| Summary: | Human genetic variants inSLC16A11are associatedwith increased risk of type 2 diabetes (T2D). We pre-viously identified two distinct mechanisms throughwhich co-inherited T2D-risk coding and non-codingvariants disruptSLC16A11expression and activity,thus implicating reduced SLC16A11 function as thedisease-relevant direction of effect. In a recent pub-lication,Zhao et al. (2019a)argue that humanSLC16A11 coding variants confer gain of function,basing their conclusions on phenotypic changesobserved following overexpression of mutant murineSlc16a11. However, data necessary to demonstrategain-of-function activity are not reported. Further-more, several fundamental flaws in their experi-mental system-including inaccurate modeling ofthe human variant haplotype and expression condi-tions that are not physiologically relevant-preventconclusions about T2D-risk variant effects on humanphysiology. This Matters Arising paper is in response toZhao et al. (2019a), published inCell Reports. Seealso the response byZhao et al. (2019b)in this issueofCell Reports.
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