Dansk resumé
I de seneste årtier har undersøgelser af arvemassen hos personer med diabetes ført til en bedre forståelse af hvordan arvelige faktorer påvirker tilbøjeligheden til at udvikle diabetes. Selvom mange tusinde enkelte ændringer i arvemassen er blevet identificeret som mulige delvise årsager til diabetes, er det ikke muligt at belyse de fulde konsekvenser af arvelige ændringer alene på baggrund af undersøgelser af arvemassen. I de senere år er det blevet muligt at undersøge det såkaldte ”proteom” som er betegnelsen for de samlede funktionelle produkter som produceres af kroppens celler. Undersøgelse af proteomet kan give ny viden om hvordan arvelige ændringer fører til sygdomsrisiko.
Tidligere har 3000 deltagere fra DD2 fået undersøgt en lille mængde af deres arvemasse som er særlig vigtig for diabetesudviklingen. I denne population ønsker vi også at undersøge proteomet for at opnå en dybere forståelse af samspillet mellem arvelige ændringer, proteomet, og udviklingen af diabetes.
Abstract
Over the past decades, thousands of genetic variants have been identified that cause or increase the risk of developing cardio-metabolic outcomes. However, functional inference based on genetic information alone is limited. Over the past years, proteomics has developed as a field that allows for unbiased quantification of the transcribed and translated proteome, facilitating functional inference and elucidation of disease processes.
Previously, the Novo Nordisk Foundation Center for Basic Metabolic Research in collaboration with DD2 has performed targeted sequencing of 3000 DD2 participants. In this new study, we wish to analyze the plasma proteome of these individuals on which we have targeted sequencing data. We aim to use the generated data to refine the classification of genetic variants, particularly those with unknown functional effects, to study the effect of polygenic diabetes risk on the proteome, and to study the utility of the proteome as a tool for clustering and prediction of diabetes phenotype and clinically relevant outcomes.
Formål
For the described cohort of people with type 2 diabetes, the specific aims are:
1) Proteomics as a tool for variant classification: We will explore the utility of proteomics as a tool to classify VUS in diabetes by comparing the proteomic signature of carriers of VUS to carriers of known pathogenic variants and non-carriers.
2) Proteomics as a tool for variant reclassification: In addition to the above, we will explore the utility of proteomics as a tool to reclassify variants that have previously been associated with disease by comparing the proteomic signature of carriers of variants classified as pathogenic, likely pathogenic or previously seen in monogenic diabetes.
3) Modifying effect of polygenic risk on the proteome: We will analyze the effect of polygenic risk as expressed by PGS alone and in combination with individual genetic variants identified by targeted sequencing on the plasma proteome.
Studiepopulation
~3000 individuals on which we have previously performed targeted sequencing of known metabolically important genes.
Finansiering
The study is fully funded by the Novo Nordisk Foundation as a Steno Collaborative Grant.
DD2 er ledet af Steno Diabetes Centrene
