Singleton A B, Gibson A M, McKeith I G, Ballard C A, Perry R H, Ince P G, Edwardson J A, Morris C M
MRC Neurochemical Pathology Unit, Institute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, UK.
Neuroreport. 1999 May 14;10(7):1507-10. doi: 10.1097/00001756-199905140-00021.
Dementia with Lewy bodies (DLB) is the second most common cause of dementia in the elderly after Alzheimer's disease (AD). The apolipoprotein E gene (APOE) is a major risk factor, but can only account for approximately 50% of AD cases. Whole genome scanning in late-onset AD families has suggested that a locus on chromosome 12 may contribute significantly to disease development. Recently the alpha2-macroglobulin gene (A2M) on chromosome 12 has been suggested as a candidate locus for AD. We therefore determined the influence of two polymorphisms in A2M, a pentanucleotide deletion 5' to the bait domain exon, and a valine to isoleucine polymorphism in the thiolester site of the protein, in AD and DLB cohorts. No evidence was observed for an association between the thiolester or deletion polymorphisms and AD or DLB alone or when accounting for the APOE epsilon4 allele. We did, however, identify a non-significant excess of deletion homozygotes in the AD and DLB groups. This genotype accounted for 4% of disease cases but was absent in the control population. Given that the A2M deletion polymorphism is non-functional, the chromosome 12 AD/DLB locus may be situated elsewhere and not with these A2M polymorphisms.
路易体痴呆（DLB）是仅次于阿尔茨海默病（AD）的老年人痴呆的第二大常见病因。载脂蛋白E基因（APOE）是一个主要风险因素，但仅能解释约50%的AD病例。对晚发性AD家系进行的全基因组扫描表明，12号染色体上的一个位点可能对疾病发展有显著影响。最近，12号染色体上的α2-巨球蛋白基因（A2M）被认为是AD的一个候选位点。因此，我们在AD和DLB队列中确定了A2M中的两种多态性的影响，一种是诱饵结构域外显子5'端的五核苷酸缺失，另一种是蛋白质硫酯位点上缬氨酸到异亮氨酸的多态性。未观察到硫酯或缺失多态性与AD或DLB单独之间或在考虑APOE ε4等位基因时的关联。然而，我们确实在AD和DLB组中发现了缺失纯合子的非显著过量。这种基因型占疾病病例的4%，但在对照人群中不存在。鉴于A2M缺失多态性无功能，12号染色体AD/DLB位点可能位于其他地方，而非这些A2M多态性所在位置。
