Clustering patterns of LOD scores for asthma-related phenotypes revealed by a genome-wide screen in 295 French EGEA families

Abstract

A genome-wide scan for asthma phenotypes was conducted in the whole sample of 295 EGEA families selected through at least one asthmatic subject. In addition to asthma, seven phenotypes involved in the main asthma physiopathological pathways were considered: SPT (positive skin prick test response to at least one of 11 allergens), SPTQ score being the number of positive skin test responses to 11 allergens, Phadiatop (positive specific IgE response to a mixture of allergens), total IgE levels, eosinophils, bronchial responsiveness (BR) to methacholine challenge and %predicted FEV(1). Four regions showed evidence for linkage (P</=0.001): 6q14 for %FEV(1), 12p13 for IgE, 17q22-q24 for SPT and 21q21 for both SPTQ and %FEV(1). Nine other regions indicated smaller linkage signals (0.001<P</=0.005). While most of these regions have been reported by previous asthma and lung function screens, 6q14 appears to be a new region potentially linked to %FEV(1). To determine which of these various asthma phenotypes are more likely to share common genetic determinants, a principal component analysis was applied to the genome-wide LOD scores. This analysis revealed clustering of LODs for asthma, SPT and Phadiatop on one axis and clustering of LODs for %FEV(1), BR and SPTQ on the other, while LODs for IgE and eosinophils appeared to be independent from all other LODs. These results provide new insights into the potential sharing of genetic determinants by asthma-related phenotypes.

Genome screen in the French EGEA study: detection of linked regions shared or not shared by allergic rhinitis and asthma

“…This region is adjacent to the 13q31 region detected for eosinophil counts in our sample. 15,16 Results of the present study support evidence of linkage to AR and/or asthma for two regions 1p31 and 2q32 and suggest indication of linkage to 3p24-p14, 9p22, 9q22-q34 11p14 and 13q32 regions. These results do not indicate any linkage specific to asthma.…”

“…It was also found to be linked to IgE in our sample but less significantly than to rhinitis and neither to skin prick test responses nor to other atopy-related phenotypes. 16 The linkage peak observed here for AR is around 15 cM apart from the CTLA-4 gene (cytotoxic T lymphocyte antigen 4), a gene that has been shown to be associated with IgE levels, 27 atopy and asthma. 28 Thus, detection of linkage in our study could correspond to the influence of this gene.…”

“…They suggest that 1p31 may contain a genetic factor common to asthma and AR while the other regions are more likely to harbor genetic factors specific to AR. Since there is no indication of linkage of the 1p31 region to atopy-related phenotypes in our sample (total IgE, SPT, specific IgE), 16 this result is likely not due to the common allergic component of asthma and rhinitis. This is supported by a recent population-based study, which showed that the strong association between asthma and rhinitis was not fully explained by atopy.…”

“…A second genome scan was recently carried out for asthma/atopy-associated phenotypes in an extended sample of 295 EGEA families (having two sibs with DNA available and at least one asthmatic subject) and using a larger panel of 396 markers. 16 Using the same family sample and panel of markers of this second scan, the aim of the present study was to investigate the genetic factors specific either to AR or to asthma as well as those shared by AR and asthma. Three phenotypes were considered for AR: two binary phenotypes based on self-reporting (1) diagnosis (AR bin1 ) and (2) symptoms (AR bin2 ) according to a standardized questionnaire and a categorical ordered trait (AR cat ) based on a score computed from various items related to AR.…”

Sex-specific effect of IL9 polymorphisms on lung function and polysensitization

“…9 This is of particular relevance for asthma-related phenotypes for which a given chromosomal region is often linked to several phenotypes, suggesting the presence of genes with pleiotropic effects. 10 Following our previous GW scan conducted for asthma-related phenotypes in the Epidemiological study on the Genetics and Environment of Asthma (EGEA) study, 11 the aim of this study was to characterize sexspecific and potentially pleiotropic genetic factors underlying four quantitative phenotypes involved in the main asthma physiopathological pathways: total serum IgE levels, a quantitative measure of allergen sensitization, eosinophil (EOS) counts and a measure of lung function. We conducted sex-stratified univariate GW linkage analyses for each of these phenotypes followed by bivariate analyses.…”