Background: We have previously identified that polymorphisms spanning the Urokinase Receptor Gene ( PLAUR ) are associated with asthma, decline in lung function and receptor levels. However, the variants driving genetic associations are not yet fully defined. Using next generation re-sequencing of the 19q13 region we aimed to identify common and rare variants differentially expressed in severe asthma and controls to bridge this gap in knowledge. Method: 200 UK severe asthma patients (GINA ≥3) and 200 non-asthma/non-atopic controls were sequenced. Samples were multiplexed, with each group split into 3 pools ( n =66, 66 and 68). Target enrichment was carried out using the Agilent SureSelect kit (67.5kb region on 19q13). Paired-end sequencing was utilised and 100bp reads for cases and controls were run on the Illumina HiSeq2000™ System. Realignment around insertion deletions, recalibration of quality scores and variant detection were carried out using the GATK and Syzgy software packages. Data were compared to reference genome build 37.1. Results: Mean coverage was 29x and 817 variants were identified, of which 399 (199 rare) were novel. In total, 12 exon variants were identified, with 2 novel rare variants in exons 1 and 6 predicted to cause functional changes to the uPAR protein sequence. Several variants were unique to cases or controls. On correcting for multiple testing, we identified 5 variants showing different representation in cases/controls. These variants were located upstream of PLAUR , with 4 variants forming a 7bp cluster of variation ∼23kb upstream of the start codon. Conclusions: Re-sequencing PLAUR has identified novel common and rare variants that may be of relevance to asthma.
Portelli et al. (Mon,) studied this question.