糖尿病与老年痴呆症有何关系？

　　

生物通报道：根据美国西奈山伊坎医学院进行的一项研究表明，某些2型糖尿病（T2D）患者可能有特定的遗传危险因子，使他们处于更高的阿尔茨海默氏病（AD）患病风险，相关研究结果发表在最近的《Molecular Aspects of Medicine》（影响因子10.302）。延伸阅读：Diabetologia：血型与糖尿病风险有何关系？。

在西奈山伊坎医学院神经学教授Giulio Maria Pasinetti博士的带领下，该研究小组使用最新的全基因组关联研究（GWAS），调查2型糖尿病和老年痴呆症是否具有相同的遗传病因，以及这些遗传因素对可能引发这两种疾病的细胞和分子机制，有何潜在影响。

GWAS研究是在全基因组层面上，开展多中心、大样本、反复验证的基因与疾病的关联研究，是通过对大规模的群体DNA样本进行全基因组高密度遗传标记（如SNP）分型，从而寻找与复杂疾病相关的遗传因素的研究方法，全面揭示疾病发生、发展与治疗相关的遗传基因。SNP是由于单个核苷酸改变而导致的核酸序列多态，即使是最小的SNP遗传变异，也可能通过32亿个“字母”（组成人类DNA密码）中的一个交换，而产生重大影响。

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2型糖尿病一个主要的长期并发症是，患老年痴呆症的风险增加。虽然以前的研究强烈建议，糖尿病在老年痴呆症开始和进展中发挥着致病作用，但是连接糖尿病和老年痴呆症的具体机理相互作用，一直没有得以描述。

Pasinetti博士说：“我们发现了多个SNP遗传差异，它们与2型糖尿病和老年痴呆症较高的遗传易感性有关。这些SNPs中有许多可追溯到某些基因，这些基因的异常已知可引发糖尿病和老年痴呆症，从而表明携带这些遗传差异的某些糖尿病患者，患上老年痴呆症的风险也较高。我们的数据强调，还需要进一步探索2型糖尿病患者对老年痴呆症的遗传易感性。”

在世界范围内，估计有3.12亿人患有糖尿病，对个人和医疗保健系统增加了巨大的负担。同样地，老年痴呆症影响着全球近4500万人，这种疾病的个人和医疗保健系统都很昂贵。这两种疾病目前还没有治愈的方法。

越来越多的证据表明，老年痴呆症可以追溯到一些病理条件，如糖尿病，在老年痴呆症临床发病前几十年就已被发现。由于2型糖尿病是老年痴呆症一个潜在可改变的危险因素，因此，揭开这一复杂关系的遗传学机制，是极为重要的，这样，我们就可以在老年痴呆症发病之前，对高危个体采取新的治疗干预措施。

本研究将支持正在进行的研究应用，进一步探索2型糖尿病患者发展为老年痴呆症的遗传易感性，并帮助改善具有老年痴呆症遗传易感性的T2D患者的新疗法，这将使2型糖尿病患者受益，并减少后期老年痴呆症的发展风险。这些研究确定了T2D和AD共有的细胞异常，这些结果可为2型糖尿病和老年痴呆症带来更好的疗法，也可能有助于防止遗传易感个体后期发展AD的可能性。

（生物通：王英）

生物通推荐原文摘要：
Shared genetic etiology underlying Alzheimer's disease and type 2 diabetes
Abstract: Epidemiological evidence supports the observation that subjects with type 2 diabetes (T2D) are at higher risk to develop Alzheimer's disease (AD). However, whether and how these two conditions are causally linked is unknown. Possible mechanisms include shared genetic risk factors, which were investigated in this study based on recent genome wide association study (GWAS) findings. In order to achieve our goal, we retrieved single nucleotide polymorphisms (SNPs) associated with T2D and AD from large-scale GWAS meta-analysis consortia and tested for overlap among the T2D- and AD-associated SNPs at various p-value thresholds. We then explored the function of the shared T2D/AD GWAS SNPs by leveraging expressional quantitative trait loci, pathways, gene ontology data, and co-expression networks. We found 927 SNPs associated with both AD and T2D with p-value ≤0.01, an overlap significantly larger than random chance (overlapping p-value of 6.93E−28). Among these, 395 of the shared GWAS SNPs have the same risk allele for AD and T2D, suggesting common pathogenic mechanisms underlying the development of both AD and T2D. Genes influenced by shared T2D/AD SNPs with the same risk allele were first identified using a SNP annotation variation (ANNOVAR) software, followed by using Association Protein-Protein Link Evaluator (DAPPLE) software to identify additional proteins that are known to physically interact with the ANNOVAR gene annotations. We found that gene annotations from ANNOVAR and DAPPLE significantly enriched specific KEGG pathways pertaining to immune responses, cell signaling and neuronal plasticity, cellular processes in which abnormalities are known to contribute to both T2D and AD pathogenesis. Thus, our observation suggests that among T2D subjects with common genetic predispositions (e.g., SNPs with consistent risk alleles for T2D and AD), dysregulation of these pathogenic pathways could contribute to the elevated risks for AD in subjects. Interestingly, we found that 532 of the shared T2D/AD GWAS SNPs had divergent risk alleles in the two diseases. For individual shared T2D/AD SNPs with divergent alleles, one of the allelic forms may contribute to one of the diseases (e.g., T2D), but not necessarily to the other (e.g., AD), or vice versa. Collectively, our GWAS studies tentatively support the epidemiological observation of disease concordance between T2D and AD. Moreover, the studies provide the much needed information for the design of future novel therapeutic approaches, for a subpopulation of T2D subjects with genetic disposition to AD, that could benefit T2D and reduce the risk for subsequent development of AD.