Proteomic analysis of diabetes genetic risk scores identifies complement C2 and neuropilin-2 as predictors of type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) Study

Brian T. Steffen, Weihong Tang, Pamela L. Lutsey, Ryan T. Demmer, Elizabeth Selvin, Kunihiro Matsushita, Alanna C. Morrison, Weihua Guan, Mary R. Rooney, Faye L. Norby, Nathan Pankratz, David Couper, James S. Pankow

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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 -3), while neuropilin-2 was inversely associated (OR 0.44 per SD; p=8.0 × 10 -3).

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.

Original languageEnglish (US)
Pages (from-to)105-115
Number of pages11
Issue number1
StatePublished - Jan 2023

Bibliographical note

Funding Information:
This work was supported by grant number 2T32HL007779-26 from the US National Heart, Lung, and Blood Institute, and by an award from the Hawley Foundation to BTS. The Atherosclerosis Risk in Communities study has been funded in whole or in part by federal funds from the US National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under contract numbers 75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005, R01HL087641, R01HL059367 and R01HL086694. Funding was also supported by US National Human Genome Research Institute contract U01HG004402, and US National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. PLL was supported by K24 HL159246. SomaLogic Inc. performed the SomaScan assays in exchange for use of ARIC study data. This work was supported in part by US National Heart, Lung, and Blood Institute/National Institutes of Health grant R01HL134320. The measurement of serum creatinine and cystatin C was performed as part of an ancillary study supported by research funding from Kyowa Kirin (principal investigator: Kunihiro Matsushita).

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.


  • Beta cell
  • Diabetes
  • Genetic risk score
  • Insulin resistance
  • Mendelian
  • Proteomics


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