Sahi Nitin, Haider Lukas, Chung Karen, Prados Carrasco Ferran, Kanber Baris, Samson Rebecca, Thompson Alan J, Gandini Wheeler-Kingshott Claudia A M, Trip S Anand, Brownlee Wallace, Ciccarelli Olga, Barkhof Frederik, Tur Carmen, Houlden Henry, Chard Declan
NMR Research Unit, Queen Square Multiple Sclerosis Centre, University College London Queen Square Institute of Neurology, London WC1N 3BG, UK.
Department of Biomedical Imaging and Image Guided Therapy, Medical University Vienna, 1090 Vienna, Austria.
Brain Commun. 2023 Oct 4;5(5):fcad255. doi: 10.1093/braincomms/fcad255. eCollection 2023.
Multiple sclerosis risk has a well-established polygenic component, yet the genetic contribution to disease course and severity remains unclear and difficult to examine. Accurately measuring disease progression requires long-term study of clinical and radiological outcomes with sufficient follow-up duration to confidently confirm disability accrual and multiple sclerosis phenotypes. In this retrospective study, we explore genetic influences on long-term disease course and severity; in a unique cohort of clinically isolated syndrome patients with homogenous 30-year disease duration, deep clinical phenotyping and advanced MRI metrics. Sixty-one clinically isolated syndrome patients [41 female (67%): 20 male (33%)] underwent clinical and MRI assessment at baseline, 1-, 5-, 10-, 14-, 20- and 30-year follow-up (mean age ± standard deviation: 60.9 ± 6.5 years). After 30 years, 29 patients developed relapsing-remitting multiple sclerosis, 15 developed secondary progressive multiple sclerosis and 17 still had a clinically isolated syndrome. Twenty-seven genes were investigated for associations with clinical outcomes [including disease course and Expanded Disability Status Scale (EDSS)] and brain MRI (including white matter lesions, cortical lesions, and brain tissue volumes) at the 30-year follow-up. Genetic associations with changes in EDSS, relapses, white matter lesions and brain atrophy (third ventricular and medullary measurements) over 30 years were assessed using mixed-effects models. -positive ( = 26) patients showed faster white matter lesion accrual [+1.96 lesions/year (0.64-3.29), = 3.8 × 10], greater 30-year white matter lesion volumes [+11.60 ml, (5.49-18.29), = 1.27 × 10] and higher annualized relapse rates [+0.06 relapses/year (0.005-0.11), = 0.031] compared with -negative patients ( = 35). -positive patients ( = 41) had more cortical lesions (+0.83 [0.08-1.66], = 0.042), faster EDSS worsening [+0.06 points/year (0.02-0.11), = 0.010], greater 30-year EDSS [+1.72 (0.49-2.93), = 0.013; multiple sclerosis cases: +2.60 (1.30-3.87), = 2.02 × 10], and greater risk of secondary progressive multiple sclerosis [odds ratio (OR) = 12.25 (1.15-23.10), = 0.031] than -negative patients ( = 18). In contrast, -positive ( = 30) patients had preserved 30-year grey matter fraction [+0.76% (0.28-1.29), = 8.4 × 10], lower risk of cortical lesions [OR = 0.22 (0.05-0.99), = 0.049] and lower 30-year EDSS [-1.35 (-0.87,-3.44), = 0.026; multiple sclerosis cases: -2.12 (-0.87, -3.44), = 5.02 × 10] than -negative patients ( = 30). In multiple sclerosis cases, -positive patients also had slower EDSS worsening [-0.07 points/year (-0.01,-0.13), = 0.015] and lower risk of secondary progressive multiple sclerosis [OR = 0.19 (0.04-0.92), = 0.042]. These exploratory findings support diverse genetic influences on pathological mechanisms associated with multiple sclerosis disease course. influenced white matter inflammation and relapses, while (protective) and (adverse) were associated with grey matter pathology (cortical lesions and atrophy), long-term disability worsening and the risk of developing secondary progressive multiple sclerosis.
多发性硬化症风险具有公认的多基因成分，然而基因对疾病进程和严重程度的影响仍不明确且难以研究。准确测量疾病进展需要对临床和影像学结果进行长期研究，并具有足够的随访时间，以可靠地确认残疾累积情况和多发性硬化症表型。在这项回顾性研究中，我们探讨了基因对长期疾病进程和严重程度的影响；研究对象是一组独特的临床孤立综合征患者队列，他们的病程均为30年，有深入的临床表型分析和先进的MRI指标。61例临床孤立综合征患者[41名女性（67%）：20名男性（33%）]在基线、1年、5年、10年、14年、20年和30年随访时接受了临床和MRI评估（平均年龄±标准差：60.9±6.5岁）。30年后，29例患者发展为复发缓解型多发性硬化症，15例发展为继发进展型多发性硬化症，17例仍处于临床孤立综合征状态。在30年随访时，研究了27个基因与临床结果[包括疾病进程和扩展残疾状态量表（EDSS）]以及脑部MRI（包括白质病变、皮质病变和脑组织体积）之间的关联。使用混合效应模型评估了基因与30年间EDSS变化、复发、白质病变和脑萎缩（第三脑室和延髓测量值）之间的关联。与阴性患者（n = 35）相比，阳性（n = 26）患者的白质病变累积更快[+1.96个病变/年（0.64 - 3.29），p = 3.8×10⁻³]，30年白质病变体积更大[+11.60 ml，（5.49 - 18.29），p = 1.27×10⁻³]，年化复发率更高[+0.06次复发/年（0.005 - 0.11），p = 0.031]。与阴性患者（n = 18）相比，阳性（n = 41）患者有更多皮质病变（+0.83 [0.08 - 1.66]，p = 0.042），EDSS恶化更快[+0.06分/年（0.02 - 0.11），p = 0.010]，30年EDSS更高[+1.72（0.49 - 2.93），p = 0.
