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Query: UMLS:C0162871 (abdominal aortic aneurysm)
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A property of susceptibility genes for complex diseases is their reduced penetrance, due to the influences of other genes, the environment, or stochastic events. With this in mind, it is possible to devise population genetic strategies and statistical methods to allow their positional cloning. The identification of the relevant effector gene in an implicated locus may provide further challenges and require functional studies. The challenges of positional cloning are demonstrated by two examples: the cloning of GPRA and AAA1 on chromosome 7p14 at a susceptibility locus for asthma and atopy, and the study of HCR on chromosome 6p21 at PSORS1, the major susceptibility locus for psoriasis. To implicate GPRA in asthma and atopy, we studied its isoform-specific expression in bronchial biopsies and other sites for allergic reactions. We also studied its expression in a mouse model of ovalbumin-induced hypersensitivity. To study the role of HCR in psoriasis, we engineered transgenic mice with either a HCR non-risk allele or the HCR *WWCC risk allele controlled by the cytokeratin 14 promoter. The results suggested that while the overexpression of HCR in mouse skin is insufficient to induce a psoriasiform phenotype, it appears to induce allele-specific gene expression changes similar to those in psoriatic skin.
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PMID:Mapping genes for asthma and psoriasis. 1599

Susceptibility genes for complex diseases are characterized by reduced penetrance, caused by the influence of other genes, the environment or stochastic events. Recently, positional cloning efforts have yielded several candidate susceptibility genes in different complex disorders such as Crohn's disease and asthma. Within a genetic locus, however, the identification of the effector gene may pose further challenges and require functional studies. I review two examples of such challenges: the cloning of GPR154 (GPRA) and AAA1 on chromosome 7p14 at a susceptibility locus for atopy and asthma, and the study of HLA-Cw6, CCHCR1 (HCR) and CDSN on chromosome 6p21 at PSORS1, the major susceptibility locus for psoriasis. The susceptibility locus for atopy and asthma contains two genes and only one of them is protein coding. We studied its isoform-specific expression in bronchial biopsies and in a mouse model of ovalbumin-induced inflammation of bronchial epithelia. In the PSORS1 locus, strong linkage disequilibrium between genes has made it difficult to distinguish the effects of the three nearby genes. We engineered transgenic mice with either a HCR non-risk allele or the HCR*WWCC risk allele controlled by the cytokeratin-14 promoter. The results suggested that the overexpression of HCR in mouse skin was insufficient to induce a psoriasiform phenotype, but it appeared to induce allele-specific gene expression changes that were similar to those observed in psoriatic skin.
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PMID:Mapping and identifying genes for asthma and psoriasis. 1609 3