Akkad Denis A, Bellenberg Barbara, Esser Sarika, Weiler Florian, Epplen Jörg T, Gold Ralf, Lukas Carsten, Haghikia Aiden
Department of Human Genetics, Ruhr-University Bochum, Universitaetstr 150, 44801, Bochum, Germany,
Neurogenetics. 2015 Jul;16(3):161-8. doi: 10.1007/s10048-015-0438-0. Epub 2015 Jan 27.
Genome-wide association studies (GWAS) underscore the genetic basis of multiple sclerosis (MS); however, only few of the newly reported genetic variations relevant in MS have been replicated or correlated for clinical/paraclinical phenotypes such as spinal cord atrophy in independent patient cohorts. We genotyped 141 MS patients for 58 variations reported to reach significance in GWAS. Expanded disability status scale (EDSS) and disease duration (DD) are available from regular clinical examinations. MRI included sagittal high-resolution 3D T1-weighted magnetization-prepared rapid acquisition gradient echo of the cervical cord region used for volumetry. Due dependency of mean upper cervical cord area (MUCCA) with EDSS and/or DD, correction operations were performed compensating for EDSS/DD. We assessed each MS risk locus for possible MUCCA association. We identified twelve risk loci that significantly correlated with MUCCA. For nine loci-BATF, CYP27B1, IL12B, NFKB1, IL7, PLEK, EVI5, TAGAP and nrs669607-patients revealed significantly higher degree of atrophy; TYK2, RGS1 and CLEC16A revealed inverse effects. The weighted genetic risk score over the twelve loci showed significant correlation with MUCCA. Our data reveal a risk gene depending paraclinical/clinical phenotype. Since MUCCA clearly correlates with disability, the candidates identified here may serve as prognostic markers for disability progression.
全基因组关联研究（GWAS）强调了多发性硬化症（MS）的遗传基础；然而，在独立患者队列中，新报道的与MS相关的遗传变异中，只有少数已被复制或与临床/副临床表型（如脊髓萎缩）相关。我们对141例MS患者进行了基因分型，检测了58个在GWAS中达到显著水平的变异。扩展残疾状态量表（EDSS）和疾病持续时间（DD）可从常规临床检查中获得。MRI包括用于体积测量的颈椎区域矢状面高分辨率3D T1加权磁化准备快速采集梯度回波。由于平均上颈髓面积（MUCCA）与EDSS和/或DD存在依赖性，因此进行了校正操作以补偿EDSS/DD。我们评估了每个MS风险位点与MUCCA的可能关联。我们确定了12个与MUCCA显著相关的风险位点。对于9个位点——BATF、CYP27B1、IL12B、NFKB1、IL7、PLEK、EVI5、TAGAP和nrs669607——患者显示出显著更高程度的萎缩；TYK2、RGS1和CLEC16A显示出相反的影响。12个位点的加权遗传风险评分与MUCCA显著相关。我们的数据揭示了一种依赖风险基因的副临床/临床表型。由于MUCCA与残疾明显相关，此处鉴定出的候选基因可能作为残疾进展的预后标志物。
