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Proteomic Signatures of Cardiac Dysfunction Among People With Diabetes: The Atherosclerosis Risk in Communities Study
Justin B Echouffo-Tcheugui1,2, Chiadi E Ndumele3, Jingsha Chen2
1Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University, Baltimore, MD (J.B.E.-T.).
Insights
Researchers identified five novel protein markers associated with heart failure (HF) risk specifically in individuals with diabetes. These proteomic signatures may reveal new mechanisms underlying diabetes-related HF.
Area of Science:
- Cardiovascular Research
- Metabolomics
- Proteomics
Background:
- Diabetes mellitus significantly increases the risk of heart failure (HF).
- The specific biological mechanisms driving this elevated HF risk in diabetic individuals remain largely unknown.
- Understanding these mechanisms is crucial for developing targeted prevention and treatment strategies.
Purpose of the Study:
- To identify proteomic signatures associated with heart failure (HF) in individuals with diabetes.
- To uncover novel protein markers that specifically predict HF risk in the context of diabetes.
- To explore the underlying biological pathways involved in diabetes-related HF.
Main Methods:
- Utilized a large cohort (ARIC study) of 10,189 participants, including those with and without diabetes, to discover protein-HF associations.
- Employed Cox regression analysis to identify plasma proteins linked to HF, stratified by diabetes status.
- Performed internal validation within the ARIC study and external validation using the MESA study cohort to confirm findings.
- Conducted pathway analyses to understand the biological functions of identified proteins.
Main Results:
- Identified 19 proteins associated with HF in individuals with diabetes in the discovery phase.
- Validated 6 proteins in an independent cohort, with 5 proteins specifically associated with HF in the diabetes subgroup.
- Four novel proteins (tyrosine-protein kinase 7, chondroadherin, LRRIG1, fibulin-5) and one known protein (CLIP2) were uniquely linked to HF risk in diabetes.
- Pathways implicated included lipid metabolism, inflammation, and brown adipose tissue function.
Conclusions:
- Discovered five proteomic markers, four of which are novel, that are uniquely associated with heart failure risk in individuals with diabetes.
- These findings provide new insights into the specific molecular mechanisms underlying heart failure in the diabetic population.
- The identified novel markers may serve as potential biomarkers for early detection or therapeutic targets for diabetes-related heart failure.
Background:
To investigate the proteomic signatures of heart failure (HF) in diabetes. The underlying mechanisms of the elevated risk of HF in diabetes are unknown.
Methods:
In 10 189 ARIC study (Atherosclerosis Risk in Communities) participants free of HF (mean age 57±7 years, 56% women, 22% Black adults, 14% with diabetes), we conducted discovery and internal validation for the associations of 4955 plasma proteins with HF by diabetes status. We performed (1) Cox regression to identify proteins associated with HF by diabetes status, (2) external validation in the MESA study (Multi-Ethnic Study of Atherosclerosis, n=5233, 633 with diabetes), and (3) pathway analyses for identified proteins.
Results:
Over 24 years in ARIC, there were 2417 HF events (605 among individuals with diabetes). In 993 individuals with diabetes in the discovery sample, 19 proteins were associated with HF (P<10-5), 12 proteins replicated in the internal validation sample (P<0.05/19). Six of the internally validated proteins replicated in MESA (false discovery rate, q<0.05). Five proteins were specifically associated with HF in those with diabetes: 4 are novel (inactive tyrosine-protein kinase 7, chondroadherin, leucine-rich repeat, and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 and fibulin-5) and 1 is the previously known (cartilage intermediate layer protein 2). NPPB (N-terminal pro-BNP) was associated with HF in those with and without diabetes. Pathways over-represented among proteins associated with diabetes-related HF were lipid metabolism, inflammation, and brown adipose tissue (false discovery rate, q<0.05).
Conclusions:
We identified 5 proteomic markers (4 novel) uniquely related to HF risk among individuals with diabetes and not among those without diabetes.
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