A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis
A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis
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DOI：
10.1038/s41588-018-0314-6
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发表时间：
2019-02-01
期刊：
影响因子：
30.8
通讯作者：
Stefansson, Kari
中科院分区：
文献类型：
--
作者：
Kristjansson, Ragnar P.;Benonisdottir, Stefania;Stefansson, Kari
鼻息肉（NP）是鼻和鼻窦粘膜上的病变，是慢性鼻窦炎（CRS）的危险因素。我们对冰岛和英国的NP和CRS进行了全基因组关联研究（使用英国生物银行数据），其中包括4，366例NP病例，5，608例CRS病例和> 700，000例对照。我们发现10个标记物与NP相关，2个与CRS相关。我们还检测了210个与嗜酸性粒细胞计数相关的标记物，产生了17个额外的NP相关性。在27个NP信号中，7个与CRS相关，13个与哮喘相关。最值得注意的是，ALOX 15中的错义变体导致花生四烯酸15-脂氧合酶（15-LO）中的p.Thr560Met改变，从而赋予大的全基因组针对NP的显著保护作用。（P = 8.0 x 10（-27），比值比= 0.32; 95%置信区间= 0.26，0.39）和CRS（P = 1.1 x 10（-8），比值比= 0.64; 95%置信区间= 0.55，0.75）。p.Thr560Met，由大约20个欧洲人中的1个携带，先前显示导致15-LO酶活性几乎完全丧失。我们的研究结果确定15-LO作为NP和CRS治疗干预的潜在靶点。
Nasal polyps (NP) are lesions on the nasal and paranasal sinus mucosa and are a risk factor for chronic rhinosinusitis (CRS). We performed genome-wide association studies on NP and CRS in Iceland and the UK (using UK Biobank data) with 4,366 NP cases, 5,608 CRS cases, and > 700,000 controls. We found 10 markers associated with NP and 2 with CRS. We also tested 210 markers reported to associate with eosinophil count, yielding 17 additional NP associations. Of the 27 NP signals, 7 associate with CRS and 13 with asthma. Most notably, a missense variant in ALOX15 that causes a p. Thr560Met alteration in arachidonate 15-lipoxygenase (15-LO) confers large genome-wide significant protection against NP (P = 8.0 x 10(-27), odds ratio = 0.32; 95% confidence interval = 0.26, 0.39) and CRS (P = 1.1 x 10(-8), odds ratio = 0.64; 95% confidence interval = 0.55, 0.75). p.Thr560Met, carried by around 1 in 20 Europeans, was previously shown to cause near total loss of 15-LO enzymatic activity. Our findings identify 15-LO as a potential target for therapeutic intervention in NP and CRS.