Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
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DOI：
10.1038/ng.2915
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发表时间：
2014-04
期刊：
影响因子：
30.8
通讯作者：
Altshuler, David
中科院分区：
文献类型：
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作者：
Flannick, Jason;Thorleifsson, Gudmar;Beer, Nicola L.;Jacobs, Suzanne B. R.;Grarup, Niels;Burtt, Noel P.;Mahajan, Anubha;Fuchsberger, Christian;Atzmon, Gil;Benediktsson, Rafn;Blangero, John;Bowden, Don W.;Brandslund, Ivan;Brosnan, Julia;Burslem, Frank;Chambers, John;Cho, Yoon Shin;Christensen, Cramer;Douglas, Desiree A.;Duggirala, Ravindranath;Dymek, Zachary;Farjoun, Yossi;Fennell, Timothy;Fontanillas, Pierre;Forsen, Tom;Gabriel, Stacey;Glaser, Benjamin;Gudbjartsson, Daniel F.;Hanis, Craig;Hansen, Torben;Hreidarsson, Astradur B.;Hveem, Kristian;Ingelsson, Erik;Isomaa, Bo;Johansson, Stefan;Jorgensen, Torben;Jorgensen, Marit Eika;Kathiresan, Sekar;Kong, Augustine;Kooner, Jaspal;Kravic, Jasmina;Laakso, Markku;Lee, Jong-Young;Lind, Lars;Lindgren, Cecilia M.;Linneberg, Allan;Masson, Gisli;Meitinger, Thomas;Mohlke, Karen L.;Molven, Anders;Morris, Andrew P.;Potluri, Shobha;Rauramaa, Rainer;Ribel-Madsen, Rasmus;Richard, Ann-Marie;Rolph, Tim;Salomaa, Veikko;Segre, Ayellet V.;Skaerstrand, Hanna;Steinthorsdottir, Valgerdur;Stringham, Heather M.;Sulem, Patrick;Tai, E. Shyong;Teo, Yik Ying;Teslovich, Tanya;Thorsteinsdottir, Unnur;Trimmer, Jeff K.;Tuomi, Tiinamaija;Tuomilehto, Jaakko;Vaziri-Sani, Fariba;Voight, Benjamin F.;Wilson, James G.;Boehnke, Michael;McCarthy, Mark I.;Njolstad, Pal R.;Pedersen, Oluf;Groop, Leif;Cox, David R.;Stefansson, Kari;Altshuler, David
对人类疾病具有保护作用的功能缺失突变可为治疗靶点提供体内验证，但对于2型糖尿病（T2D）尚未有相关描述。通过对五个种族约150,000人进行测序或基因分型，我们在SLC30A8中鉴定出12种罕见的蛋白质截断变异体，该基因编码一种胰岛锌转运蛋白（ZnT8），并且包含一个与T2D风险、血糖和胰岛素原水平相关的常见变异体（p.Trp325Arg）。总体而言，蛋白质截断变异体携带者的T2D风险降低了65%（p = 1.7×10⁻⁶），冰岛的移码变异体（p.Lys34SerfsX50）非糖尿病携带者表现出血糖水平降低（−0.17标准差，p = 4.6×10⁻⁴）。两种最常见的蛋白质截断变异体（p.Arg138X和p.Lys34SerfsX50）各自与T2D保护相关，并编码不稳定的ZnT8蛋白。先前对SLC30A8的功能研究表明，锌转运减少会增加T2D风险，但在啮齿动物Slc30a8基因敲除中观察到表型异质性。相反，人类的功能缺失突变提供了强有力的证据，表明SLC30A8单倍体不足可预防T2D，这提示抑制ZnT8可作为T2D预防的一种治疗策略。
Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, yet none are described for type 2 diabetes (T2D). Through sequencing or genotyping ~150,000 individuals across five ethnicities, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk, glucose, and proinsulin levels. Collectively, protein-truncating variant carriers had 65% reduced T2D risk (p=1.7×10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34SerfsX50) demonstrated reduced glucose levels (−0.17 s.d., p=4.6×10−4). The two most common protein-truncating variants (p.Arg138X and p.Lys34SerfsX50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested reduced zinc transport increases T2D risk, yet phenotypic heterogeneity was observed in rodent Slc30a8 knockouts. Contrastingly, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, proposing ZnT8 inhibition as a therapeutic strategy in T2D prevention.
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影响因子：
3.7
作者：
Pound LD;Sarkar SA;Ustione A;Dadi PK;Shadoan MK;Lee CE;Walters JA;Shiota M;McGuinness OP;Jacobson DA;Piston DW;Hutton JC;Powell DR;O'Brien RM
通讯作者：
O'Brien RM
DOI：
10.1042/bj20090530
发表时间：
2009-07-15
期刊：
The Biochemical journal
影响因子：
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作者：
Pound LD;Sarkar SA;Benninger RK;Wang Y;Suwanichkul A;Shadoan MK;Printz RL;Oeser JK;Lee CE;Piston DW;McGuinness OP;Hutton JC;Powell DR;O'Brien RM
通讯作者：
O'Brien RM
影响因子：
7.7
作者：
Strawbridge, Rona J.;Dupuis, Josee;Florez, Jose C.
通讯作者：
Florez, Jose C.
影响因子：
30.8
作者：
Jonathan, C;Pertsemlidis, A;Hobbs, HH
通讯作者：
Hobbs, HH
新的遗传基因座涉及禁食葡萄糖稳态及其对2型糖尿病风险的影响。
影响因子：
30.8
作者：
通讯作者：
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