deCODE genetics/Amgen Inc., Reykjavik, Iceland.
Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands.
Nat Genet. 2019 Feb;51(2):267-276. doi: 10.1038/s41588-018-0314-6. Epub 2019 Jan 14.
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 × 10, odds ratio = 0.32; 95% confidence interval = 0.26, 0.39) and CRS (P = 1.1 × 10, 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.
鼻息肉 (NP) 是鼻腔和鼻旁窦黏膜的病变，是慢性鼻-鼻窦炎 (CRS) 的一个危险因素。我们在冰岛和英国（使用英国生物库数据）对 NP 和 CRS 进行了全基因组关联研究，纳入了 4366 例 NP 病例、5608 例 CRS 病例和 >70 万例对照。我们发现了 10 个与 NP 相关的标记物和 2 个与 CRS 相关的标记物。我们还测试了 210 个报告与嗜酸性粒细胞计数相关的标记物，产生了 17 个额外的 NP 关联。在 27 个 NP 信号中，有 7 个与 CRS 相关，13 个与哮喘相关。最值得注意的是，载脂蛋白 15 中的错义变异导致花生四烯酸 15-脂氧合酶 (15-LO) 的 Thr560Met 改变，这使得 NP（P = 8.0×10，比值比 = 0.32；95%置信区间 = 0.26，0.39）和 CRS（P = 1.1×10，比值比 = 0.64；95%置信区间 = 0.55，0.75）的全基因组显著保护。大约每 20 个欧洲人中就有 1 人携带 p.Thr560Met，先前的研究表明，这种变异会导致 15-LO 酶活性几乎完全丧失。我们的研究结果确定 15-LO 是 NP 和 CRS 治疗干预的潜在靶点。
