Corvol Harriet, Blackman Scott M, Boëlle Pierre-Yves, Gallins Paul J, Pace Rhonda G, Stonebraker Jaclyn R, Accurso Frank J, Clement Annick, Collaco Joseph M, Dang Hong, Dang Anthony T, Franca Arianna, Gong Jiafen, Guillot Loic, Keenan Katherine, Li Weili, Lin Fan, Patrone Michael V, Raraigh Karen S, Sun Lei, Zhou Yi-Hui, O'Neal Wanda K, Sontag Marci K, Levy Hara, Durie Peter R, Rommens Johanna M, Drumm Mitchell L, Wright Fred A, Strug Lisa J, Cutting Garry R, Knowles Michael R
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Trousseau, Pediatric Pulmonary Department; Institut National de la Santé et la Recherche Médicale (INSERM) U938, Paris 75012, France.
Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Paris 75005, France.
Nat Commun. 2015 Sep 29;6:8382. doi: 10.1038/ncomms9382.
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 × 10(-11)), chr5p15.3 (SLC9A3; P=6.8 × 10(-12)), chr6p21.3 (HLA Class II; P=1.2 × 10(-8)) and chrXq22-q23 (AGTR2/SLC6A14; P=1.8 × 10(-9)) contain genes of high biological relevance to CF pathophysiology. The fifth locus, on chr11p12-p13 (EHF/APIP; P=1.9 × 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.
靶向特定CFTR变体的小分子的鉴定开启了囊性纤维化（CF）治疗的新时代，然而，CF的最佳个体化治疗将需要鉴定疾病修饰因子并对其进行靶向治疗。在此，我们使用全基因组关联分析来鉴定CF肺部疾病的遗传修饰因子，CF肺部疾病是主要的死亡原因。对6365名CF患者的荟萃分析确定了五个与肺部疾病变异显著相关的基因座。3号染色体q29区域（MUC4/MUC20；P = 3.3×10^(-11)）、5号染色体p15.3区域（SLC9A3；P = 6.8×10^(-12)）、6号染色体p21.3区域（HLA II类；P = 1.2×10^(-8)）和X染色体q22 - q23区域（AGTR2/SLC6A14；P = 1.8×10^(-9)）包含与CF病理生理学具有高度生物学相关性的基因。第五个基因座位于11号染色体p12 - p13区域（EHF/APIP；P = 1.9×10^(-10)），先前已证明与肺部疾病相关。这些结果为调节CF肺部疾病严重程度的潜在靶点提供了新的见解。
