Genetic signature of human longevity in PKC and NF-κB signaling.
Genetic signature of human longevity in PKC and NF-κB signaling.
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作者：
Ryu S;Han J;Norden-Krichmar TM;Zhang Q;Lee S;Zhang Z;Atzmon G;Niedernhofer LJ;Robbins PD;Barzilai N;Schork NJ;Suh Y
与长寿相关的基因变异也与预防认知能力下降、痴呆和阿尔茨海默病有关，这表明常见的生理途径作用于长寿和认知功能的界面。为了检验与认知功能相关的基因变异可能促进超长寿命的假设，我们进行了一项全面的三阶段研究，通过目标捕获测序分析，在多达 450 名百岁老人和 500 名对照者的约 700 个候选基因中鉴定了与功能性长寿相关的变异。通过基于基因的关联分析，我们发现 nPKC 和 NF-κB 信号通路中长寿相关基因的富集。对前三个基因变体（NFKBIA、CLU、PRKCH）的功能分析表明，非编码变体调节同源基因的表达，从而减少通过 nPKC 和 NF-κB 的信号传导。这与多种模型生物体中的遗传研究相匹配，表明在超长寿命中，PKC 和 NF-κB 信号通路减少的进化保守性可能包括人类。为了验证与认知功能相关的基因变异可能促进超长寿命的假设，我们进行了一项三阶段研究，通过目标捕获测序分析，在多达 450 名百岁老人和 500 名对照者的约 700 个候选基因中鉴定了与功能性长寿相关的变异。通过基于基因的关联分析，我们发现 nPKC 和 NF-kB 信号通路中长寿相关基因的富集。对前三个基因变异（NFKBIA、CLU、PRKCH）的功能分析表明，非编码变异减少了通过 nPKC 和 NF-kB 的信号传导。
Gene variants associated with longevity are also associated with protection against cognitive decline, dementia and Alzheimer's disease, suggesting that common physiologic pathways act at the interface of longevity and cognitive function. To test the hypothesis that variants in genes implicated in cognitive function may promote exceptional longevity, we performed a comprehensive 3‐stage study to identify functional longevity‐associated variants in ~700 candidate genes in up to 450 centenarians and 500 controls by target capture sequencing analysis. We found an enrichment of longevity‐associated genes in the nPKC and NF‐κB signaling pathways by gene‐based association analyses. Functional analysis of the top three gene variants (NFKBIA, CLU, PRKCH) suggests that non‐coding variants modulate the expression of cognate genes, thereby reducing signaling through the nPKC and NF‐κB. This matches genetic studies in multiple model organisms, suggesting that the evolutionary conservation of reduced PKC and NF‐κB signaling pathways in exceptional longevity may include humans. To test the hypothesis that variants in genes implicated in cognitive function may promote exceptional longevity, we performed a 3‐stage study to identify functional longevity‐associated variants in ~700 candidate genes in up to 450 centenarians and 500 controls by target capture sequencing analysis. We found an enrichment of longevity‐associated genes in the nPKC and NF‐kB signaling pathways by gene‐based association analyses. Functional analysis of the top three gene variants (NFKBIA, CLU, PRKCH) suggests that non‐coding variants reduce signaling through the nPKC and NF‐kB.
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影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
15.9
作者：
Mclaughlin, L;Zhu, G;Aronow, BJ
通讯作者：
Aronow, BJ
DOI：
10.1093/gerona/glr223
发表时间：
2012-04-01
影响因子：
5.1
作者：
Andersen, Stacy L.;Sebastiani, Paola;Perls, Thomas T.
通讯作者：
Perls, Thomas T.
影响因子：
64.5
作者：
Kawahara TL;Michishita E;Adler AS;Damian M;Berber E;Lin M;McCord RA;Ongaigui KC;Boxer LD;Chang HY;Chua KF
通讯作者：
Chua KF