Abstract 13944: Biracial Proteomic Profiling Reveals Novel Candidate Pathways in Left Ventricular Hypertrophy and Incident Heart Failure Specific to Black Individuals

Abstract

Background: Increased left ventricular (LV) mass is associated with future adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect black individuals. To understand the mechanisms that drive disease, particularly in black individuals, we undertook a proteomic screen in a black cohort and compared it to a white cohort. Methods: We measured 1305 plasma proteins using an aptamer-based proteomic platform (SOMAscan™) in 1772 black participants in the Jackson Heart Study (JHS) with available baseline LV mass as assessed by 2D echocardiography, as well as 1600 free of HF with follow-up assessment of incident cases. Mean follow-up time was 11 years; 152 cases of incident HF hospitalization were identified. Models were adjusted for age, sex, body mass index, estimated glomerular filtration rate (as calculated by CKD-EPI equation), systolic blood pressure, hypertension treatment, presence of diabetes, total/HDL cholesterol, prevalent coronary disease, and current smoking status. Incident HF models were also adjusted for incident coronary heart disease. We then compared protein associations in JHS to those observed in whites from the Framingham Heart Study (FHS) to examine significant differences. Results: In JHS, there were 112 proteins associated with LV mass and 10 proteins associated with incident HF hospitalization with FDR <5%. Several proteins showed expected associations with both LV mass and HF, including N-terminal pro-BNP (β = 0.04 [0.02, 0.05], p = 1.0 x 10 -8 , HR = 1.46 [1.20, 1.79], p = 0.0002). The strongest association with LV mass was more novel: leukotriene A4 hydrolase (LKHA4) (β = 0.05 [0.04, 0.06], p = 2.6 x 10 -15 ). Conversely, Fractalkine/CX3CL1 showed a novel association with incident HF (HR = 1.32 [1.14, 1.54], p = 0.0003). While proteins like Cystatin C and N-terminal pro-BNP showed consistent effects in FHS, LKHA4 and Fractalkine were significantly different. Conclusions: We identify several novel biological pathways specific to black individuals hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and Fractalkine. Further studies are needed to validate these results and elucidate the detailed underlying mechanisms.

Linking Genetics and Proteomics: Gene-Protein Associations Built on Diversity

“…Leveraging the full diversity of the human pool will help associate genetic variants with the full spectrum of transcriptomic, proteomic, and ultimately phenotypic variation. Katz et al 7 in this issue of Circulation filled a scientific gap in that they associated whole genome sequence with plasma proteomes from the Black population, revealing that about a quarter of significant associations were missed so far. CV indicates cardiovascular; and SNP, single nucleotide polymorphism.…”

“…An article in this issue of Circulation contributes to mapping the Black map of genome-proteome associations. 7 Katz and colleagues integrated whole genome DNA sequencing and proteomic profiling of ≈1300 proteins in the plasma of individuals of Black descent. They report 569 associations between genomic variants and plasma proteins that reach a Bonferroni-adjusted significance level.…”

“…They report 569 associations between genomic variants and plasma proteins that reach a Bonferroni-adjusted significance level. 7 One in 3 proteins found in the plasma was quantitatively modulated by genetic variants, of which about two-thirds were in cis , ie, in the vicinity of respective genes, and one-third was in trans . 7 Overall, about a third of the variability of plasma protein concentrations was found the be partially heritable on the basis of the 28 million genomic variants studied.…”

“…7 One in 3 proteins found in the plasma was quantitatively modulated by genetic variants, of which about two-thirds were in cis , ie, in the vicinity of respective genes, and one-third was in trans . 7 Overall, about a third of the variability of plasma protein concentrations was found the be partially heritable on the basis of the 28 million genomic variants studied. In this respect, Sun et al had previously reported a far lower heritability (8%).…”

“…A variant at the APOL1 locus, rs73885319, was found to have a minor allele frequency of 23% in the Black population, whereas the variant is not present in individuals of European ancestry. In addition to being associated with levels of APOL1, Katz et al 7 observed the sentinel single nucleotide polymorphism at this locus also determines plasma levels of CKAP2 (cytoskeleton-associated protein 2), which has been linked to tumor formation and renal tubular necrosis. 6…”