Nat Genet:SLC30A8基因突变或有助防止2型糖尿病

2014-07-28 伊文 生物谷

美国哈佛医学院遗传学David Altshuler 教授最近发现一个有助防止2型糖尿病的基因突变(也即该基因突变的话,有助防止糖尿病),这为治疗糖尿病带来了新的希望。同时研究也揭示了如何使用遗传学工具,来猎取那些能起到防止疾病作用的“被破坏基因”(被关闭基因)。 研究者筛选一类人的基因组(此类人理论应该患糖尿病,但实际上没有患此疾病),通过将、将该基因组结果与其他人群比较

美国哈佛医学院遗传学David Altshuler 教授最近发现一个有助防止2型糖尿病的基因突变(也即该基因突变的话,有助防止糖尿病),这为治疗糖尿病带来了新的希望。同时研究也揭示了如何使用遗传学工具,来猎取那些能起到防止疾病作用的“被破坏基因”(被关闭基因)。

研究者筛选一类人的基因组(此类人理论应该患糖尿病,但实际上没有患此疾病),通过将、将该基因组结果与其他人群比较,挑出能提供保护作用(免于患糖尿病)的遗传差异,寻找到那些意外地被关闭的基因。




参与疾病的基因可以用不同的方式来运作,一些情况下基因会被完全关闭,基因也可以在错误的时间开启,在错误的时间关闭。Altshuler表示:我们一直搜索“被破坏基因”(被关闭基因),寻找哪些基因的保护作用来自于其自身的关闭和功能停止,同时我们认为寻找停止基因发挥作用的药物比寻找开启基因或者改变基因功能的药物相对而言更简单。国际上几个团队均对此进行了大规模研究,发现了一系列可能有关的突变。最近一项研究进一步证实了SLC30A8突变的作用。该基因编码胰岛锌转运体(islet zinc transporter,ZnT8) ,抑制ZnT8也可能成为糖尿病治疗的新策略。

研究人员筛选150,000名患者,鉴定数千名有糖尿病危险因素包括高龄和肥胖,但尚未患糖尿病的人的基因组。在那些人中,研究人员检查了一套与糖尿病相关的已知基因,找到了基因SLC30A8的突变,SLC30A8突变停止其基因功能,会起到保护免于患上糖尿病的作用。

糖尿病药物开发已经以令人沮丧的低速度持续了几十年,实验室技术进步已经大大减少药物毒性(毒性是导致大部分的候选药物在过去几十年中失败的原因),但是成功通过临床试验的药物数量仍没有变化。

而上述现象的主要原因是,这些药物绝大多数只是不发挥作用,尽管有更好的技术和动物模型,来模仿人类生物学,但当开展人体实验时,超过95%的实验室有效候选药物也是无效的。Altshuler说:目前我们仍然不完全明白人类生物学,也不能充分了解药物是如何工作的,甚至还未弄清楚人类和实验动物之间的主要生物学差异,这些问题都有待解决。

原始出处:

Alvin Powell.Diabetes discovery illuminates path to new drugs.Medical Xrress July 25, 2014

Zhou Y, Park SY, Su J, Bailey K, Ottosson-Laakso E, Shcherbina L, Oskolkov N, Zhang E, Thevenin T, Fadista J, Bennet H, Vikman P, Wierup N, Fex M, Rung J, Wollheim C, Nobrega M, Renström E, Groop L, Hansson O.TCF7L2 is a master regulator of insulin production and processing.Hum Mol Genet. 2014 Jul 11. pii: ddu359

Gerber PA, Bellomo EA, Hodson DJ, Meur G, Solomou A, Mitchell RK, Hollinshead M, Chimienti F, Bosco D, Hughes SJ, Johnson PR, Rutter GA.Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn(2+) in pancreatic beta cells.Diabetologia. 2014 Aug;57(8):1635-44.

