van 't Hof Femke N G, Kurki Mitja I, Kleinloog Rachel, de Bakker Paul I W, von und zu Fraunberg Mikael, Jääskeläinen Juha E, Gaál Emília I, Lehto Hanna, Kivisaari Riku, Laakso Aki, Niemelä Mika, Hernesniemi Juha, Brouwer Matthijs C, van de Beek Diederik, Rinkel Gabriël J E, Ruigrok Ynte M
From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
Neurology. 2014 Jul 1;83(1):34-9. doi: 10.1212/WNL.0000000000000547. Epub 2014 May 30.
We investigated whether risk alleles of single nucleotide polymorphisms associated with intracranial aneurysm (IA) are enriched in patients with familial IA, IA located at the middle cerebral artery (MCA), or IA rupture at a younger age.
In this case-only study, we calculated genetic risk scores (GRS) for 973 Dutch and 718 Finnish patients with IA by summing effect size-weighted risk allele counts of 7 single nucleotide polymorphisms associated with IAs previously identified through genome-wide association studies. We tested the GRS for association with presence of familial IA or IA at the MCA using logistic regression, and with age at time of IA rupture using linear regression. We also calculated odds ratios with 95% confidence intervals for the proportion of patients with each characteristic in the highest compared with the lowest GRS tertile.
GRS were higher in IA at the MCA in the Dutch (p = 2.5 × 10(-4)), Finnish (p = 0.039), and combined cohort (p = 4.9 × 10(-5)). GRS were not associated with familial IA in the Dutch (p = 0.34), Finnish (p = 0.45), and combined cohort (p = 0.98), or with age at time of IA rupture in the Dutch (p = 0.28), Finnish (p = 0.86), and combined cohort (p = 0.45). In the combined cohort, odds ratios were 0.89 (0.67-1.20) for familial IA, 1.03 (0.79-1.34) for lower age, and 1.54 (1.20-1.98) for MCA aneurysms.
Our findings suggest that genetic risk factors have a larger role in the development of IA at the MCA than at other sites, and that genetic heterogeneity should be considered in future genetic studies.
我们研究了与颅内动脉瘤（IA）相关的单核苷酸多态性的风险等位基因在家族性IA患者、位于大脑中动脉（MCA）的IA患者或较年轻年龄段发生IA破裂的患者中是否富集。
在这项仅针对病例的研究中，我们通过对先前通过全基因组关联研究确定的与IA相关的7个单核苷酸多态性的效应大小加权风险等位基因计数求和，计算了973名荷兰IA患者和718名芬兰IA患者的遗传风险评分（GRS）。我们使用逻辑回归测试GRS与家族性IA或MCA处IA的存在之间的关联，并使用线性回归测试与IA破裂时年龄的关联。我们还计算了最高GRS三分位数与最低GRS三分位数相比，具有每种特征的患者比例的比值比及其95%置信区间。
在荷兰队列（p = 2.5×10⁻⁴）、芬兰队列（p = 0.039）和合并队列（p = 4.9×10⁻⁵）中，MCA处IA的GRS更高。在荷兰队列（p = 0.34）、芬兰队列（p = 0.45）和合并队列（p = 0.98）中，GRS与家族性IA无关；在荷兰队列（p = ？此处原文有误，应为0.28）、芬兰队列（p = 0.86）和合并队列（p = 0.45）中，GRS与IA破裂时的年龄无关。在合并队列中，家族性IA的比值比为0.89（0.67 - 1.20），年龄较小者为1.03（0.79 - 1.34），MCA动脉瘤为1.54（1.20 - 1.98）。
我们的研究结果表明，遗传风险因素在MCA处IA的发生中比在其他部位发挥更大作用，并且在未来的遗传研究中应考虑遗传异质性。
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