Detection of a recessive major gene for high IgE levels acting independently of specific response to allergens

Abstract

The genetic control of the total IgE, the immunoglobulins E involved in allergy, remains still unclear. Although high IgE levels were found to be determined by a recessive major gene in several studies, other modes of inheritance were also reported. Moreover, at least two different genetic mechanisms controlling the IgE regulation have been suggested: one involved in the specific IgE response and the other one in the nonspecific response. To better understand the genetic mechanisms controlling IgE variation, we performed segregation analysis of IgE levels by ignoring or taking into account the specific response to allergens (SRA). Analyses were conducted using the class D regressive model, in a sample of 234 Australian nuclear families randomly selected during the winter months, when IgE levels are the lowest (basal). SRA, when included as a covariate in the model, was defined by one of the three following criteria: (1) raised specific IgE level for one or more allergens, (2) positive skin test for one or more allergens, and (3) at least one of the (1) or (2) criteria. When the presence of SRA is ignored, the familial transmission of total IgE level is compatible with the segregation of a recessive major gene and residual familial correlations. When the presence of SRA is accounted for in the analysis, whether defined by criteria (1), (2), or (3), there is still evidence for a recessive major gene controlling IgE levels but residual familial correlations are no longer significant. In addition, no interaction between this major gene and SRA is shown here. Our results suggest that this gene, which accounts for 28% of the variation of the trait, may be involved in the control of basal IgE production, independently of specific response to allergens.

Allergen-Specific IgG1 Provides Parsimonious Heritability Estimates for Atopy-Associated Immune Responses to Allergens

“…Using total IgE as a quantitative trait for genetic studies of atopy has produced widely conflicting results, particularly with regard to the proportions of the responses putatively attributed to inheritance [1][2][3][4][5][6][7][8][9][10]. Although controlled by tight metabolic regulation, the production of IgE involves multiple pathways [26][27][28], but the details of these interrelationships are not completely understood.…”

“…However, the use of total IgE as a quantitative trait for genetic studies of atopy has produced widely conflicting results, with evidence for co-dominant genetic effects [1], recessive effects [2][3][4], pleiotropic effects [5] and other modes of inheritance [6][7][8][9][10]. Further, it has not been clearly established that enhanced total IgE production is a predisposing cause for atopy, as it may only be a consequence that accompanies clinical conditions, so the physiological 'sources' of total IgE are unclear.…”

The genetics of asthma and atopy

“…Previous segregation analyses on families do not agree on the model of inheritance. However, several studies have found evidence of recessive inheritance of high total serum IgE levels (51)(52)(53)(54). Martinez et al reported evidence of codominant inheritance in a large sample of families (55).…”

Epidemiologic and Genetic Approaches in the Study of Gene-Environment Interaction: an Overview of Available Methods

“…Dizier et al (58) used the regressive models to better understand the genetic mechanisms controlling immunoglobulin E in allergy in 234 Australian nuclear families. Segregation analysis of immunoglobulin E levels taking into account specific response to allergens was performed.…”