Exploring the potential of public proteomics data

In a global effort for scientific transparency, it has become feasible and good practice to share experimental data supporting novel findings. Consequently, the amount of publicly available MS-based proteomics data has grown substantially in recent years. With some notable exceptions, this extensive material has however largely been left untouched. The time has now come for the proteomics community to utilize this potential gold mine for new discoveries, and uncover its untapped potential. In this review, we provide a brief history of the sharing of proteomics data, showing ways in which publicly available proteomics data are already being (re-)used, and outline potential future opportunities based on four different usage types: use, reuse, reprocess, and repurpose. We thus aim to assist the proteomics community in stepping up to the challenge, and to make the most of the rapidly increasing amount of public proteomics data

The Chromosome 9p21 CVD-and T2D-Associated Regions in a Norwegian Population (The HUNT2 Survey)

Background. Two adjacent regions upstream CDKN2B on chromosome 9p21 have been associated with type 2 diabetes (T2D) and progression of cardiovascular disease (CVD). The precise location and number of risk variants have not been completely delineated and a possible synergistic relationship between the adjacent regions is not fully addressed. By a population based cross-sectional case-control design, we genotyped 18 SNPs upstream of CDKN2B tagging 138 kb in and around two LD-blocks associated with CVD and T2D and investigated associations with T2D, angina pectoris (AP), myocardial infarction (MI), coronary heart disease (CHD; AP or AMI), and stroke using 5,564 subjects from HUNT2. Results. Single point and haplotype analysis showed evidence for only one common T2D risk haplotype (rs10757282|rs10811661: OR = 1.19, = 2.0 × 10 −3 ) in the region. We confirmed the strong association between SNPs in the 60 kb CVD region with AP, MI, and CHD ( < 0.01). Conditioning on the lead SNPs in the region, we observed two suggestive independent single SNP association signals for MI, rs2065501 ( = 0.03) and rs3217986 ( = 0.04). Conclusions. We confirmed the association of known variants within the 9p21 interval with T2D and CHD. Our results further suggest that additional CHD susceptibility variants exist in this region

Early Developmental Perturbations in a Human Stem Cell Model of MODY5/HNF1B Pancreatic Hypoplasia

Summary Patients with an HNF1BS148L/+ mutation (MODY5) typically exhibit pancreatic hypoplasia. However, the molecular mechanisms are unknown due to inaccessibility of patient material and because mouse models do not fully recapitulate MODY5. Here, we differentiated MODY5 human-induced pluripotent stem cells (hiPSCs) into pancreatic progenitors, and show that the HNF1BS148L/+ mutation causes a compensatory increase in several pancreatic transcription factors, and surprisingly, a decrease in PAX6 pancreatic gene expression. The lack of suppression of PDX1, PTF1A, GATA4, and GATA6 indicates that MODY5-mediated pancreatic hypoplasia is mechanistically independent. Overexpression studies demonstrate that a compensatory increase in PDX1 gene expression is due to mutant HNF1BS148L/+ but not wild-type HNF1B or HNF1A. Furthermore, HNF1B does not appear to directly regulate PAX6 gene expression necessary for glucose tolerance. Our results demonstrate compensatory mechanisms in the pancreatic transcription factor network due to mutant HNF1BS148L/+ protein. Thus, patients typically develop MODY5 but not neonatal diabetes despite exhibiting pancreatic hypoplasia

Carboxyl-Ester Lipase Maturity-Onset Diabetes of the Young Disease Protein Biomarkers in Secretin-Stimulated Duodenal Juice

Patients with carboxyl-ester lipase-maturity-onset diabetes of the young (CEL-MODY) display distinct disease stages toward the development of monogenic diabetes and exocrine pancreatic disease. The finding of differentially increased proteins, some related to MAPK signaling, in a discovery proteomics study of secretin-stimulated duodenal juice in three CEL-MODY patients, prompted us to monitor their abundance in an extensive number of CEL-MODY subjects at different disease stages and controls using targeted proteomics. In the current study, we demonstrate the feasibility of selected reaction monitoring assays to quantify protein levels in secretin-stimulated duodenal juice. Furthermore, we define a set of five peptides for potential use as diagnostic tests in CEL-MODY patients. Finally, we propose a further set of seven proteins with a likely pathogenic role in CEL-MODY disease progression

Abnormal Exocrine-Endocrine Cell Cross-Talk Promotes Β-Cell Dysfunction and Loss in MODY8

MODY8 (maturity-onset diabetes of the young, type 8) is a dominantly inherited monogenic form of diabetes associated with mutations in the carboxyl ester lipase (CEL) gene expressed by pancreatic acinar cells. MODY8 patients develop childhood-onset exocrine pancreas dysfunction followed by diabetes during adulthood. However, it is unclear how CEL mutations cause diabetes. In the present study, we report the transfer of CEL proteins from acinar cells to β-cells as a form of cross-talk between exocrine and endocrine cells. Human β-cells show a relatively higher propensity for internalizing the mutant versus the wild-type CEL protein. After internalization, the mutant protein forms stable intracellular aggregates leading to β-cell secretory dysfunction. Analysis of pancreas sections from a MODY8 patient reveals the presence of CEL protein in the few extant β-cells. The present study provides compelling evidence for the mechanism by which a mutant gene expressed specifically in acinar cells promotes dysfunction and loss of β-cells to cause diabetes