糖尿病與老年癡呆癥有何關系？

根據(jù)美國西奈山伊坎醫(yī)學院進行的一項研究表明，某些2型糖尿病(T2D)患者可能有特定的遺傳危險因子，使他們處于更高的阿爾茨海默氏病(AD)患病風險，相關研究結果發(fā)表在最近的《molecular Aspects of Medicine》(影響因子10.302)。

在西奈山伊坎醫(yī)學院神經(jīng)學教授Giulio Maria Pasinetti博士的帶領下，該研究小組使用最新的全基因組關聯(lián)研究(GWAS)，調(diào)查2型糖尿病和老年癡呆癥是否具有相同的遺傳病因，以及這些遺傳因素對可能引發(fā)這兩種疾病的細胞和分子機制，有何潛在影響。

GWAS研究是在全基因組層面上，開展多中心、大樣本、反復驗證的基因與疾病的關聯(lián)研究，是通過對大規(guī)模的群體DNA樣本進行全基因組高密度遺傳標記(如SNP)分型，從而尋找與復雜疾病相關的遺傳因素的研究方法，全面揭示疾病發(fā)生、發(fā)展與治療相關的遺傳基因。SNP是由于單個核苷酸改變而導致的核酸序列多態(tài)，即使是最小的SNP遺傳變異，也可能通過32億個“字母”(組成人類DNA密碼)中的一個交換，而產(chǎn)生重大影響。

2型糖尿病一個主要的長期并發(fā)癥是，患老年癡呆癥的風險增加。雖然以前的研究強烈建議，糖尿病在老年癡呆癥開始和進展中發(fā)揮著致病作用，但是連接糖尿病和老年癡呆癥的具體機理相互作用，一直沒有得以描述。

Pasinetti博士說：“我們發(fā)現(xiàn)了多個snp遺傳差異，它們與2型糖尿病和老年癡呆癥較高的遺傳易感性有關。這些SNPs中有許多可追溯到某些基因，這些基因的異常已知可引發(fā)糖尿病和老年癡呆癥，從而表明攜帶這些遺傳差異的某些糖尿病患者，患上老年癡呆癥的風險也較高。我們的數(shù)據(jù)強調(diào)，還需要進一步探索2型糖尿病患者對老年癡呆癥的遺傳易感性?！?/p>

在世界范圍內(nèi)，估計有3.12億人患有糖尿病，對個人和醫(yī)療保健系統(tǒng)增加了巨大的負擔。同樣地，老年癡呆癥影響著全球近4500萬人，這種疾病的個人和醫(yī)療保健系統(tǒng)都很昂貴。這兩種疾病目前還沒有治愈的方法。

越來越多的證據(jù)表明，老年癡呆癥可以追溯到一些病理條件，如糖尿病，在老年癡呆癥臨床發(fā)病前幾十年就已被發(fā)現(xiàn)。由于2型糖尿病是老年癡呆癥一個潛在可改變的危險因素，因此，揭開這一復雜關系的遺傳學機制，是極為重要的，這樣，我們就可以在老年癡呆癥發(fā)病之前，對高危個體采取新的治療干預措施。

本研究將支持正在進行的研究應用，進一步探索2型糖尿病患者發(fā)展為老年癡呆癥的遺傳易感性，并幫助改善具有老年癡呆癥遺傳易感性的T2D患者的新療法，這將使2型糖尿病患者受益，并減少后期老年癡呆癥的發(fā)展風險。這些研究確定了T2D和AD共有的細胞異常，這些結果可為2型糖尿病和老年癡呆癥帶來更好的療法，也可能有助于防止遺傳易感個體后期發(fā)展AD的可能性。

原文標題：Shared genetic etiology underlying Alzheimer's disease and type 2 diabetes

原文摘要：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.

作者：秩名