PLAUR polymorphisms are associated with asthma, PLAUR levels, and lung function decline - 15/08/11
, Gerard H. Koppelman, MD, PhD c, , Judith M. Vonk, PhD d, Claudia A. Browning, BSc f, Ilja M. Nolte, PhD d, Ceri E. Stewart, PhD f, Sue Bainbridge, BSc g, Stacey Mutch, BSc g, Matthew J. Rose-Zerilli, BSc a, b, Dirkje S. Postma, MD, PhD e, Nikolas Maniatis, PhD h, Amanda P. Henry, PhD f, Ian P. Hall, MD, DM f, Stephen T. Holgate, MD, DSc a, Patrick Tighe, PhD g, John W. Holloway, PhD a, b, Ian Sayers, PhD f, ⁎ 
Reprint requests: Ian Sayers, PhD, Division of Therapeutics and Molecular Medicine, University Hospital of Nottingham, Nottingham, NG7 2UH, United Kingdom.Abstract |
Background |
Several studies have suggested that chromosome 19q13.1-3 contains asthma susceptibility genes.
Objective |
Linkage and association analyses using 587 United Kingdom and Dutch asthma families (n = 2819 subjects) were used to investigate this region.
Methods |
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.
Results |
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.
Conclusion |
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.
Le texte complet de cet article est disponible en PDF.Key words : Asthma, susceptibility, PLAUR, remodeling
Abbreviations used : BHR, FBAT, FVC, LD, LDU, LOD score, MAF, MERLIN, PLAUR, SNP, UK
Plan
| I.S. is supported by the Medical Research Council (New Investigator Award), and the Dutch family studies were supported by The Netherlands Asthma Foundation. The Southampton Asthma Family Cohort was originally recruited in collaboration with Genome Therapeutics Corp and Schering-Plough. |
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| Disclosure of potential conflict of interest: I. Sayers has received research support from the Medical Research Council UK. N. Maniatis has received research support from the Fellowship from the Medical School, University of Southampton. I. P. Hall has received research support from Medical Research Council UK, Asthma UK, and GlaxoSmithKline/Novartis Pharma and has served as an expert witness regarding medical negligence. J. W. Holloway has received research support from the Medical Research Council UK and Asthma UK. The rest of the authors have declared that they have no conflict of interest. |
Vol 123 - N° 6
P. 1391 - juin 2009 Retour au numéro
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