A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts.
A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts.
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DOI：
10.1007/s00125-012-2537-x
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发表时间：
2012-07
期刊：
影响因子：
8.2
通讯作者：
Pearson, E. R.
中科院分区：
文献类型：
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作者：
van Leeuwen, N.;Nijpels, G.;Becker, M. L.;Deshmukh, H.;Zhou, K.;Stricker, B. H. C.;Uitterlinden, A. G.;Hofman, A.;van 't Riet, E.;Palmer, C. N. A.;Guigas, B.;Slagboom, P. E.;Durrington, P.;Calle, R. A.;Neil, A.;Hitman, G.;Livingstone, S. J.;Colhoun, H.;Holman, R. R.;McCarthy, M. I.;Dekker, J. M.;'t Hart, L. M.;Pearson, E. R.
在这项研究中，我们的目的是在多个其他人群中复制先前报道的二甲双胍血糖反应与包含共济失调毛细血管扩张突变 (ATM) 基因的位点上的 SNP rs11212617 之间的关联。从荷兰西弗里斯兰糖尿病护理系统 (DCS，n = 929) 和鹿特丹研究 (n = 182) 以及英国 CARDS 试验 (n = 254) 中选出的二甲双胍事件使用者进行了 rs11212617 基因分型，并测试了其与 HbA1c 降低和治疗成功的关联，定义为达到 HbA1c ≤7% (53 mmol/mol) 的治疗目标的能力。最后，进行了包括文献数据的荟萃分析。在 DCS 队列中，我们观察到 rs11212617 基因型与二甲双胍治疗成功之间存在关联（OR 1.27，95% CI 1.03、1.58，p = 0.028）；在规模较小的鹿特丹研究队列中，观察到数值相似但不显着的趋势（OR 1.45，95% CI 0.87，2.39，p = 0.15）；而在 CARDS 队列中则没有显着关联。在这三个队列单独或与之前发表的队列相结合的荟萃分析中，rs11212617基因型与二甲双胍治疗成功相关（OR 1.24，95％CI 1.04，1.49，p = 0.016和OR 1.25，95％CI 1.33，1.38， p = 7.8 × 10−6，分别）。 ATM 附近的基因变异与荷兰和英国 2 型糖尿病患者的二甲双胍治疗反应显着相关。这是第一个被发现与二甲双胍治疗反应相关的可靠复制的常见易感基因座。本文的在线版本 (doi:10.1007/s00125-012-2537-x) 包含经过同行评审但未经编辑的补充材料，可供授权用户使用。
In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA1c reduction and treatment success, defined as the ability to reach the treatment target of an HbA1c ≤7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p = 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10−6, respectively). A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response. The online version of this article (doi:10.1007/s00125-012-2537-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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