Genetics of Asthma: A Review: Asthma: 5-Lipoxygenase(5-LO) Gene Polymorphism and Asthma
5-Lipoxygenase(5-LO) Gene Polymorphism and Asthma
5-LO is an enzyme that mediates the derivation of leukotrienes from arachidonic acid. Leokotrienes are mediators of airway inflammation and bronchocon-striction. Treatment with zileuton, a 5-LO inhibitor, has been shown to improve asthma control.91 A polymorphism has been identified in the promoter region of the 5-LO gene that decreases gene expression. This polymorphism has been associated with a poorer response to 5-LO inhibitor therapy. canadian health&care mall
Tumor Necrosis Factor (TNF) Gene Polymorphism and Asthma
TNF may play an important role in asthma. Increased levels of TNF have been found in blood and sputum during asthma attacks and elevated TNF expression has been demonstrated in airway biopsy specimens from asthmatics. An association between a polymorphism in the promoter region of the TNF-a gene and BHR has been described.
Platelet-Activating Factor (PAF) Acetylhydroxylase Gene and Asthma
PAF is a proinflammatory molecule, which in the airways causes profound microvascular leakage, bronchoconstriction, and sustained BHR.96 PAF is degraded by the enzyme PAF acetylhydroxylase. PAF acetylhydroxylase activity is absent in 4% of the Japanese population and its absence is associated with severe childhood asthma. Recently, the gene for PAF acetylhydroxylase has been identified and mapped to chromosome 6pl2-21.1. The mutant gene has a Val279 Phe substitution which results in abolition of the enzymatic activity of PAF acetylhydroxylase.
Transforming Growth Factor-fij (TGF-fij) and Atopy
TGF-Pjl is an anti-inflammatory molecule that inhibits B lymphocytes, T helper and cytotoxic lymphocytes, IgE production, and mast cell proliferation. A polymorphism has been identified in the promoter region of TGF-Pi that is associated with higher total serum IgE.
Large genome-wide searches are being pursued worldwide. Some studies have focused on isolated/ inbred populations, while others are examining out-bred populations. Linkage results from some of these studies are just being reported.
Tristan da Cunha is a remote island in the south Atlantic Ocean containing a small population that is highly inbred and has a high prevalence of asthma (around 30%).” Therefore, this is a promising population in whom to look for asthma genes. Affected sib-pairs have been analyzed using 270 markers. There is strong evidence of linkage of asthma to two chromosomal locations. This study is sponsored by a pharmaceutical company and the map locations have not been made public. It has been reported that the linkage has been replicated in Australian and Canadian populations, and that one of the chromosomal regions has been narrowed down to a few genes.
The Hutterites are a highly inbred, isolated group living in South Dakota; 321 members of a multigen-erational pedigree have been phenotyped for asthma. Preliminary results from linkage analysis have revealed some evidence for linkage of BHR and asthma to five chromosomal regions.