ZNF638

来自国际多发性硬化症遗传学协会的科学家们通过对超过2.2万名多发性硬化症患者进行研究发现了首个与快速疾病进展相关的遗传突变，其或许会随着时间的延续让患者丧失运动能力和独立性。 多发性硬化症（MS）是一种中枢神经系统的自身免疫性疾病，其会大多数患者出现严重的神经变性，而且也是年轻成年人发生慢性神经系统残疾的一种常见原因。近日，一篇发表在国际杂志Nature上题为“Locus for severity implicates CNS resilience in progression of multiple sclerosis”的研究报告中，来自国际多发性硬化症遗传学协会的科学家们通过对超过2.2万名多发性硬化症患者进行研究发现了首个与快速疾病进展相关的遗传突变，其或许会随着时间的延续让患者丧失运动能力和独立性。 多发性硬化症是免疫系统错误地攻击大脑和脊髓所引起的结果，其会导致症状发作（称为复发）以及患者机体的长期退化，尽管目前有针对疾病复发的有效疗法，其中一些就是剑桥大学研究人员开发的，但并没有一种方法能够可靠地预防患者机体残疾的积累。这项研究中，研究人员报道了一种能增加患者疾病严重性的遗传突变，并未理解最终抵御人类多发性硬化症提供了一种真正的进展。研究者Sergio Baranzini说道，从父母那里继承这种遗传突变会使其需要步行辅助工具的时间加快近4年；理解这种遗传突变如何对多发性硬化症的严重性产生影响或许有望为开发新一代预防疾病进展的新型疗法提供新的希望。 为了解决多发性硬化症的严重性之谜，两个大型的多发性硬化症联盟（国际多发性硬化症遗传学联盟（IMSGC）和多发性硬化症联盟（MultipleMS Consortium））进行了联合研究，这就使得来自全球的多发性硬化症研究人员能集中必要的资源开始识别出影响多发性硬化症患者治疗结局的遗传因素。此前研究结果表明，多发性硬化症的易感性或风险在很大程度上源于宿主机体免疫系统的功能异常，而且其中一部分功能障碍能被治疗，而且能减缓患者的疾病；但研究者Baranzini解释道，这些风险因素并不能解释为何在确诊10年后，一些多发性硬化症患者仍然会坐在轮椅上，而一些则能继续跑马拉松。这两个研究联盟结合了1.2万多名多发性硬化症患者的数据完成了一项全基因组关联性研究，其使用统计学手段仔细分析了遗传突变和特定形状之间的关联，在这种情况下，感兴趣的性状往往与多发性硬化症的严重性有关，包括每个人从诊断到进展为某种程度的残疾所需要的时间。 在筛选了700多万个遗传突变体后，研究人员发现了其中一个突变体与多发性硬化症的疾病快速进展有关，这一突变体位于两个此前与多发性硬化症并没有关联的基因（DYSF和ZNF638）之间，第一个基因能参与损伤细胞的修复，而第二个基因则能帮助控制病毒感染，这一突变体与这些基因的接近就表明其或许与疾病的进展直接相关。Adil Harroud博士表示，这些基因通常会在大脑和脊髓中保持活跃，而并非是免疫系统；我们的研究结果表明，神经系统的恢复力和修复力能决定多发性硬化症进展的过程，而且我们还应该重点关注人类生物学的这些研究部分，从而帮助开发更好的治疗性手段。 重磅！科学家识别出了能指示人类多发性硬化症严重程度的首个遗传标志物。 图片来源：Nature (2023). DOI:10.1038/s41586-023-06250-x 这一发现为研究多发性硬化症的神经系统部分提供了首个线索，此外，研究人员还使用称之为“孟德尔随机化”的统计学方法来探索环境影响的重要性，结果发现，接受教育的年限和父母的年龄或许会降低个体患多发性硬化症的严重性，而吸烟则会恶化疾病的症状，发现与这些与大脑健康的间接措施或许能进一步强调恢复力在确定多发性硬化症结果中的重要性。尽管机体大脑对损伤的恢复力会决定诸如多发性硬化症等疾病的严重性似乎是显而易见的，但这项最新研究已经为科学家们阐明支撑这种恢复力的关键过程提供了一定的线索。为了证实这些研究发现，科学家们调查了另外近1万名多发性硬化症患者机体的遗传学特征，即那些携带两个突变体使其变得更快残疾的个体。 后期研究人员非常有必要进一步研究来确定这种遗传突变如何影响DYSF, ZNF638以及更为普遍的神经系统，目前他们正在收集一组更大的多发性硬化症患者的DNA样本，他们希望找到能促使多发性硬化症患者长期残疾的其它突变体。这一研究或许也给了研究人员开发新药的机会，有望帮助改善更多多发性硬化症患者的健康。自20世纪80年代末以来，研究多发性硬化症的遗传学特性一直是剑桥大学神经科学研究人员的一个主要研究领域，他们通过联合研究揭示了绝大多数会增加个体易感性的基因突变。Alastair Compston教授补充道，自20世纪70年代以来，我们一直在从事研究来识别出多发性硬化症的易感基因，如今已经发现了完全独立的风险突变体。而且这项研究再次阐明了国际合作对于推动科学家们理解多发性硬化症和其它人类疾病背后发病机制的重要性。 综上，相比免疫驱动的易感性而言，这些研究结果揭示了中枢神经系统恢复力和潜在的神经认知储备在决定多发性硬化症患者治疗结局中所发挥的关键角色。（生物谷Bioon.com） 原始出处： International Multiple Sclerosis Genetics Consortium., MultipleMS Consortium. Locus for severity implicates CNS resilience in progression of multiple sclerosis. Nature (2023). doi：10.1038/s41586-023-06250-x

Scientists identify the first genetic marker for MS severity, opening the door to preventing long-term disability. Scientists identify the first genetic marker for MS severity, opening the door to preventing long-term disability. A study of more than 22,000 people with multiple sclerosis has discovered the first genetic variant associated with faster disease progression that can rob patients of their mobility and independence over time. Multiple sclerosis (MS) is the result of the immune system mistakenly attacking the brain and the spinal cord, resulting in symptom flares known as relapses as well as longer-term degeneration known as progression. Despite the development of effective treatments for relapses, none can reliably prevent the accumulation of disability. The breakthrough findings, published in Nature on June 28, 2023, point to a genetic variant that increases the disease's severity and provide the first real progress in understanding and eventually fighting this aspect of MS. "Inheriting this genetic variant from both parents accelerates the time to needing a walking aid by almost four years," said Sergio Baranzini, PhD, professor of neurology at the University of California, San Francisco (UCSF) and co-senior author of the study. The work was the result of a large international collaboration of more than 70 institutions from around the world, led by researchers from UCSF and the University of Cambridge. "Understanding how the variant exerts its effects on MS severity will hopefully pave the way to a new generation of treatments that are able to prevent disease progression," said Stephen Sawcer, a professor at Cambridge and the other co-senior author of the study. A renewed focus on the nervous system To address the mystery of MS severity, two large MS research consortia joined forces: The International Multiple Sclerosis Genetics Consortium (IMSGC) and The MultipleMS Consortium. This enabled MS researchers from around the world to pool the resources needed to begin to identify the genetic factors influencing MS outcomes. Previous studies have shown that MS susceptibility, or risk, stems in large part from dysfunction in the immune