Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis

Corvol, H.; Blackman, S. M.; Boelle, P. Y.; Gallins, P. J.; Pace, R. G.; Stonebraker, J. R.; Accurso, F. J.; Clement, A.; Collaco, J. M.; Dang, H.; Dang, A. T.; Franca, A.; Gong, J.; Guillot, L.; Keenan, K.; Li, W.; Lin, F.; Patrone, M. V.; Raraigh, K. S.; Sun, L.; Zhou, Y. H.; O'Neal, W. K.; Sontag, M. K.; Levy, H.; Durie, P. R.; Rommens, J. M.; Drumm, M. L.; Wright, F. A.; Strug, L. J.; Cutting, G. R.; Knowles, M. R.

Nat Commun. 2015 Sep 30; 6:8382


The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease. Regions on chr3q29 (MUC4/MUC20; P=3.3 x 10(-11)), chr5p15.3 (SLC9A3; P=6.8 x 10(-12)), chr6p21.3 (HLA Class II; P=1.2 x 10(-8)) and chrXq22-q23 (AGTR2/SLC6A14; P=1.8 x 10(-9)) contain genes of high biological relevance to CF pathophysiology. The fifth locus, on chr11p12-p13 (EHF/APIP; P=1.9 x 10(-10)), was previously shown to be associated with lung disease. These results provide new insights into potential targets for modulating lung disease severity in CF.

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