A functional 12T-insertion polymorphism in the ATP1A1 promoter confers decreased susceptibility to hypertension in a male Sardinian population.
A functional 12T-insertion polymorphism in the ATP1A1 promoter confers decreased susceptibility to hypertension in a male Sardinian population.
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DOI：
10.1371/journal.pone.0116724
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Ruiz-Opazo N
中科院分区：
文献类型：
--
作者：
Herrera VL;Pasion KA;Moran AM;Zaninello R;Ortu MF;Fresu G;Piras DA;Argiolas G;Troffa C;Glorioso V;Masala W;Glorioso N;Ruiz-Opazo N
由于原发性高血压的发病机制是多因素的，涉及基因-基因、基因-环境相互作用、发育程序和性别特异性差异等，因此其易感基因的鉴定一直是一个挑战。这些并发的功能使得难以用单一方法鉴定致病性高血压易感基因，因此需要涉及遗传、生化和生物学实验的多条证据线来建立致病性功能突变。在这里，我们报告的实验证据，包括遗传，生化和体内建模，完全支持ATP 1A 1作为高血压易感基因在撒丁岛，意大利的男性。ATP 1A 1编码α 1 Na，K-ATP酶亚型，是血管内皮细胞和肾小管上皮细胞中唯一的钠泵。DNA测序检测到一个12个核苷酸长的胸苷（12 T）插入（ins）/缺失（del）多态性内的多聚T序列（38 T与26 T）在ATP 1A 1 5 '-调节区与高血压在男性撒丁岛人口。12 T插入等位基因使高血压易感性降低（P = 0.035; OR = 0.50 [0.28-0.93]），收缩压降低12.1 mmHg（P = 0.02），舒张压降低6.6 mmHg（P = 0.046）。在体外转录活性测定系统中，与缺失12 T的ATP 1A 1启动子相比，插入12 T的ATP 1A 1启动子的转录活性降低，表明插入12 T的ATP 1A 1启动子的α 1 Na，K-ATPase表达降低。为了测试α 1 Na，K-ATP酶表达降低对血压的影响，我们通过无线电遥测技术测量了三个月大的高度近交杂合敲除ATP 1A 1 +/−雄性小鼠的血压，结果ATP 1A 1蛋白水平降低了58%。雄性ATP 1A 1 +/−小鼠的血压显著低于年龄匹配的雄性野生型同窝对照小鼠（P < 0.03）。一致地，预期较低的ATP 1A 1表达会降低肾脏中的钠重吸收，从而降低钠相关的高血压和钠诱导的内皮僵硬和功能障碍的风险。总之，数据支持ATP 1A 1作为高血压易感基因在男性撒丁岛人口，并授权进一步调查其参与高血压在一般人群。
Identification of susceptibility genes for essential hypertension in humans has been a challenge due to its multifactorial pathogenesis complicated by gene-gene and gene-environment interactions, developmental programing and sex specific differences. These concurrent features make identification of causal hypertension susceptibility genes with a single approach difficult, thus requiring multiple lines of evidence involving genetic, biochemical and biological experimentation to establish causal functional mutations. Here we report experimental evidence encompassing genetic, biochemical and in vivo modeling that altogether support ATP1A1 as a hypertension susceptibility gene in males in Sardinia, Italy. ATP1A1 encodes the α1Na,K-ATPase isoform, the sole sodium pump in vascular endothelial and renal tubular epithelial cells. DNA-sequencing detected a 12-nucleotide long thymidine (12T) insertion(ins)/deletion(del) polymorphism within a poly-T sequence (38T vs 26T) in the ATP1A1 5’-regulatory region associated with hypertension in a male Sardinian population. The 12T-insertion allele confers decreased susceptibility to hypertension (P = 0.035; OR = 0.50 [0.28–0.93]) accounting for 12.1 mmHg decrease in systolic BP (P = 0.02) and 6.6 mmHg in diastolic BP (P = 0.046). The ATP1A1 promoter containing the 12T-insertion exhibited decreased transcriptional activity in in vitro reporter-assay systems, indicating decreased α1Na,K-ATPase expression with the 12T-insertion, compared with the 12T-deletion ATP1A1 promoter. To test the effects of decreased α1Na,K-ATPase expression on blood pressure, we measured blood pressure by radiotelemetry in three month-old, highly inbred heterozygous knockout ATP1A1+/− male mice with resultant 58% reduction in ATP1A1 protein levels. Male ATP1A1+/− mice showed significantly lower blood pressure (P < 0.03) than age-matched male wild-type littermate controls. Concordantly, lower ATP1A1 expression is expected to lower Na-reabsorption in the kidney thereby decreasing sodium-associated risk for hypertension and sodium-induced endothelial stiffness and dysfunction. Altogether, data support ATP1A1 as a hypertension susceptibility gene in a male Sardinian population, and mandate further investigation of its involvement in hypertension in the general population.
