear to be a more powerful approach to data analysis and may help alleviate concerns about sample sizes and the influence of age and environment in genetic analysis. Using a longitudinal study, they demonstrated that the influence of the CD14–159C as one of the genetic controls areas that may be age specific. The effect was exerted in individuals between the ages of 8 and 12, but was no longer apparent by early adulthood. Models such as these will provide important approaches to investigate the relationship between candidate genes and the longitudinal course of a disease such as atopy. FOOTNOTES Conflict of Interest Statement: M.N.B. has no declared conflict of interest. REFERENCES
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, and interleukin-4, which are essential for T cell growth and T cell–dependent isotype switching by B cells. Allergen-specific antibody production is a complex T lymphocyte–dependent process involving genes and environment interactions resulting in a variety of different phenotypes. Atopy initially was defined as a result of "obligate inheritance" where genetic errors associated with obligated pathways under appropriate conditions lead to disease process. Now there is much evidence for a "stochastic bias" where inherited metabolic anomalies alter the likelihood of progressing along one pathway or another. The outcome of atopy may appear to be random. 
