University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; University Center for Primary Care and Public Health, 1010 Lausanne, Switzerland.
Cell Rep Med. 2023 Aug 15;4(8):101155. doi: 10.1016/j.xcrm.2023.101155.
New approaches are needed to treat people whose obesity and type 2 diabetes (T2D) are driven by specific mechanisms. We investigate a deletion on chromosome 16p11.2 (breakpoint 2-3 [BP2-3]) encompassing SH2B1, a mediator of leptin and insulin signaling. Phenome-wide association scans in the UK (N = 502,399) and Estonian (N = 208,360) biobanks show that deletion carriers have increased body mass index (BMI; p = 1.3 × 10) and increased rates of T2D. Compared with BMI-matched controls, deletion carriers have an earlier onset of T2D, with poorer glycemic control despite higher medication usage. Cystatin C, a biomarker of kidney function, is significantly elevated in deletion carriers, suggesting increased risk of renal impairment. In a Mendelian randomization study, decreased SH2B1 expression increases T2D risk (p = 8.1 × 10). We conclude that people with 16p11.2 BP2-3 deletions have early, complex obesity and T2D and may benefit from therapies that enhance leptin and insulin signaling.
需要新的方法来治疗那些肥胖和 2 型糖尿病（T2D）由特定机制驱动的人群。我们研究了染色体 16p11.2 上的缺失（断点 2-3 [BP2-3]），该缺失包括瘦素和胰岛素信号的中介物 SH2B1。在英国（N=502399）和爱沙尼亚（N=208360）生物库中的全表型关联扫描显示，缺失携带者的体重指数（BMI）增加（p=1.3×10），T2D 发病率也增加。与 BMI 匹配的对照组相比，缺失携带者的 T2D 发病更早，尽管用药更多，但血糖控制更差。胱抑素 C，一种肾功能的生物标志物，在缺失携带者中显著升高，表明肾功能损害的风险增加。在一项孟德尔随机化研究中，SH2B1 表达的降低增加了 T2D 的风险（p=8.1×10）。我们得出结论，携带 16p11.2 BP2-3 缺失的人患有早期、复杂的肥胖和 T2D，可能受益于增强瘦素和胰岛素信号的治疗方法。
