Publications (2)14.51 Total impact
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ABSTRACT: Ataxia Telangiectasia (A-T) is a genetic condition leading to neurological defects and immune deficiency. The nature of the immune deficiency is highly variable, and in some causes significant morbidity and mortality due to recurrent sinopulmonary infections. Although the neurological defects in A-T are progressive, the natural history of the immune deficiency in A-T has not formally been evaluated. Here we analyse the clinical history and immunological data in 44 patients with A-T who attended the National Ataxia Telangiectasia clinic in Nottingham between 2001-2011. Using patient medical records and Nottingham University Hospitals (NUH) NHS Trust medical IT systems, data regarding clinical history, use of immunoglobulin replacement therapy, total immunoglobulin levels, specific antibody levels and lymphocyte subset counts was obtained. TCR spectratyping results in some patients were already available and where possible, repeat blood samples were collected for analysis. This study shows that subtle quantitative changes in certain immunological parameters such as lymphocyte subset counts may occur in patients with A-T over time. However, in general for the majority of patients the severity of immune deficiency (both clinically and in terms of immunological blood markers) does not seem to significantly deteriorate with time. This finding serves to inform long term management of this cohort of patients, as if recurrent respiratory tract infections present later in life, then other contributory factors (e.g cough/swallowing difficulties, underlying lung disease) should be aggressively investigated. Our findings also offer some form of reassurance for parents of children with A-T, which is otherwise a progressively severely debilitating condition.
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ABSTRACT: Several studies have suggested that chromosome 19q13.1-3 contains asthma susceptibility genes. Linkage and association analyses using 587 United Kingdom and Dutch asthma families (n = 2819 subjects) were used to investigate this region. A 3-phase procedure was used: (1) linkage and association analyses using 15 microsatellite markers spanning 14.4 mega base pairs (Mbps) on 19q13, (2) fine mapping of the refined region using 26 haplotype tagging single nucleotide polymorphisms (SNPs), and (3) dense gene analyses using 18 SNPs evaluated for association with asthma, bronchial hyperresponsiveness (BHR), FEV1, plasma urokinase plasminogen activator receptor (PLAUR), and rate of annual FEV1 decline in subjects with asthma. The microsatellite analyses provided tentative support for an asthma/lung function susceptibility locus (48.9-49.1Mbps), and fine mapping localized modest association to the PLAUR gene. PLAUR SNPs in the 5' region, intron 3, and 3' region are associated with asthma and BHR susceptibility and predict FEV1 and plasma PLAUR levels. SNPs in the 5' region showed association for asthma (2 populations), FEV1 (2 populations), and BHR (2 populations) phenotypes. SNPs in intron 3 showed association with asthma (2 populations) and BHR (3 populations). Importantly, the same 5' region and intron 3 SNPs were associated with plasma PLAUR levels. The same 5' region and 3' region SNPs were found to be determinants of FEV1 decline in subjects with asthma. This study represents the first report to identify PLAUR as a potential asthma susceptibility gene and determine PLAUR regions underlying this association, including a role in influencing plasma PLAUR levels. Finally, the association of PLAUR with lung function decline supports a role for PLAUR in airway remodeling in asthma.
University of Nottingham
Nottigham, England, United Kingdom
- Division of Therapeutics and Molecular Medicine