Djoussé L, Knowlton B, Hayden M, Almqvist E W, Brinkman R, Ross C, Margolis R, Rosenblatt A, Durr A, Dode C, Morrison P J, Novelletto A, Frontali M, Trent R J A, McCusker E, Gómez-Tortosa E, Mayo D, Jones R, Zanko A, Nance M, Abramson R, Suchowersky O, Paulsen J, Harrison M, Yang Q, Cupples L A, Gusella J F, MacDonald M E, Myers R H
Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Am J Med Genet A. 2003 Jun 15;119A(3):279-82. doi: 10.1002/ajmg.a.20190.
Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P = 0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.
亨廷顿舞蹈症（HD）是一种神经退行性疾病，由4号染色体p16.3区域HD基因中CAG重复序列的异常扩增引起。过去的研究表明，扩增的CAG重复序列大小与HD的发病年龄（AO）呈负相关。尚不清楚正常的亨廷顿等位基因大小是否会影响扩增重复序列与HD发病年龄之间的关系。从两个独立队列收集的数据用于检验以下假设：未扩增的CAG重复序列与扩增的CAG重复序列相互作用，影响HD的发病年龄。在新英格兰无墙亨廷顿舞蹈症中心（NEHD）队列中的221名HD患者以及HD-MAPS队列中的533名HD患者中，我们发现有证据支持扩增和未扩增的CAG重复序列大小之间存在相互作用，这种相互作用会影响HD的发病年龄（P值分别为0.08和0.07）。当两个队列合并时，这种关联具有统计学意义（P = 0.012）。在对正常和扩增重复序列及其相互作用进行调整后，发病年龄残差的估计遗传度为0.56。对重复序列大小三分位数的分析表明，在HD重复序列较大（47 - 83）的人群中可以看到正常等位基因的作用。这些发现表明，正常重复序列大小的增加可能会减轻CAG重复序列大量扩增的HD患者的疾病表现。