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NFKB1基因中的功能启动子-94 INS/DEL ATTG多态性与中国人群中的膀胱癌风险有关。
影响因子：
3.7
作者：
Li P;Gu J;Yang X;Cai H;Tao J;Yang X;Lu Q;Wang Z;Yin C;Gu M
通讯作者：
Gu M
影响因子：
64.8
作者：
Ehret, Georg B.;Munroe, Patricia B.;Rice, Kenneth M.;Bochud, Murielle;Johnson, Andrew D.;Chasman, Daniel I.;Smith, Albert V.;Tobin, Martin D.;Verwoert, Germaine C.;Hwang, Shih-Jen;Pihur, Vasyl;Vollenweider, Peter;O'Reilly, Paul F.;Amin, Najaf;Bragg-Gresham, Jennifer L.;Teumer, Alexander;Glazer, Nicole L.;Launer, Lenore;Zhao, Jing Hua;Aulchenko, Yurii;Heath, Simon;Sober, Siim;Parsa, Afshin;Luan, Jian'an;Arora, Pankaj;Dehghan, Abbas;Zhang, Feng;Lucas, Gavin;Hicks, Andrew A.;Jackson, Anne U.;Peden, John F.;Tanaka, Toshiko;Wild, Sarah H.;Rudan, Igor;Igl, Wilmar;Milaneschi, Yuri;Parker, Alex N.;Fava, Cristiano;Chambers, John C.;Fox, Ervin R.;Kumari, Meena;Go, Min Jin;van der Harst, Pim;Kao, Wen Hong Linda;Sjogren, Marketa;Vinay, D. G.;Alexander, Myriam;Tabara, Yasuharu;Shaw-Hawkins, Sue;Whincup, Peter H.;Liu, Yongmei;Shi, Gang;Kuusisto, Johanna;Tayo, Bamidele;Seielstad, Mark;Sim, Xueling;Khanh-Dung Hoang Nguyen;Lehtimaki, Terho;Matullo, Giuseppe;Wu, Ying;Gaunt, Tom R.;Onland-Moret, N. Charlotte;Cooper, Matthew N.;Platou, Carl G. P.;Org, Elin;Hardy, Rebecca;Dahgam, Santosh;Palmen, Jutta;Vitart, Veronique;Braund, Peter S.;Kuznetsova, Tatiana;Uiterwaal, Cuno S. P. M.;Adeyemo, Adebowale;Palmas, Walter;Campbell, Harry;Ludwig, Barbara;Tomaszewski, Maciej;Tzoulaki, Ioanna;Palmer, Nicholette D.;Aspelund, Thor;Garcia, Melissa;Chang, Yen-Pei C.;O'Connell, Jeffrey R.;Steinle, Nanette I.;Grobbee, Diederick E.;Arking, Dan E.;Kardia, Sharon L.;Morrison, Alanna C.;Hernandez, Dena;Najjar, Samer;McArdle, Wendy L.;Hadley, David;Brown, Morris J.;Connell, John M.;Hingorani, Aroon D.;Day, Ian N. M.;Lawlor, Debbie A.;Beilby, John P.;Lawrence, Robert W.;Clarke, Robert;Hopewell, Jemma C.;Ongen, Halit;Dreisbach, Albert W.;Li, Yali;Young, J. Hunter;Bis, Joshua C.;Kahonen, Mika;Viikari, Jorma;Adair, Linda S.;Lee, Nanette R.;Chen, Ming-Huei;Olden, Matthias;Pattaro, Cristian;Bolton, Judith A. Hoffman;Koettgen, Anna;Bergmann, Sven;Mooser, Vincent;Chaturvedi, Nish;Frayling, Timothy M.;Islam, Muhammad;Jafar, Tazeen H.;Erdmann, Jeanette;Kulkarni, Smita R.;Bornstein, Stefan R.;Graessler, Juergen;Groop, Leif;Voight, Benjamin F.;Kettunen, Johannes;Howard, Philip;Taylor, Andrew;Guarrera, Simonetta;Ricceri, Fulvio;Emilsson, Valur;Plump, Andrew;Barroso, Ine