摘要 : 根據(jù)美國(guó)西奈山伊坎醫(yī)學(xué)院進(jìn)行的一項(xiàng)研究表明，某些2型糖尿病（T2D）患者可能有特定的遺傳危險(xiǎn)因子，使他們處于更高的阿爾茨海默氏病（AD）患病風(fēng)險(xiǎn)，相關(guān)研究結(jié)果發(fā)表在最近的《Molecular Aspects of Medicine》（影響因子10.302）。
根據(jù)美國(guó)西奈山伊坎醫(yī)學(xué)院進(jìn)行的一項(xiàng)研究表明，某些2型糖尿病(T2D)患者可能有特定的遺傳危險(xiǎn)因子，使他們處于更高的阿爾茨海默氏病(AD)患病風(fēng)險(xiǎn)，相關(guān)研究結(jié)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(xué)院神經(jīng)學(xué)教授Giulio Maria Pasinetti博士的帶領(lǐng)下，該研究小組使用最新的全基因組關(guān)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(duì)可能引發(fā)這兩種疾病的細(xì)胞和分子機(jī)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(fù)驗(yàn)證的基因與疾病的關(guān)聯(lián)研究，是通過對(duì)大規(guī)模的群體DNA樣本進(jìn)行全基因組高密度遺傳標(biāo)記(如SNP)分型，從而尋找與復(fù)雜疾病相關(guān)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(guān)的遺傳基因。SNP是由于單個(gè)核苷酸改變而導(dǎo)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(gè)“字母”(組成人類DNA密碼)中的一個(gè)交換，而產(chǎn)生重大影響。
2型糖尿病一個(gè)主要的長(zhǎng)期并發(fā)癥是，患老年癡呆癥的風(fēng)險(xiǎn)增加。雖然以前的研究強(qiáng)烈建議，糖尿病在老年癡呆癥開始和進(jìn)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(jī)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(gè)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(guān)。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(fēng)險(xiǎn)也較高。我們的數(shù)據(jù)強(qiáng)調(diào)，還需要進(jìn)一步探索2型糖尿病患者對(duì)老年癡呆癥的遺傳易感性。”
在世界范圍內(nèi)，估計(jì)有3.12億人患有糖尿病，對(duì)個(gè)人和醫(yī)療保健系統(tǒng)增加了巨大的負(fù)擔(dān)。同樣地，老年癡呆癥影響著全球近4500萬人，這種疾病的個(gè)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?xiàng)l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(gè)潛在可改變的危險(xiǎn)因素，因此，揭開這一復(fù)雜關(guān)系的遺傳學(xué)機(jī)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(duì)高危個(gè)體采取新的治療干預(yù)措施。
本研究將支持正在進(jìn)行的研究應(yīng)用，進(jìn)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(fēng)險(xiǎn)。這些研究確定了T2D和AD共有的細(xì)胞異常，這些結(jié)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(gè)體后期發(fā)展AD的可能性。
原文標(biāo)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
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