Abstract P192: Integrative Analysis of Extracellular Molecular Profiles Associated With Cardiovascular Health in Black Americans: Results From the Morehouse-Emory Cardiovascular (MECA) Center for Health Equity
Authors: Islam Shabatun , Mohandas Appesh N , Liu Chang , Jones Kia , Rooney Kimberly , Ko Yi-An , Kim Jeong Hwan , Topel Matthew L , Dunbar Sandra B , Lewis Tene T , Taylor Herman A , Jones Dean , uppal karan , QUYYUMI Arshed A , Searles Charles D 
Published: March 2020

Introduction:
While cardiovascular disease (CVD) morbidity and mortality is particularly pronounced among Black Americans, there is a great deal of intra-racial heterogeneity within the population. Our objective was to identify novel circulating biomarkers (extracellular miRNA and metabolites) that predict cardiovascular health (CVH) within Blacks, while providing insight into CVD pathophysiology.

Hypothesis:
We hypothesize that an integrative analysis of miRNA and metabolomics profiles will enable a systems biology approach to understanding CVH as defined by the American Heart Association's Life’s Simple 7 (LS7) score within Blacks.

Methods:
Platelet free plasma (PFP) was collected from 382 Black adults (age 53
+
10, 40% male) without known CVD living in Atlanta, GA. CVH was determined by LS7 scores calculated from measured blood pressure, blood glucose, cholesterol, body mass index (BMI), and self-reported exercise, diet, and smoking. In the discovery phase, next generation sequencing was performed on PFP samples from 20 participants with low CVH (LS7
<
6) and 20 with high CVH (LS7
>
10). DESeq was used to identify differentially expressed miRNAs. In the validation phase, RT-qPCR was used to assess levels of eight miRNAs in 382 samples. Spearman correlation and linear regression analyses were performed to assess ability of miRNA levels to predict LS7. High-resolution metabolomics profiling was performed on all 382 samples. Integrative analysis of miRNA, metabolomics profiles, and clinical domains of CVH (LS7) was performed using the program xMWAS to determine connectivity among these markers.

Results:
RNA sequencing identified 13 extracellular miRNAs differentially expressed between low CVH and high CVH (FDR < 0.05). Analysis of data from validation phase found the expression of four extracellular miRNAs (miRs-122, -150, -30c, -769-3p) significantly correlated with LS7. Metabolome wide association study (MWAS) identified 141 features that were differentially expressed between low and high CVH with false discovery rate of <0.2: 54 features were lower in low LS7, and 87 were higher in low LS7. These metabolomics features were enriched in 19 metabolic pathways, including glutathione metabolism, alanine and aspartate metabolism, and methionine and cysteine metabolism. Integrative analysis revealed 6 clusters in which differentially expressed miRNAs, metabolites and clinical domains of CVH were connected.

Conclusions:
CVH in Blacks is associated with distinct extracellular miRNA and metabolomics profiles, and these molecular profiles are associated with pathways linked to vascular dysfunction. Integrative analysis revealed connectivity between miRNA-metabolome networks and clinical domains of CVH. This novel method represents an unique opportunity to gain insights into epigenetic and environmental influences on CVD disparities.