S.;Khaw, Kay-Tee;Weder, Alan B.;Hunt, Steven C.;Sun, Yan V.;Bergman, Richard N.;Collins, Francis S.;Bonnycastle, Lori L.;Scott, Laura J.;Stringham, Heather M.;Peltonen, Leena;Perola, Markus;Vartiainen, Erkki;Brand, Stefan-Martin;Staessen, Jan A.;Wang, Thomas J.;Burton, Paul R.;Artigas, Maria Soler;Dong, Yanbin;Snieder, Harold;Wang, Xiaoling;Zhu, Haidong;Lohman, Kurt K.;Rudock, Megan E.;Heckbert, Susan R.;Smith, Nicholas L.;Wiggins, Kerri L.;Doumatey, Ayo;Shriner, Daniel;Veldre, Gudrun;Viigimaa, Margus;Kinra, Sanjay;Prabhakaran, Dorairaj;Tripathy, Vikal;Langefeld, Carl D.;Rosengren, Annika;Thelle, Dag S.;Corsi, Anna Maria;Singleton, Andrew;Forrester, Terrence;Hilton, Gina;McKenzie, Colin A.;Salako, Tunde;Iwai, Naoharu;Kita, Yoshikuni;Ogihara, Toshio;Ohkubo, Takayoshi;Okamura, Tomonori;Ueshima, Hirotsugu;Umemura, Satoshi;Eyheramendy, Susana;Meitinger, Thomas;Wichmann, H. -Erich;Cho, Yoon Shin;Kim, Hyung-Lae;Lee, Jong-Young;Scott, James;Sehmi, Joban S.;Zhang, Weihua;Hedblad, Bo;Nilsson, Peter;Smith, George Davey;Wong, Andrew;Narisu, Narisu;Stancakova, Alena;Raffel, Leslie J.;Yao, Jie;Kathiresan, Sekar;O'Donnell, Christopher J.;Schwartz, Stephen M.;Ikram, M. Arfan;Longstreth, W. T., Jr.;Mosley, Thomas H.;Seshadri, Sudha;Shrine, Nick R. G.;Wain, Louise V.;Morken, Mario A.;Swift, Amy J.;Laitinen, Jaana;Prokopenko, Inga;Zitting, Paavo;Cooper, Jackie A.;Humphries, Steve E.;Danesh, John;Rasheed, Asif;Goel, Anuj;Hamsten, Anders;Watkins, Hugh;Bakker, Stephan J. L.;van Gilst, Wiek H.;Janipalli, Charles S.;Mani, K. Radha;Yajnik, Chittaranjan S.;Hofman, Albert;Mattace-Raso, Francesco U. S.;Oostra, Ben A.;Demirkan, Ayse;Isaacs, Aaron;Rivadeneira, Fernando;Lakatta, Edward G.;Orru, Marco;Scuteri, Angelo;Ala-Korpela, Mika;Kangas, Antti J.;Lyytikainen, Leo-Pekka;Soininen, Pasi;Tukiainen, Taru;Wurtz, Peter;Ong, Rick Twee-Hee;Doerr, Marcus;Kroemer, Heyo K.;Voelker, Uwe;Voelzke, Henry;Galan, Pilar;Hercberg, Serge;Lathrop, Mark;Zelenika, Diana;Deloukas, Panos;Mangino, Massimo;Spector, Tim D.;Zhai, Guangju;Meschia, James F.;Nalls, Michael A.;Sharma, Pankaj;Terzic, Janos;Kumar, M. V. 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通讯作者：
Johnson, Toby
影响因子：
4.6
作者：
Herrera, Victoria L. M.;Tsikoudakis, Aristides;Ruiz-Opazo, Nelson
通讯作者：
Ruiz-Opazo, Nelson
影响因子：
15.9
作者：
Herrera, VLM;Xie, HX;Ruiz-Opazo, N
通讯作者：
Ruiz-Opazo, N
影响因子：
16
作者：
James, PF;Grupp, IL;Lingrel, JB
通讯作者：
Lingrel, JB