Pedersen Kasper Mønsted, Çolak Yunus, Ellervik Christina, Hasselbalch Hans Carl, Bojesen Stig Egil, Nordestgaard Børge Grønne
Department of Clinical Biochemistry, Copenhagen University Hospital, Herlev and Gentofte Hospital, Borgmester Ib Juuls Vej 1, DK-2730 Herlev, Denmark.
The Copenhagen General Population Study, Copenhagen University Hospital, Herlev and Gentofte Hospital, Herlev, Denmark.
EClinicalMedicine. 2020 Feb 19;21:100280. doi: 10.1016/j.eclinm.2020.100280. eCollection 2020 Apr.
Whether inflammation is independently associated with development of V617F mutation and myeloproliferative neoplasm is not clear. We tested the hypothesis that a loss-of-function polymorphism in (marked by rs4537545) reduces risk of V617F mutation and myeloproliferative neoplasm in a Mendelian randomization study.
We genotyped 107,969 Danes from the Copenhagen General Population Study for the rs4537545 genotype, where the T-allele is associated with impaired interleukin-6 receptor signaling and reduced inflammation. V617F was examined in a subset of 49,143 individuals. We investigated the association between rs4537545 and risk of V617F using logistic regression and myeloproliferative neoplasm using Cox regression.
36,871 were non-carriers, 52,500 heterozygotes, and 18,598 homozygotes for the T-allele of the rs4537545 genotype. Among 107,969 individuals, 352 were diagnosed with myeloproliferative neoplasm, and among 49,143 individuals, 62 were V617F-positive (of these 62 individuals, 46 had myeloproliferative neoplasm diagnosed). Compared to non-carriers, age- and sex-adjusted odds ratios for risk of V617F were 0·55(95%CI:0·32-0·94) in heterozygotes, 0·51(0·24-1·12) in homozygotes, 0·54(0·33-0·89) in carriers, and 0·66(0·45-0·96) per T-allele. Compared to non-carriers, age- and sex-adjusted hazard ratios for risk of myeloproliferative neoplasm were 0·82(95% CI: 0·65-1·02) in heterozygotes, 0·65(0·47-0·91) in homozygotes, 0·77(0·63-0·96) in carriers, and 0·81(0·70-0·94) per T-allele. Associations were primarily observed for polycythaemia vera and myelofibrosis, and for V617F-positive myeloproliferative neoplasm.
A loss-of-function polymorphism in reduces risk of V617F mutation and myeloproliferative neoplasm. This finding supports inflammation as an independent risk factor for V617F mutation and myeloproliferative neoplasm and indicates that therapeutics designed to block interleukin-6 receptor signaling might prevent or retard progression of myeloproliferative neoplasm.
Karen Elise Jensen Foundation.
炎症是否与V617F突变及骨髓增殖性肿瘤的发生独立相关尚不清楚。在一项孟德尔随机化研究中，我们检验了一种假设，即（由rs4537545标记的）功能缺失多态性会降低V617F突变及骨髓增殖性肿瘤的风险。
我们对哥本哈根普通人群研究中的107,969名丹麦人进行rs4537545基因型基因分型，其中T等位基因与白细胞介素-6受体信号传导受损及炎症减轻相关。在49,143名个体的子集中检测V617F。我们使用逻辑回归研究rs4537545与V617F风险之间的关联，并使用Cox回归研究其与骨髓增殖性肿瘤风险之间的关联。
rs4537545基因型T等位基因的非携带者有36,871人，杂合子有52,500人，纯合子有18,598人。在107,969名个体中，352人被诊断为骨髓增殖性肿瘤，在49,143名个体中，62人V617F呈阳性（在这62名个体中，46人被诊断为骨髓增殖性肿瘤）。与非携带者相比，杂合子中V617F风险的年龄和性别调整优势比为0·55（95%CI：0·32 - 0·94），纯合子中为0·51（0·24 - 1·12），携带者中为0·54（0·33 - 0·89），每个T等位基因为0·66（0·45 - 0·96）。与非携带者相比，杂合子中骨髓增殖性肿瘤风险的年龄和性别调整风险比为0·82（95%CI：0·65 - 1·02），纯合子中为0·65（0·47 - 0·91），携带者中为0·77（0·63 - 0·96），每个T等位基因为0·81（0·70 - 0·94）。主要在真性红细胞增多症和骨髓纤维化以及V617F阳性骨髓增殖性肿瘤中观察到关联。
的功能缺失多态性降低了V617F突变和骨髓增殖性肿瘤的风险。这一发现支持炎症是V617F突变和骨髓增殖性肿瘤的独立危险因素，并表明旨在阻断白细胞介素-6受体信号传导的疗法可能预防或延缓骨髓增殖性肿瘤的进展。
卡伦·伊丽莎·詹森基金会。
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