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首页> 外文期刊>Brain: A journal of neurology >Genotype-Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures.
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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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摘要

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 (1)HMR spectroscopy (P = 0.025), (ii) an increase in the volume of white matter (WM) lesions utilizing conventional anatomical MRI techniques (1,127 mm(3); 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。在此，我们对505名健壮，临床特征明确的MS患者进行了基因型-表型关联性调查，结果显示DRB1 * 1501携带者状态与疾病严重程度的四个域之间存在明显关联：（i）N-乙酰基减少（1）HMR光谱法（P = 0.025）在正常出现的白质（NAWM）中的天冬氨酸（NAA）浓度，（ii）使用常规解剖MRI技术增加白质（WM）病变的体积（1,127 mm（ 3）; P = 0.031），（iii）标准化的脑实质体积（nBPV）的降低（P = 0.023），以及（iv）认知听觉障碍，如通过步速听觉串行加法测试（PASAT-3）进行的测量（平均值Z得分：DRB1 * 1501 +：0.110，而DRB1 * 1501-：0.048; P = 0.004）。此外，DRB1 * 1501 +患者的女性发病率明显更高（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。这些结构异常可能解释了DRB1 * 1501组之间观察到的认知表现的显着差异。深入了解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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