
Faculty, Staff and Student Publications
Publication Date
1-1-2023
Abstract
AIMS/HYPOTHESIS: Genetic predisposition to type 2 diabetes is well-established, and genetic risk scores (GRS) have been developed that capture heritable liabilities for type 2 diabetes phenotypes. However, the proteins through which these genetic variants influence risk have not been thoroughly investigated. This study aimed to identify proteins and pathways through which type 2 diabetes risk variants may influence pathophysiology.
METHODS: Using a proteomics data-driven approach in a discovery sample of 7241 White participants in the Atherosclerosis Risk in Communities Study (ARIC) cohort and a replication sample of 1674 Black ARIC participants, we interrogated plasma levels of 4870 proteins and four GRS of specific type 2 diabetes phenotypes related to beta cell function, insulin resistance, lipodystrophy, BMI/blood lipid abnormalities and a composite score of all variants combined.
RESULTS: Twenty-two plasma proteins were identified in White participants after Bonferroni correction. Of the 22 protein-GRS associations that were statistically significant, 10 were replicated in Black participants and all but one were directionally consistent. In a secondary analysis, 18 of the 22 proteins were found to be associated with prevalent type 2 diabetes and ten proteins were associated with incident type 2 diabetes. Two-sample Mendelian randomisation indicated that complement C2 may be causally related to greater type 2 diabetes risk (inverse variance weighted estimate: OR 1.65 per SD; p=7.0 × 10
CONCLUSIONS/INTERPRETATION: Identified proteins may represent viable intervention or pharmacological targets to prevent, reverse or slow type 2 diabetes progression, and further research is needed to pursue these targets.
Keywords
Humans, Diabetes Mellitus, Type 2, Complement C2, Proteomics, Risk Factors
DOI
10.1007/s00125-022-05801-7
PMID
36194249
PMCID
PMC9742300
PubMedCentral® Posted Date
1-1-2024
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes