Genetics of Asthma: A Review: Asthma: Linkage of Atopy and BHR to Chromosome 5q
Linkage of Atopy and BHR to Chromosome 5q
Cytokines play a major role in the development of atopy and asthma. The genes for many of these cytokines, including interleukin-3,4,5,9,13, and gran-ulocyte-macrophage colony-stimulating factor, have been mapped to a small region on 5q31-33 known as the “cytokine-gene cluster.”66 Under the hypothesis that one of these cy tokine genes may be an atopy/ asthma gene, two groups have looked for linkage between atopy and markers in and around 5q31.
Marsh et al studied Amish families, who were phenotyped for total serum IgE and the presence of antigen-specific IgE antibodies against a panel of 20 common aeroallergens; 349 affected-sib pairs were genotyped for eight markers in and around 5q31. There was significant linkage of total serum IgE to five markers located in 5q31. However, there was no linkage of antigen-specific IgE to the markers. Moreover, when sibs with elevated total serum IgE levels in the absence of antigen-specific IgE were analyzed, the linkage to 5q31.1 markers was stronger. This suggested that different genetic mechanisms may be involved in total serum IgE and antigen-specific IgE responses, and that while the gene(s) regulating total serum IgE levels were located in this region, genes regulating the development of antigen-specific IgE were probably located elsewhere.
Meyers et al studied Dutch families, who were phenotyped for total serum IgE and genotyped for eight markers on 5q. Both affected-sib pair analysis and linkage analysis revealed linkage of total serum IgE to three markers in this region. Further analysis suggested that there may be another locus unlinked to (ie, away from) 5q that may also contribute to variability in serum IgE levels. In a follow-up study, linkage of BHR to markers on 5q was also demonstrated.
This area of linkage to atopy spans approximately 6 Mb and as many as 300 genes may be present Attempts are underway to refine the area of linkage to a narrower region and to investigate candidate genes in this region. A polymorphism has been identified in the promoter region of interleukin-4 that results in enhanced gene expression in vitro and is associated with higher serum IgE levels in atopic asthmatics.71 Two alleles at the IL9 locus have been identified that are associated with atopy.
Linkage of Atopy and Asthma to Chromosome 12q
Chromosome 12q is of interest because it contains several candidate genes, including interferon-7 (IFN-7), mast cell growth factor (MGF), insulin-like growth factor-1 (IGF-1), and the constitutive form of nitric oxide synthetase (NOS1). IFN-7 promotes differentiation of TH1 lymphocytes and inhibits differentiation and IL-4 production by TH2 lymphocytes, IGF-1 promotes differentiation of both B and T lymphocytes, and MGF is required for proliferation of mature mast cells. Asthma and elevated serum IgE levels have been linked to markers in this region in Barbadian and Amish populations, and in a British population.