Early complement genes are associated with visual system degeneration in multiple sclerosis
Early complement genes are associated with visual system degeneration in multiple sclerosis
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DOI：
10.1093/brain/awz188
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发表时间：
2019-09-01
期刊：
影响因子：
14.5
通讯作者：
Calabresi, Peter A.
中科院分区：
文献类型：
--
作者：
Fitzgerald, Kathryn C.;Kim, Kicheol;Calabresi, Peter A.
多发性硬化症是一种异质性疾病，具有不可预测的病程和广泛的严重程度;一些人迅速进展为残疾状态，而另一些人仅出现轻微症状。虽然遗传学研究已经确定了与多发性硬化症风险增加相关的变异，但没有任何变异与多发性硬化症的严重程度始终相关。在某种程度上，研究结果的缺乏与临床评定量表的固有局限性有关;这些量表对疾病进展的早期退行性变化不敏感。视网膜光学相干断层扫描成像和低对比度字母视力与多发性硬化症的临床和影像学结局相关并可预测其预后因此，它们可以作为敏感的表型来发现疾病过程的遗传预测因子。我们对多发性硬化症的纵向结构和功能视觉通路表型进行了一系列全基因组关联研究。首先，我们评估了神经节细胞/内网状层萎缩的遗传预测因素，在一个发现队列的374例多发性硬化症患者中，使用混合效应模型调整年龄，性别，病程，视神经炎和遗传血统，并使用单变量和基于网络的分析相结合。对于在发现中鉴定的候选变体，我们在复制队列（n = 376）中进行了一组类似的神经节细胞/内网状层变薄的分析。其次，我们使用多变量调整的考克斯比例风险模型评估了发现中低对比度字母敏锐度持续丢失5个字母的遗传预测因子（n = 582）。然后，我们评估了复制队列中的候选变体/途径。（n = 253）。这两项研究的结果都揭示了在与疾病严重程度相关的早期补体激活中高度富集连接基因的新型子网络。在这些网络中，C3是与神经节细胞/内丛状层萎缩最密切相关的基因（P = 0.004），C1 QA和CR 1是持续低对比度字母视力丧失分析的主要结果。也就是说，在荟萃分析汇总发现和复制队列中，与C1 QA相关的变异rs 158772和与CR 1相关的变异rs61822967分别与持续LCLA丢失风险增加71%和40（rs 158772：风险比：1.71; 95%置信区间：1.30-2.25; P = 1.3 x 10（-4）; rs61822967：风险比：1.40; 95%置信区间：1.16-1.68; P = 4.1 x 10（-4））。总之，早期补体途径基因变异始终与多发性硬化严重程度的结构和功能指标相关。来自无偏分析的这些结果得到了先前几份报告的有力支持，这些报告在神经变性中机械地涉及早期补体因子。
Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms. Though genetic studies have identified variants that are associated with an increased risk of developing multiple sclerosis, no variants have been consistently associated with multiple sclerosis severity. In part, the lack of findings is related to inherent limitations of clinical rating scales; these scales are insensitive to early degenerative changes that underlie disease progression. Optical coherence tomography imaging of the retina and low-contrast letter acuity correlate with and predict clinical and imaging-based outcomes in multiple sclerosis. Therefore, they may serve as sensitive phenotypes to discover genetic predictors of disease course. We conducted a set of genome-wide association studies of longitudinal structural and functional visual pathway phenotypes in multiple sclerosis. First, we assessed genetic predictors of ganglion cell/inner plexiform layer atrophy in a discovery cohort of 374 patients with multiple sclerosis using mixed-effects models adjusting for age, sex, disease duration, optic neuritis and genetic ancestry and using a combination of single-variant and network-based analyses. For candidate variants identified in discovery, we conducted a similar set of analyses of ganglion cell/inner plexiform layer thinning in a replication cohort (n = 376). Second, we assessed genetic predictors of sustained loss of 5-letters in low-contrast letter acuity in discovery (n = 582) using multivariable-adjusted Cox proportional hazards models. We then evaluated candidate variants/pathways in a replication cohort. (n = 253). Results of both studies revealed novel subnetworks highly enriched for connected genes in early complement activation linked to measures of disease severity. Within these networks, C3 was the gene most strongly associated with ganglion cell/inner plexiform layer atrophy (P = 0.004) and C1QA and CR1 were top results in analysis of sustained low-contrast letter acuity loss. Namely, variant rs158772, linked to C1QA, and rs61822967, linked to CR1, were associated with 71% and 40% increases in risk of sustained LCLA loss, respectively, in meta-analysis pooling discovery and replication cohorts (rs158772: hazard ratio: 1.71; 95% confidence interval 1.30-2.25; P = 1.3 x 10(-4); rs61822967: hazard ratio: 1.40; 95% confidence interval: 1.16-1.68; P = 4.1 x 10(-4)). In conclusion, early complement pathway gene variants were consistently associated with structural and functional measures of multiple sclerosis severity. These results from unbiased analyses are strongly supported by several prior reports that mechanistically implicated early complement factors in neurodegeneration.