There is a disproportionate burden of cardiometabolic disease and chronic kidney disease (CKD) among African Americans (AA), but the responsible environmental and/or genetic mechanisms are incompletely defined. Quantitation of selected plasma proteins is clinically valuable, and new findings presented here argue strongly that broadening the array of proteins analyzed can provide new insight into pathogenesis and offer novel markers of disease risk and events. To address important knowledge gaps, we propose to analyze an unprecedented array of proteins in plasma samples of AA in the Jackson Heart Study (JHS) and the Southern Community Cohort Study (SCCS). We will test the overall hypothesis that proteomic profiling in well- phenotyped cohorts will identify new pathogenic pathways of particular importance in AA.
In Specific Aim 1, we propose cross-sectional studies to identify novel proteomic biomarkers of cardiometabolic and renal traits.
In Specific Aim 2, we will assess whether baseline plasma protein concentrations predict incident coronary heart disease (CHD) and CKD.
For Specific Aims 1 and 2 the JHS will be the discovery cohort; cross-sectional and longitudinal findings will be clinically validated in the SCCS.
In Specific Aim 3, we will use GWAS, exome sequence, and whole genome sequence to explore the genetic determinants of proteins that are associated with cardiometabolic disease and CKD, and will test whether variants that are associated with protein levels predict incident CHD and CKD in large meta-analyses. We will leverage a powerful new analytic platform in which single-stranded DNA molecules called aptamers have been modified to have high avidity and specificity for an array of 1,310 targeted plasma proteins. The aptamers bind in proportion to each protein's concentration, and are released and quantified by fluorescence, using microarrays. We present extensive experimental validation of these analyses including orthogonal validation by liquid chromatography-mass spectrometry. Our multi-disciplinary team at the JHS, BIDMC, Broad Institute, and Vanderbilt University brings expertise in proteomics, biomarkers, genetic and population epidemiology, bioinformatics, and health disparities. All data will be made publically available, providing a unique and valuable resource to the scientific community.
There is a disproportionate burden of metabolic, cardiovascular, and renal disease among African Americans, but the responsible environmental and/or genetic mechanisms are incompletely defined. We will use powerful new techniques to study blood plasma, seeking proteins that indicate disease risk or provide hints regarding disease mechanisms. These studies may lead to earlier treatment and to the development of new medicines.
|Benson, Mark D; Yang, Qiong; Ngo, Debby et al. (2018) Genetic Architecture of the Cardiovascular Risk Proteome. Circulation 137:1158-1172|
|Jacob, Jaison; Ngo, Debby; Finkel, Nancy et al. (2018) Application of Large-Scale Aptamer-Based Proteomic Profiling to Planned Myocardial Infarctions. Circulation 137:1270-1277|