85-kDa cytosolic phospholipase A2 group IVα gene promoter polymorphisms in patients with severe asthma: a gene expression and case-control study
Authors: Sokolowska, M.1; Borowiec, M.2; Ptasinska, A.3; Cieslak, M.4; Shelhamer, J. H.3; Kowalski, M. L.4; Pawliczak, R.
Source: Clinical & Experimental Immunology, Volume 150, Number 1, October 2007 , pp. 124-131(8)
Publisher: Blackwell Publishing
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Abstract:
Summary Cytosolic phospholipase A2 (cPLA2) group IVα is a critical enzyme involved in the liberation of arachidonic acid from cellular membranes. cPLA2−/− mice have reduced allergen-induced bronchoconstriction and bronchial hyperresponsiveness. The goal of this study was to investigate polymorphisms of the (CA)n and (T)n microsatellites and surrounding regions in the cPLA2α gene promoter. We analysed the cPLA2 promoter regions containing (CA)n and (T)n repeats in 87 patients with severe asthma and in 48 control subjects by bidirectional sequencing. Functional studies were performed utilizing reporter genes derived from subjects with varying numbers of these repeats, and on constructs with a series of deletions. We found that the (CA)n and (T)n regions are polymorphic and that constructs with CA or T repeats or CA and T repeats deleted revealed, respectively, a 41·8 ± 7%, 22·3 ± 5% and 100 ± 20% increase in reporter gene activity. A lower number of CA or T repeats caused higher cPLA2 promoter luciferase activity. The group of shorter alleles of the (CA)n microsatellite region (n = 12-18) (Pcor = 0·00006), and the group of shorter alleles of (T)n repeats region (n = 17-38) (Pcor = 0·0039) occurred significantly more often in patients with severe asthma. We also found novel SNPs in positions −292 C > G, −185 A > C, −180 T > C and −165 A > C. Two of them were associated with the severe asthma phenotype: −180T allele (Pcor = 0·03996) and −185 A allele (Pcor = 0·03966). These results demonstrate that (CA)n and (T)n repeats may have an influence on cPLA2 transcription which might play a role in severe asthma pathogenesis.Keywords: airway inflammation; cytosolic phospholipase A2; gene expression; microsatellites; severe asthma
Document Type: Research article
DOI: 10.1111/j.1365-2249.2007.03459.x
Affiliations: 1: Department of Immunopathology, Chair of Immunology, Medical University of Lodz, Poland, 2: Joslin Diabetes Center, Harvard University, Boston, MA, USA, 3: Critical Care Medicine Department, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA, and 4: Department of Immunology, Rheumatology and Allergy, Chair of Immunology, Medical University of Lodz, Poland
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