Flannick J, Thorleifsson G, Beer NL, Jacobs SB, Grarup N, Burtt NP, Mahajan A, Fuchsberger C, Atzmon G, Benediktsson R, Blangero J, Bowden DW, Brandslund I, Brosnan J, Burslem F, Chambers J, Cho YS, Christensen C, Douglas DA, Duggirala R, Dymek Z, Farjoun Y, Fennell T, Fontanillas P, Forsén T, Gabriel S, Glaser B, Gudbjartsson DF, Hanis C, Hansen T, Hreidarsson AB, Hveem K, Ingelsson E, Isomaa B, Johansson S, Jørgensen T, Jørgensen ME, Kathiresan S, Kong A, Kooner J, Kravic J, Laakso M, Lee JY, Lind L, Lindgren CM, Linneberg A, Masson G, Meitinger T, Mohlke KL, Molven A, Morris AP, Potluri S, Rauramaa R, Ribel-Madsen R, Richard AM, Rolph T, Salomaa V, Segrè AV, Skärstrand H, Steinthorsdottir V, Stringham HM, Sulem P, Tai ES, Teo YY, Teslovich T, Thorsteinsdottir U, Trimmer JK, Tuomi T, Tuomilehto J, Vaziri-Sani F, Voight BF, Wilson JG, Boehnke M, McCarthy MI, Njølstad PR, Pedersen O; Go-T2D Consortium; T2D-GENES Consortium, Groop L, Cox DR, Stefansson K, Altshuler D.Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.Nat Genet. 2014 Apr;46(4):357-63. doi: 10.1038/ng.2915

Sprouse C, Gordish-Dressman H, Orkunoglu-Suer EF, Lipof JS, Moeckel-Cole S, Patel RR, Adham K, Larkin JS, Hubal MJ, Kearns AK, Clarkson PM, Thompson PD, Angelopoulos TJ, Gordon PM, Moyna NM, Pescatello LS, Visich PS, Zoeller RF, Hoffman EP, Tosi LL, Devaney JM.SLC30A8 nonsynonymous variant is associated with recovery following exercise and skeletal muscle size and strength.Diabetes. 2014 Jan;63(1):363-8. doi: 10.2337/db13-1150.

Strawbridge RJ, Dupuis J, Prokopenko I, Barker A, Ahlqvist E, Rybin D, Petrie JR, Travers ME, Bouatia-Naji N, Dimas AS, Nica A, Wheeler E, Chen H, Voight BF, Taneera J, Kanoni S, Peden JF, Turrini F, Gustafsson S, Zabena C, Almgren P, Barker DJ, Barnes D, Dennison EM, Eriksson JG, Eriksson P, Eury E, Folkersen L, Fox CS, Frayling TM, Goel A, Gu HF, Horikoshi M, Isomaa B, Jackson AU, Jameson KA, Kajantie E, Kerr-Conte J, Kuulasmaa T, Kuusisto J, Loos RJ, Luan J, Makrilakis K, Manning AK, Martínez-Larrad MT, Narisu N, Nastase Mannila M, Ohrvik J, Osmond C, Pascoe L, Payne F, Sayer AA, Sennblad B, Silveira A, Stancáková A, Stirrups K, Swift AJ, Syvänen AC, Tuomi T, van 't Hooft FM, Walker M, Weedon MN, Xie W, Zethelius B; DIAGRAM Consortium; GIANT Consortium; MuTHER Consortium; CARDIoGRAM Consortium; C4D Consortium, Ongen H, Mälarstig A, Hopewell JC, Saleheen D, Chambers J, Parish S, Danesh J, Kooner J, Ostenson CG, Lind L, Cooper CC, Serrano-Ríos M, Ferrannini E, Forsen TJ, Clarke R, Franzosi MG, Seedorf U, Watkins H, Froguel P, Johnson P, Deloukas P, Collins FS, Laakso M, Dermitzakis ET, Boehnke M, McCarthy MI, Wareham NJ, Groop L, Pattou F, Gloyn AL, Dedoussis GV, Lyssenko V, Meigs JB, Barroso I, Watanabe RM, Ingelsson E, Langenberg C, Hamsten A, Florez JC.Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.Diabetes. 2011 Oct;60(10):2624-34

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    2015-04-11 x35042875

    糖尿病肾病进展风险的关系没有发现。

    0

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    2015-01-20 cy0324
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    2014-12-26 liye789132251
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    2015-02-19 canlab
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    2014-07-28 lovetcm

    这真是里程碑式的研究,相信10年左右就有针对这个基因的靶向药物问世

    0

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