Association of Genetic Variant Linked to Hemochromatosis With Brain Magnetic Resonance Imaging Measures of Iron and Movement Disorders.
Association of Genetic Variant Linked to Hemochromatosis With Brain Magnetic Resonance Imaging Measures of Iron and Movement Disorders.
复制标题
DOI：
10.1001/jamaneurol.2022.2030
复制
发表时间：
2022-09-01
期刊：
影响因子：
29
通讯作者：
Fan, Chun Chieh
中科院分区：
文献类型：
--
作者：
Loughnan, Robert;Ahern, Jonathan;Tompkins, Cherisse;Palmer, Clare E.;Iversen, John;Thompson, Wesley K.;Andreassen, Ole;Jernigan, Terry;Sugrue, Leo;Dale, Anders;Boyle, Mary E. T.;Fan, Chun Chieh
遗传性血色素沉着症是一种常染色体隐性遗传病，导致铁超载。先前的研究结果使一些人相信大脑不会受到HH中铁的毒性影响。在比以往同类研究大得多的样本中，测试HH最强遗传风险变体与i）对铁沉积敏感的全脑测量值和ii）运动障碍发生率的关联。来自英国生物库的参与者的横断面回顾性研究。于2006年1月至2021年5月收集基因型、健康记录及神经影像学数据。数据分析于二零二一年一月至二零二二年四月进行。英国生物库队列是一个基于人口的样本。神经影像学分析包括836名个体，神经系统疾病分析包括488，288名主要为北方欧洲血统的个体。检测的疾病包括运动障碍[ICD 10：G20-G26]、步态和活动异常[ICD 10：R26]和其他神经系统疾病[ICD 10：G90-99]。206名受试者因撤回知情同意而被排除在分析之外。p.C282Y的纯合性，HH的最大已知遗传风险因素。来自脑MRI扫描的T2加权和T2* 信号强度，对铁沉积和神经系统疾病的临床诊断敏感的测量。总队列包括488，288名年龄在49-87岁之间的个体（223，569名男性），其中2，889名为p.C282Y纯合子。对165例p.C282Y纯合子（66例男性）和671例匹配对照（272例男性）进行的神经影像学分析显示，p.C282Y纯合子与皮质下运动结构（基底神经节、丘脑、红核和小脑;科恩d > 1）中T2加权和T2* 信号强度降低相关，与大量铁沉积一致。在整个英国生物样本库（2，889 p.C282Y纯合子，485，399对照）中，我们发现男性纯合子的运动障碍患病率显著增加（OR（95%CI）= 1.80（1.28-2.55），p=0.001），但女性则没有（OR（95%CI）= 1.09（0.70-1.73），p=0.69）。在31例p.C282Y纯合子男性运动障碍患者中，仅10例同时诊断为HH。这些结果表明，增加铁沉积在皮质下运动电路在p.C282Y纯合子，并确认运动障碍的纯合子男性的风险增加。HH的早期治疗可有效预防肝脏和心脏铁超负荷的负面后果。我们的工作表明，在高风险个体中筛查p.C282Y纯合性也有可能减少脑铁积累，并降低该突变纯合的男性运动障碍的风险。
Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder that leads to iron overload. Conflicting results of previous research has led some to believe the brain is spared from the toxic effects of iron in HH. To test the association of the strongest genetic risk variant for HH on i) brain wide measures sensitive to iron deposition and ii) the rates of movement disorders, in a substantially larger sample than previous studies of its kind. Cross-sectional retrospective study of participants from the UK Biobank. Genotype, health record and neuroimaging data was collected from January 2006 to May 2021. Data analysis was conducted from January 2021 to April 2022. The UK Biobank cohort is a population-based sample. Neuroimaging analysis consisted of 836 individuals and analysis of neurological disorders consisted of 488,288 individuals of largely northern European ancestry. Disorders tested included movement disorders [ICD10: G20-G26], abnormalities of gait and mobility [ICD10: R26], and other disorders of the nervous system [ICD10: G90–99]. 206 individuals were excluded from analysis due to withdrawal of consent. Homozygosity for p.C282Y, the largest known genetic risk factor for HH. T2-weighted and T2* signal intensity from brain MRI scans, measures sensitive to iron deposition and clinical diagnosis of neurological disorders. The total cohort consisted of 488,288 individuals (223,569 males) aged 49–87 years, 2,889 of whom were p.C282Y homozygotes. The neuroimaging analysis, which consisted of 165 p.C282Y homozygotes (66 male) and 671 matched controls (272 male), showed that p.C282Y homozygosity was associated with decreased T2-weighted and T2* signal intensity in subcortical motor structures (basal ganglia, thalamus, red nucleus, and cerebellum; Cohen’s d > 1) consistent with substantial iron deposition. Across the whole UK Biobank (2,889 p.C282Y homozygotes, 485,399 controls), we found a significantly increased prevalence for movement disorders in male homozygotes (OR (95% CI) = 1.80 (1.28–2.55), p=0.001), but not females (OR (95% CI) = 1.09 (0.70–1.73), p=0.69). Among the 31 p.C282Y homozygote males with a movement disorder only 10 had a concurrent HH diagnosis. These findings indicate increased iron deposition in subcortical motor circuits in p.C282Y homozygotes and confirm an increased risk of movement disorders in homozygous males. Early treatment in HH effectively prevents the negative consequences of iron-overload in the liver and heart. Our work suggests that screening for p.C282Y homozygosity in high-risk individuals also has the potential to reduce brain iron accumulation and to reduce the risk of movement disorders among males who are homozygous for this mutation.
登录
查看更多内容
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
3.4
作者：
Holtbernd F;Shah NJ
通讯作者：
Shah NJ
影响因子：
2.5
作者：
Buchanan, DD;Silburn, PA;Mellick, GD
通讯作者：
Mellick, GD
影响因子：
2.5
作者：
Dekker, MCJ;Giesbergen, PC;van Duijn, CM
通讯作者：
van Duijn, CM
影响因子：
5.9
作者：
Henninger, Benjamin;Alustiza, Jose;Gandon, Yves
通讯作者：
Gandon, Yves