Zhao-Fleming Hannah H, Decker Paul A, Kosel Matthew L, Drucker Kristen L, Kollmeyer Thomas, Lachance Daniel H, Clarkson Benjamin D, Howe Charles L, Jenkins Robert, Tobin W Oliver, Eckel-Passow Jeanette
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
Mult Scler. 2025 Sep 8:13524585251371984. doi: 10.1177/13524585251371984.
Tumefactive demyelination (TD) is a rare variant of multiple sclerosis (MS) characterized by tumor-like lesions that often require aggressive management. Genome-wide association studies (GWAS) identified variants associated with MS; similar analyses in TD are lacking.
A GWAS was performed to identify variants associated with TD.
The case-control study included 142 TD cases and 293 controls. TD patients were required to have a demyelinating event and magnetic resonance imaging (MRI) showing one or more lesions. Controls were patients without a neurologic or systemic inflammatory disease or cancer. Logistic regression was used to compare cases versus controls for each variant; age, sex, and principal components were included as covariates. A -value threshold of 5 × 10 was GWAS significant and 5 × 10 nominally significant. A polygenic risk score (PRS) was compared across TD and controls.
Variants on chromosome 14 (rs117797734, = 2.06 × 10, odds ratio (OR) = 13.14) and chromosome 6 (most significant rs6936540, = 5.5 × 10, OR = 2.61) near were significant. Seven non-MHC and two MHC variants associated with MS were associated with TD. The PRS was significantly higher in TD versus controls.
We identified novel regions associated with TD, demonstrating the importance of performing GWAS in homogeneous subtypes of MS. Further validation and functional experiments are necessary.
瘤样脱髓鞘病变（TD）是多发性硬化症（MS）的一种罕见变异型，其特征为肿瘤样病变，通常需要积极治疗。全基因组关联研究（GWAS）已确定与MS相关的变异；但缺乏对TD进行类似分析。
进行一项GWAS以确定与TD相关的变异。
病例对照研究纳入了142例TD病例和293例对照。TD患者需有脱髓鞘事件且磁共振成像（MRI）显示一个或多个病变。对照为无神经或全身性炎症性疾病或癌症的患者。采用逻辑回归比较每个变异的病例与对照；将年龄、性别和主成分作为协变量纳入。P值阈值为5×10⁻⁸为GWAS显著，5×10⁻⁵为名义上显著。比较了TD和对照之间的多基因风险评分（PRS）。
14号染色体上的变异（rs117797734，P = 2.06×10⁻⁸，比值比（OR）= 13.14）和6号染色体上靠近的变异（最显著的rs6936540，P = 5.5×10⁻⁷，OR = 2.61）具有显著性。七个与MS相关的非MHC和两个MHC变异与TD相关。TD的PRS显著高于对照。
我们确定了与TD相关的新区域，证明了在MS的同质亚型中进行GWAS的重要性。进一步的验证和功能实验是必要的。
