Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
Cell Rep. 2019 Oct 15;29(3):778-780. doi: 10.1016/j.celrep.2019.09.021.
Human genetic variants in SLC16A11 are associated with increased risk of type 2 diabetes (T2D). We previously identified two distinct mechanisms through which co-inherited T2D-risk coding and non-coding variants disrupt SLC16A11 expression and activity, thus implicating reduced SLC16A11 function as the disease-relevant direction of effect. In a recent publication, Zhao et al. (2019a) argue that human SLC16A11 coding variants confer gain of function, basing their conclusions on phenotypic changes observed following overexpression of mutant murine Slc16a11. However, data necessary to demonstrate gain-of-function activity are not reported. Furthermore, several fundamental flaws in their experimental system-including inaccurate modeling of the human variant haplotype and expression conditions that are not physiologically relevant-prevent conclusions about T2D-risk variant effects on human physiology. This Matters Arising paper is in response to Zhao et al. (2019a), published in Cell Reports. See also the response by Zhao et al. (2019b) in this issue of Cell Reports.
人类 SLC16A11 中的遗传变异与 2 型糖尿病（T2D）的风险增加有关。我们之前已经确定了两种不同的机制，即共遗传的 T2D 风险编码和非编码变异通过破坏 SLC16A11 的表达和活性，从而暗示 SLC16A11 功能降低是与疾病相关的效应方向。在最近的一篇出版物中，Zhao 等人（2019a）认为人类 SLC16A11 编码变异赋予了功能获得，其结论基于观察到突变型 Slc16a11 过表达后观察到的表型变化。然而，没有报告证明功能获得活性所需的数据。此外，他们的实验系统存在几个基本缺陷——包括对人类变异单倍型的不准确建模和与生理无关的表达条件——阻碍了关于 T2D 风险变异对人类生理学影响的结论。本争议论文是对 Zhao 等人（2019a）在《Cell Reports》上发表的文章的回应。也可参见 Zhao 等人（2019b）在本期《Cell Reports》上的回应。
