Linkage to atopy on chromosome 19 in north-eastern Italian families with allergic asthma.

BACKGROUND: Allergic asthma is a multifactorial disease for which there is a widely assessed, although poorly understood, genetic involvement. Genome-wide screens reported evidence for linkage of allergic asthma-related phenotypes to several chromosomal locations. Markers on chromosome 19 have been linked to allergic asthma phenotypes in different populations in independent studies. OBJECTIVE: The aim of this study was to perform a genetic linkage analysis on chromosome 19 to search for DNA markers linked to phenotypes related to allergic asthma. METHODS: Using non-parametric multipoint linkage analysis on a total of 22 random DNA markers in 2 stages, a sample of 111 families (542 subjects) from north-eastern Italy, recruited through an asthmatic allergic proband, was investigated. Phenotypes examined were: clinical asthma, total serum elevated IgE, skin prick test positivity, bronchial hyper-responsiveness, and atopy defined as skin prick test positivity and/or elevated IgE. Simulation studies were performed to confirm the significance of the results. RESULTS: A novel linkage of atopy and skin prick test positivity to marker D19S601 (19q13.3) was found. Modest evidence for linkage of atopy, skin prick test positivity, and IgE was also found to marker D19S591 (19p13.3). Simulation analysis for atopy gave an NPL-Z > 3.326 in 2 replicates out of 1000 (P = 0.002) for D19S601, and an NPL-Z > 2.56 in 16 replicates out of 1000 (P = 0.016) for D19S591. CONCLUSIONS: On chromosome 19, suggestive linkage of atopy and skin prick test positivity with marker D19S601 (19q13.3) and modest evidence of linkage of marker D19S591 (19p13.3) to the atopic phenotypes investigated were found. These results suggest that these regions may contain susceptibility loci associated to atopic phenotypes.

Chromosome 14 linkage analysis and mutation study of 2 serpin genes in allergic asthmatic families.

BACKGROUND: Genome and chromosome screens reported DNA markers on chromosome 14 linked to allergic asthma or intermediate phenotypes in several populations. OBJECTIVE: We sought to perform a linkage study on chromosome 14 and a further association study on candidate genes mapped in the region found to be linked to allergic asthma or intermediate phenotypes. METHODS: The study consisted of a sample of 189 families (847 genotyped individuals) from a restricted geographic area in northeastern Italy. The subjects were characterized for the following phenotypes: allergic asthma, total serum IgE levels, skin prick test responses, and bronchial hyperresponsiveness (BHR) to methacholine. Genotyping was done with 14 DNA markers and 4 polymorphisms in the genes encoding alpha(1)-anti-trypsin and alpha(1)-antichymotrypsin (ACT). RESULTS: Multipoint analysis indicated a potential linkage of BHR with marker D14S617 (nonparametric linkage z score = 2.32, P =.01). Transmission disequilibrium of Thr -15Ala in the gene encoding ACT was observed with all the phenotypes investigated: allergic asthma, BHR, total IgE levels, or skin prick test responses (P =.041,.02,.0053, or.026, respectively). CONCLUSION: Chromosome 14 screening and transmission disequilibrium testing on the gene encoding ACT suggest that it or a closely located gene may be involved in susceptibility to allergic asthma in the Italian population.

Linkage analysis of chromosome 12 markers in Italian families with atopic asthmatic children.

We investigated 116 Italian atopic families (560 individuals) for linkage with 13 DNA markers on chromosome 12. All the subjects were phenotyped for asthma, total serum IgE, bronchial hyperresponsiveness, skin-prick positivity to common aeroallergens, and atopy. A relative location map of the markers was prepared from Centre d'Etude du Polymorphisme Humain families. Affected sib pair multipoint linkage methods were used to perform the statistical analyses. We report suggestive linkage for asthma with markers on chromosome 12. The region of interest centers around marker D12S390 (maximum logarithm of odds [mlod] = 2.81; p = 0.003). These results provide additional support that asthma susceptibility factors are located on chromosome 12q.

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.