1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
Nat Genet. 2014 Apr;46(4):357-63. doi: 10.1038/ng.2915. Epub 2014 Mar 2.
Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138 and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
通过对 5 个种族群体的约 15 万人进行测序或基因分型，我们在 SLC30A8 中鉴定出 12 种罕见的蛋白截断变异，该基因编码胰岛锌转运体（ZnT8），并含有与 2 型糖尿病风险和葡萄糖及胰岛素原水平相关的常见变异（p.Trp325Arg）。总的来说，蛋白截断变异携带者的 2 型糖尿病风险降低了 65%（P=1.7×10(-6))，携带移码变异（p.Lys34Serfs50）的非糖尿病冰岛携带者的葡萄糖水平降低了（-0.17 个标准差，P=4.6×10(-4))。两种最常见的蛋白截断变异（p.Arg138和 p.Lys34Serfs*50）分别与 2 型糖尿病的保护作用相关，并编码不稳定的 ZnT8 蛋白。之前对 SLC30A8 的功能研究表明，锌转运减少会增加 2 型糖尿病的风险，而在 Slc30a8 敲除小鼠中观察到表型异质性。相反，人类中的功能丧失突变提供了强有力的证据，表明 SLC30A8 半合子不足可预防 2 型糖尿病，这表明抑制 ZnT8 可能成为 2 型糖尿病预防的一种治疗策略。
