Gibbs sampling–based segregation analysis of asthma‐associated quantitative traits in a population‐based sample of nuclear families

Abstract

Asthma is a common, complex human disease. Elevated serum immunoglobulin E (IgE) levels, elevated blood eosinophil counts, and increased airway responsiveness are physiological traits that are characteristic of asthma. Few studies have investigated major gene effects for these traits in a population-based sample. Further, it is not known if any putative major genes may be common to two or more of these traits. We investigated the existence and nature of major genes modulating asthma-associated quantitative traits in an Australian population-based sample of 210 Caucasian nuclear families. The sharing of these major genes was also investigated. Segregation analysis was based upon a Markov Chain Monte Carlo (Gibbs sampling) approach as implemented in the program BUGS v0.6. All models included adjustment for age, height, tobacco smoke exposure, and gender. The segregation of total IgE levels, blood eosinophil counts, and dose-response slope (DRS) of methacholine challenge were all consistent with major loci at which a recessive allele acted to increase or decrease the phenotype. The respective estimated frequencies of the recessive alleles were 68% (total IgE), 10% (blood eosinophil count), and 27% (DRS). Extensive modelling suggested that the major loci controlling total serum IgE levels, blood eosinophil counts, and airway responsiveness represent different genes. These data provide evidence, for the first time, of the existence of at least 3 distinct genetic pathways involving major gene effects on physiological traits closely associated with asthma. These results have implications for gene discovery programs.

Familial correlations and inter-relationships of four asthma-associated quantitative phenotypes in 320 French EGEA families ascertained through asthmatic probands

“…These results are in agreement with the independence of genetic components of variance between airway responsiveness and either IgE levels or RAST index and the absence of common major genes underlying airway responsiveness and either IgE or EOS, as found in two samples of Australian families. 17,18 In conclusion, the present study confirms the presence of multiple determinants of four important asthmaassociated phenotypes and shows that these determinants are largely unshared by these phenotypes. However, a few of these determinants with modest effects may be common to atopy-related phenotypes.…”

“…A similar analysis in randomly selected Australian families showed significant evidence for 70% overlap of genetic additive variants between IgE and RAST index, 17 while a segregation analysis of IgE and EOS, in the same sample, indicated the presence of two different major genes underlying these phenotypes. 18 The higher degree of sharing of familial determinants between total IgE and RAST index in the Australian sample than between IgE and SPTQ in the EGEA sample can be first explained by a difference in the phenotypes studied. The RAST index measuring the specific IgE response may be more closely related to total IgE levels than SPTQ, which measures the skin test reactivity to a battery of allergens.…”

“…To our knowledge, only one study, in Australian families selected at random from the population, has examined the sharing of genetic determinants by asthma-associated quantitative phenotypes using variance component models and segregation analysis. 17,18 To provide guidance for further linkage and association studies with genetic markers and thus facilitate the identification of asthma-genes, we examined the patterns of familial correlations and inter-relationships of four asthma-associated quantitative phenotypes (total serum IgE level, a quantitative score of skin prick tests, blood eosinophil counts and FEV 1 ), which have not been yet considered together, in 320 French nuclear families ascertained through one asthmatic proband (parent or offspring) using the regressive models. 19 These models, which describe family patterns of dependence in terms of correlations without introducing a particular scheme of causal relationships, have been shown to be more general than variance component models that specify a causal structure to account for the observed familial correlations and thus impose constraints among these correlations.…”

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.…”