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Increased expression of anion transporter SLC26A9 delays diabetes onset in cystic fibrosis
The Journal of Clinical Investigation ( IF 15.9 ) Pub Date : 2019-10-03 , DOI: 10.1172/jci129833
Anh-Thu N. Lam , Melis A. Aksit , Briana Vecchio-Pagan , Celeste A. Shelton , Derek L. Osorio , Arianna F. Anzmann , Loyal A. Goff , David C. Whitcomb , Scott M. Blackman , Garry R. Cutting

Diabetes is a common complication of cystic fibrosis (CF) that affects approximately 20% of adolescents and 40%–50% of adults with CF. The age at onset of CF-related diabetes (CFRD) (marked by clinical diagnosis and treatment initiation) is an important measure of the disease process. DNA variants associated with age at onset of CFRD reside in and near SLC26A9. Deep sequencing of the SLC26A9 gene in 762 individuals with CF revealed that 2 common DNA haplotypes formed by the risk variants account for the association with diabetes. Single-cell RNA sequencing (scRNA-Seq) indicated that SLC26A9 is predominantly expressed in pancreatic ductal cells and frequently coexpressed with CF transmembrane conductance regulator (CFTR) along with transcription factors that have binding sites 5′ of SLC26A9. These findings were replicated upon reanalysis of scRNA-Seq data from 4 independent studies. DNA fragments derived from the 5′ region of SLC26A9-bearing variants from the low-risk haplotype generated 12%–20% higher levels of expression in PANC-1 and CFPAC-1 cells compared with the high- risk haplotype. Taken together, our findings indicate that an increase in SLC26A9 expression in ductal cells of the pancreas delays the age at onset of diabetes, suggesting a CFTR-agnostic treatment for a major complication of CF.

中文翻译:

阴离子转运蛋白SLC26A9的表达增加延迟糖尿病在囊性纤维化中的发作

糖尿病是囊性纤维化(CF)的常见并发症,影响约20%的青少年和40%–50%的CF成年人。CF相关性糖尿病(CFRD)的发病年龄(以临床诊断和治疗开始为特征)是疾病过程的重要指标。与CFRD发病年龄相关的DNA变异体位于SLC26A9及其附近。在762名患有CF的个体中对SLC26A9基因进行了深度测序,发现由风险变异体形成的2种常见DNA单倍型与糖尿病有关。单细胞RNA测序(scRNA-Seq)表明SLC26A9主要在胰腺导管细胞中表达,并经常与CF跨膜电导调节剂(CFTR)共表达)以及具有SLC26A9结合位点5'的转录因子。重新分析来自4项独立研究的scRNA-Seq数据后,便重复了这些发现。与高风险单倍型相比,来自SLC26A9的5'区域的低风险单倍型衍生的DNA片段在PANC-1和CFPAC-1细胞中的表达水平高出12%–20%。综上所述,我们的发现表明胰腺导管细胞中SLC26A9表达的增加延迟了糖尿病发作的年龄,表明CF的主要并发症与CFTR无关。
更新日期:2020-01-04
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