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

doi:10.1007/s00125-022-05801-7

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 journal › Article › peer-review

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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 × 10⁻³), 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. Graphical abstract: [Figure not available: see fulltext.]

Original language	English (US)
Pages (from-to)	105-115
Number of pages	11
Journal	Diabetologia
Volume	66
Issue number	1
DOIs	https://doi.org/10.1007/s00125-022-05801-7
State	Published - Jan 2023

Bibliographical note

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

Keywords

Beta cell
Diabetes
Genetic risk score
Insulin resistance
Mendelian
Proteomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s00125-022-05801-7

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Steffen, B. T., Tang, W., Lutsey, P. L., Demmer, R. T., Selvin, E., Matsushita, K., Morrison, A. C., Guan, W., Rooney, M. R., Norby, F. L., Pankratz, N., Couper, D., & Pankow, J. S. (2023). 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. Diabetologia, 66(1), 105-115. https://doi.org/10.1007/s00125-022-05801-7

Steffen, BT , Tang, W , Lutsey, PL , Demmer, RT, Selvin, E, Matsushita, K, Morrison, AC, Guan, W, Rooney, MR, Norby, FL , Pankratz, N, Couper, D & Pankow, JS 2023, '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', Diabetologia, vol. 66, no. 1, pp. 105-115. https://doi.org/10.1007/s00125-022-05801-7

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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 × 10−3), 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. Graphical abstract: [Figure not available: see fulltext.]",

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AU - Lutsey, Pamela L.

AU - Demmer, Ryan T.

AU - Selvin, Elizabeth

AU - Matsushita, Kunihiro

AU - Morrison, Alanna C.

AU - Guan, Weihua

AU - Rooney, Mary R.

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N2 - 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. Graphical abstract: [Figure not available: see fulltext.]

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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

Abstract

Bibliographical note

Keywords

UN SDGs

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