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Genotype-Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures

机译：多发性硬化症中的基因型与表型相关性：HLA基因影响1HMR光谱法和MRI手段推断出的疾病严重程度

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Genetic susceptibility to multiple sclerosis (MS) is associated with the human leukocyte antigen (HLA) DRB1*1501 allele. Here we show a clear association between DRB1*1501 carrier status and four domains of disease severity in an investigation of genotype-phenotype associations in 505 robust, clinically well characterized MS patients evaluated cross-sectionally: (i) a reduction in the N-acetyl-aspartate (NAA) concentration within normal appearing white matter (NAWM) via 1HMR spectroscopy (P = 0.025), (ii) an increase in the volume of white matter (WM) lesions utilizing conventional anatomical MRI techniques (1,127 mm3; P = 0.031), (iii) a reduction in normalized brain parenchymal volume (nBPV) (P = 0.023), and (iv) impairments in cognitive function as measured by the Paced Auditory Serial Addition Test (PASAT-3) performance (Mean Z Score: DRB1*1501+: 0.110 versus DRB1*1501-: 0.048; P = 0.004). In addition, DRB1*1501+ patients had significantly more women (74% versus 63%; P = 0.009) and a younger mean age at disease onset (32.4 years versus 34.3 years; P = 0.025). Our findings suggest that DRB1*1501 increases disease severity in MS by facilitating the development of more T2-foci, thereby increasing the potential for irreversible axonal compromise and subsequent neuronal degeneration, as suggested by the reduction of NAA concentrations in NAWM, ultimately leading to a decline in brain volume. These structural aberrations may explain the significant differences in cognitive performance observed between DRB1*1501 groups. The overall goal of a deep phenotypic approach to MS is to develop an array of meaningful biomarkers to monitor the course of the disease, predict future disease behaviour, determine when treatment is necessary, and perhaps to more effectively recommend an available therapeutic intervention
机译：多发性硬化症（MS）的遗传易感性与人类白细胞抗原（HLA）DRB1 * 1501等位基因相关。在这里，我们在505名健壮，临床特征良好的MS患者的基因型-表型关联性调查中显示了DRB1 * 1501携带者状态与疾病严重性的四个域之间的明确关联：（i）N-乙酰基的降低1HMR光谱法测定正常出现的白质（NAWM）中的天冬氨酸（NAA）浓度（P = 0.025），（ii）使用常规解剖MRI技术增加白质（WM）病变的体积（1,127 mm3; P = 0.031 ），（iii）正常脑实质体积（nBPV）降低（P = 0.023），以及（iv）通过步速听觉串行加法测试（PASAT-3）表现测得的认知功能受损（平均值Z评分：DRB1 * 1501 +：0.110，而DRB1 * 1501-：0.048； P = 0.004）。此外，DRB1 * 1501 +患者的女性发病率显着增加（74％比63％； P = 0.009），平均发病年龄更年轻（32.4岁vs 34.3岁； P = 0.025）。我们的发现表明，DRB1 * 1501通过促进更多T2病灶的发展而增加了MS的疾病严重程度，从而增加了不可逆的轴突损害和随后神经元变性的可能性，这是由于NAWM中NAA浓度的降低所暗示的，最终导致脑容量下降。这些结构畸变可以解释DRB1 * 1501组之间观察到的认知表现的显着差异。深入研究MS的表型方法的总体目标是开发一系列有意义的生物标记物，以监测疾病的进程，预测未来的疾病行为，确定何时需要治疗以及也许更有效地推荐可用的治疗干预措施

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