Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility.
Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility.
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DOI：
10.1038/s41467-017-00837-5
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发表时间：
2017-11-24
影响因子：
16.6
通讯作者：
Jablonski MM
中科院分区：
文献类型：
--
作者：
Chintalapudi SR;Maria D;Di Wang X;Bailey JNC;NEIGHBORHOOD consortium;International Glaucoma Genetics consortium;Hysi PG;Wiggs JL;Williams RW;Jablonski MM
青光眼是一种多因素致盲疾病，遗传因素在其中起重要作用。眼压升高是原发性开角型青光眼的高度遗传危险因素，也是目前青光眼治疗的唯一目标。我们的研究有助于更好地了解调节眼压的潜在遗传和分子机制，并确定了一个新的候选基因Cacna2d1，它调节眼压和一种很有前途的治疗药物普瑞巴林，它与Cacna2d1蛋白结合，显著降低眼压。由于我们的研究使用了具有已知序列变异的遗传多样性的小鼠种群，我们能够确定普瑞巴林的眼压降低作用依赖于Cacna2d1单倍型。利用人类全基因组关联研究（GWAS）数据，发现了CACNA2D1单核苷酸多态性与原发性开角型青光眼相关的证据。重要的是，这些结果表明，我们的系统遗传学方法代表了一种识别遗传变异的有效方法，可以指导治疗靶点的选择。眼压升高是原发性开角型青光眼的遗传危险因素。利用小鼠遗传学、细胞生物学、药理学和人类遗传学数据，作者在动物模型中确定了CACNA2D1是一种IOP风险基因，可以通过药物普瑞巴林进行治疗。
Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets. Elevated intraocular pressure (IOP) is a heritable risk factor for primary open angle glaucoma. Using forward mouse genetics, cell biology, pharmacology and human genetic data, the authors identify CACNA2D1 as an IOP risk gene that can be therapeutically targeted by the drug pregabalin in animal models.
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影响因子：
4.4
作者：
Jablonski, Monica M.;Freeman, Natalie E.;Orr, William E.;Templeton, Justin P.;Lu, Lu;Williams, Robert W.;Geisert, Eldon E.
通讯作者：
Geisert, Eldon E.
影响因子：
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作者：
Hugosson, Therese;Friedman, James S.;Andreasson, Sten
通讯作者：
Andreasson, Sten
影响因子：
30.8
作者：
Gharahkhani, Puya;Burdon, Kathryn P.;Fogarty, Rhys;Sharma, Shiwani;Hewitt, Alex W.;Martin, Sarah;Law, Matthew H.;Cremin, Katie;Bailey, Jessica N. Cooke;Loomis, Stephanie J.;Pasquale, Louis R.;Haines, Jonathan L.;Hauser, Michael A.;Viswanathan, Ananth C.;McGuffin, Peter;Topouzis, Fotis;Foster, Paul J.;Graham, Stuart L.;Casson, Robert J.;Chehade, Mark;White, Andrew J.;Zhou, Tiger;Souzeau, Emmanuelle;Landers, John;Fitzgerald, Jude T.;Klebe, Sonja;Ruddle, Jonathan B.;Goldberg, Ivan;Healey, Paul R.;Mills, Richard A.;Wang, Jie Jin;Montgomery, Grant W.;Martin, Nicholas G.;Radford-Smith, Graham;Whiteman, David C.;Brown, Matthew A.;Wiggs, Janey L.;Mackey, David A.;Mitchell, Paul;MacGregor, Stuart;Craig, Jamie E.
通讯作者：
Craig, Jamie E.
影响因子：
4.1
作者：
Carbonaro, F.;Andrew, T.;Hammond, C. J.
通讯作者：
Hammond, C. J.
影响因子：
17.8
作者：
Araie, Makoto;Mayama, Chihiro
通讯作者：
Mayama, Chihiro