Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis.
Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis.
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DOI：
10.1038/ncomms9382
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发表时间：
2015-09-29
影响因子：
16.6
通讯作者：
Knowles MR
中科院分区：
文献类型：
--
作者：
Corvol H;Blackman SM;Boëlle PY;Gallins PJ;Pace RG;Stonebraker JR;Accurso FJ;Clement A;Collaco JM;Dang H;Dang AT;Franca A;Gong J;Guillot L;Keenan K;Li W;Lin F;Patrone MV;Raraigh KS;Sun L;Zhou YH;O'Neal WK;Sontag MK;Levy H;Durie PR;Rommens JM;Drumm ML;Wright FA;Strug LJ;Cutting GR;Knowles MR
靶向特异性CFTR变体的小分子的鉴定开创了囊性纤维化（CF）治疗的新时代，但CF的最佳个体化治疗将需要鉴定和靶向疾病修饰剂。在这里，我们使用全基因组关联分析，以确定CF肺疾病的遗传修饰，死亡的主要原因。对6，365名CF患者进行的荟萃分析确定了与肺部疾病变异显著相关的五个位点。chr 3q 29（MUC 4/MUC 20; P=3.3 × 10−11）、chr5p15.3（SLC 9A 3; P=6.8 × 10−12）、chr6p21.3（HLA II类; P=1.2 × 10−8）和chrXq 22-q23（AGTR 2/SLC 6A 14; P=1.8 × 10−9）上的区域包含与CF病理生理学高度生物学相关的基因。第五个基因座位于chr 11 p12-p13（EHF/APIP; P=1.9 × 10−10）上，以前被证明与肺部疾病相关。这些结果为调节CF中肺部疾病严重程度的潜在靶点提供了新的见解。囊性纤维化导致生活质量下降，但正在开发针对特定CFTR变体的新治疗方法。在这里，作者在荟萃分析中确定了与疾病严重程度变化显著相关的五个基因组位点，这可能为囊性纤维化的个体化治疗提供靶点。
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. Cystic fibrosis imposes a decline in quality of life but new treatments are being developed that target specific CFTR variants. Here the authors identify five genome loci significantly associated with variation in disease severity in a meta-analysis, which may provide targets for individualized treatment of cystic fibrosis.