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.
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.
Authors: Brian D Modena; Eugene R Bleecker; William W Busse; Serpil C Erzurum; Benjamin M Gaston; Nizar N Jarjour; Deborah A Meyers; Jadranka Milosevic; John R Tedrow; Wei Wu; Naftali Kaminski; Sally E Wenzel Journal: Am J Respir Crit Care Med Date: 2017-06-01 Impact factor: 21.405
Authors: Gregory S Whitehead; Seddon Y Thomas; Karim H Shalaby; Keiko Nakano; Timothy P Moran; James M Ward; Gordon P Flake; Hideki Nakano; Donald N Cook Journal: J Clin Invest Date: 2017-07-31 Impact factor: 14.808
Authors: Nathaniel Weathington; Michael E O'Brien; Josiah Radder; Thomas C Whisenant; Eugene R Bleecker; William W Busse; Serpil C Erzurum; Benjamin Gaston; Annette T Hastie; Nizar N Jarjour; Deborah A Meyers; Jadranka Milosevic; Wendy C Moore; John R Tedrow; John B Trudeau; Hesper P Wong; Wei Wu; Naftali Kaminski; Sally E Wenzel; Brian D Modena Journal: Am J Respir Crit Care Med Date: 2019-10-01 Impact factor: 21.405
Authors: Angela Simpson; Adnan Custovic; Robert Tepper; Penelope Graves; Debra A Stern; Marcus Jones; Jenny Hankinson; John A Curtin; Jiakai Wu; Mario Blekic; Blazenka Kljaic Bukvic; Neda Aberle; Susana Marinho; Danielle Belgrave; Wayne J Morgan; Fernando D Martinez Journal: Am J Respir Crit Care Med Date: 2012-03-29 Impact factor: 21.405
Authors: Ceri E Stewart; Ian P Hall; Stuart G Parker; Miriam F Moffat; Andrew J Wardlaw; Martin J Connolly; Charlotte Ruse; Ian Sayers Journal: BMC Med Genet Date: 2009-10-31 Impact factor: 2.103