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 child hood, 1083 subjects were identified, mainly from the Veneto region and Bolz ano province in North-east Italy, of whom 817 were from 172 families with a t least two affected people, 189 were sporadic cases, and 77 unrelated cont rols. All the subjects were characterized for clinical asthma (asthma), tot al serum IgE (IgE), skin prick test (SPT) reactivity to common aeroallergen s and bronchial hyperresponsiveness (BHR) to methacoline test. Atopy was de fined as SPT positivity and/or increased IgE levels. Several candidate gene s were investigated, and genome-wide linkage analysis was been initiated. T he high affinity IgE receptor beta chain (Fc epsilon RI beta) locus showed significant allele sharing in affected sib-pairs for BHR and for SPT positi vity. Lymphotoxin alpha (Lt alpha) gene Ncol mutation showed a suggestive l inkage with atopy, and the LT alpha Ncol 2/2 genotype was found to be assoc iated with increased total IgE levels in all females. No evidence for linka ge or association of any phenotype to the tumour necrosis factor alpha (TNF alpha) - 308 mutation or to the interleukin 4 receptor alpha (IL-4R alpha) Q576R mutation was found. BHR, asthma and increased IgE were found to be l inked to X and Y long an pseudoautosomal region (PAR2) markers. Initial dat a were also collected from linkage analysis with chromosome 12, 14, and 19, DNA markers. Non-parametric multipoint analysis provides preliminary evide nce for linkage of asthma with D12S390, of atopy with D19S601, and of BHR w ith D14S617. These results suggest that several genetic factors contribute to different allergic asthma phenotypes in the population investigated.