Candidate genes and a genome-wide search in Italian families with atopic asthmatic children.

To identify genetic factors for susceptibility to atopy and asthma in childhood, 1,083 subjects were identified, mainly from the Veneto region and Bolzano province in North-east Italy, of whom 817 were from 172 families with at least two affected people, 189 were sporadic cases, and 77 unrelated controls. All the subjects were characterized for clinical asthma (asthma), total serum IgE (IgE), skin prick test (SPT) reactivity to common aeroallergens and bronchial hyperresponsiveness (BHR) to methacoline test. Atopy was defined as SPT positivity and/or increased IgE levels. Several candidate genes were investigated, and genome-wide linkage analysis was been initiated. The high affinity IgE receptor beta chain (FcepsilonRIbeta) locus showed significant allele sharing in affected sib-pairs for BHR and for SPT positivity. Lymphotoxin alpha (Ltalpha) gene Ncol mutation showed a suggestive linkage with atopy, and the LTalphaNcol 2/2 genotype was found to be associated with increased total IgE levels in all females. No evidence for linkage or association of any phenotype to the tumour necrosis factor alpha (TNFalpha) - 308 mutation or to the interleukin 4 receptor alpha (IL-4Ralpha) Q576R mutation was found. BHR, asthma and increased IgE were found to be linked to X and Y long arm pseudoautosomal region (PAR2) markers. Initial data were also collected from linkage analysis with chromosome 12, 14, and 19, DNA markers. Non-parametric multipoint analysis provides preliminary evidence for linkage of asthma with D12S390, of atopy with D19S601, and of BHR with D14S617. These results suggest that several genetic factors contribute to different allergic asthma phenotypes in the population investigated.