system, and some of this dysfunction can be treated, slowing down the disease. But "these risk factors don't explain why, 10 years after diagnosis, some MS patients are in wheelchairs, while others continue to run marathons," explained Baranzini. The two consortia combined data from more than 12,000 people with MS to complete a genome-wide association study (GWAS), which uses statistics to carefully link genetic variants to particular traits. In this case, the traits of interest were related to MS severity, including the years it took for each individual to advance from diagnosis to a certain level of disability. After sifting through more than 7 million genetic variants, the scientists found one that was associated with faster disease progression. The variant sits between two genes with no prior connection to MS, called DYSF and ZNF638. The first is involved in repairing damaged cells, and the second helps to control viral infections. The variant's proximity to these genes suggests that they may be involved in the disease's progression. "These genes are normally active within the brain and spinal cord, rather than the immune system," said Adil Harroud, MD, lead author of the study and former postdoctoral researcher in Baranzini's lab. "Our findings suggest that resilience and repair in the nervous system determine the course of MS progression and that we should focus on these parts of human biology for better therapies." The findings give the field its first leads to address the nervous system component of MS."Although it seems obvious that your brain's resilience to injury would determine the severity of a disease like MS, this new study has pointed us towards the key processes that underlie this resilience," Sawcer said. To confirm their findings, the scientists investigated the genetics of nearly 10,000 additional MS patients. Those with two copies of the variant became disabled faster. Netherlands Institute for Neuroscience But how do we know how relevant this DNA variant actually is? That's where the Dutch Brain Bank steps in. A team of researchers from the Netherlands Institute for Neuroscience (Aletta van den Bosch, Jeen Engelenburg, Dennis Wever, Jorg Hamann, Inge Huitinga and Joost Smolders), within the International MS Genetics Consortium (IMSGC), looked at the genetic architecture underlying the course of MS, using donor brains. Joost Smolders (aside from his employment at the Netherlands Institute for Neuroscience, also working as a neurologist at Erasmus MC Rotterdam and member of the IMSGC): 'In terms of treatment, there's already a lot that we can do for people with MS, but we can't yet predict the speed at which their health deteriorates. For this we need more insight into underlying mechanisms, with the discovery of the SNP being an important first step. A SNP is a variation in the DNA of a single DNA building block. At the Netherlands Institute for Neuroscience, we can perform the second step, which involves looking into the brain tissue to see the effect of this SNP. At the Brain Bank, we have brains from deceased donors with MS who already have an entire disease history behind them, all available for research. We asked ourselves whether carriers of the genetic abnormality had more severe MS-related changes in their brains.' 'Our results show that homozygous carriers of the risk allele (rs10191320), or double carriers of the gene, have almost twice as many MS abnormalities in their gray and white matter than MS donors without this genetic variation. This is very important, because it allows us to validate that this SNP may really be relevant to people with MS. This also illustrates the strength of the Brain Bank: you can look at the pathology very closely. The effect of such a SNP is magnified far more in the pathology than in the effect it has on someone's experience with MS. Something that would typically require tens of thousands of people with MS for living measurements can be confirmed with a hundred or so of these particular MS brain donors.' Next steps Further work will be necessary to determine exactly how this genetic variant affects DYSF, ZNF638, and the nervous system more generally. The researchers are also collecting an even larger set of DNA samples from people with MS, expecting to find other variants that contribute to long-term disability. "This gives us a new opportunity to develop new drugs that may help preserve the health of all who suffer from MS," said Harroud. Could we say instead, "treatments to prevent long-term disability"?