RESUMEN
Genome wide association studies (GWAS) have identified over 100 signals associated with type 1 diabetes (T1D). However, translating any given T1D GWAS signal into mechanistic insights, including putative causal variants and the context (cell type and cell state) in which they function, has been limited. Here, we present a comprehensive multi-omic integrative analysis of single-cell/nucleus resolution profiles of gene expression and chromatin accessibility in healthy and autoantibody+ (AAB+) human islets, as well as islets under multiple T1D stimulatory conditions. We broadly nominate effector cell types for all T1D GWAS signals. We further nominated higher-resolution contexts, including effector cell types, regulatory elements, and genes for three independent T1D risk variants acting through islet cells within the pancreas at the DLK1/MEG3, RASGRP1, and TOX loci. Subsequently, we created isogenic gene knockouts DLK1-/-, RASGRP1-/-, and TOX-/-, and the corresponding regulatory region knockout, RASGRP1Δ, and DLK1Δ hESCs. Loss of RASGRP1 or DLK1, as well as knockout of the regulatory region of RASGRP1 or DLK1, increased ß cell apoptosis. Additionally, pancreatic ß cells derived from isogenic hESCs carrying the risk allele of rs3783355A/A exhibited increased ß cell death. Finally, RNA-seq and ATAC-seq identified five genes upregulated in both RASGRP1-/- and DLK1-/- ß-like cells, four of which are associated with T1D. Together, this work reports an integrative approach for combining single cell multi-omics, GWAS, and isogenic hESC-derived ß-like cells to prioritize the T1D associated signals and their underlying context-specific cell types, genes, SNPs, and regulatory elements, to illuminate biological functions and molecular mechanisms.
RESUMEN
PURPOSE: To retrospectively evaluate the imaging features of duodenal carcinoids with clinical-pathologic comparison. MATERIALS AND METHODS: The institutional review board approved this study; informed consent was not required. The study was HIPAA compliant. The authors retrospectively reviewed the barium studies (n = 20), computed tomographic (CT) scans (n = 16), magnetic resonance (MR) images (n = 2), pathology reports (n = 33), gross pathology photographs (n = 15), and clinical data (n = 33) from 33 patients (16 men and 17 women; age range, 19-90 years; mean age, 52.6 years) with a confirmed diagnosis of duodenal carcinoid admitted into our institution during a 52-year period. The imaging studies were evaluated by consensus of two abdominal radiologists for the number of masses and their location and morphologic characteristics (polypoid or mural). The CT and MR images were also assessed for contrast enhancement characteristics. RESULTS: Most carcinoids were located in the proximal duodenum (10 in the bulb, 19 in the second portion, two in the third portion, and two in the fourth portion). Seventeen patients (52%) had focal intraluminal polypoid masses and 13 (39%) had mural masses; in three patients (9%), the tumor was not visualized at CT. Five of the 33 patients (15%) had multiple carcinoids. CT showed heterogeneous contrast enhancement in all patients who received intravenous contrast material in the arterial or portal venous phases of enhancement. Nonenhancing masses were present in patients who underwent CT during the equilibrium phase. Two patients had Zollinger-Ellison syndrome. Five patients (15%) had neurofibromatosis type 1 (NF-1); four of the five patients (80%) were women, and four patients were African American. In all five patients with NF-1, the carcinoids were located in the periampullary region. CONCLUSION: Duodenal carcinoids are uncommon tumors with a wide clinical-pathologic spectrum. They occur most commonly in the proximal duodenum and manifest as an intraluminal polyp or a mural mass.