Biomedical subjects

James S Floyd

Publications and source records attributed to James S Floyd.

5 recordsLinked to original sources

PubMed2026

A validated, modifiable proteomic score from the EXSCEL trial predicts cardiovascular events in diabetes.

BACKGROUNDAdults with type 2 diabetes mellitus (T2DM) are at increased risk for stroke, myocardial infarction, and cardiovascular death, yet individual risk is heterogeneous and incompletely captured by clinical models.METHODSIn the Exenatide Study of Cardiovascular Event Lowering (EXSCEL), adults with T2DM were randomized to a GLP-1 RA (exenatide) or a placebo and followed longitudinally for major adverse cardiovascular events (MACE). High-throughput discovery proteomics was done in plasma collected at baseline and 12 months. Proteins associated with time to MACE were identified using multivariable regression and incorporated into supervised machine learning models. A multi-protein score was developed and externally validated in 2 independent population-based and trial cohorts.RESULTSThe proteomic score showed incremental improvement in cardiovascular risk discrimination beyond clinical factors alone, and several proteins were consistently prioritized across modeling approaches. The protein score and a top-ranked protein, tetranectin, were modified by GLP-1 RA treatment, and a decrease in protein score was associated with improved outcomes, supporting modifiability of MACE risk.CONCLUSIONExternal validation confirmed generalizability across cohorts with and without diabetes. Together, these findings demonstrate that plasma proteomic signatures can enhance cardiovascular risk stratification and identify treatment-responsive biomarkers in T2DM, supporting their potential role in precision prevention strategiesFUNDINGThe EXSCEL study was funded by Amylin Pharmaceuticals. This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006, and grants R01HL146145, U01HL080295, U01HL130114, R01HL172803, and R01HL144483 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by R01AG023629 from the National Institute on Aging.

Aged↗

PubMed2026

Proteomic pathways mediating low socioeconomic status and cardiovascular events in older adults in CHS and ARIC.

BACKGROUND AND AIMS: Many studies have linked socioeconomic status (SES) and cardiovascular outcomes, yet the biologic mechanisms mediating these associations are only partially understood. The objective of this study was to identify molecular mediators of the association of low SES with coronary heart disease (CHD) and stroke. METHODS: This research was conducted in 2942 Black and White adults in the Cardiovascular Health Study (mean age 76.2 years) and 10,689 Black and White adults in the Atherosclerosis Risk in Communities Study (mean age 60.0 years). We used factor analysis to create a composite measure of low educational attainment, low-income, and blue-collar occupation. Approximately 5000 proteins were measured with an aptamer-based method, and CHD and stroke events were adjudicated. Results were stratified by race, which was conceptualized as a social factor. RESULTS: Low SES was associated with 44 and 262 proteins, in Black and White adults, respectively. No protein met the Bonferroni adjusted threshold for statistically significantly mediation among Black participants. Among White participants, 23 proteins mediated the association between SES adversity and CHD and 5 mediated the association between SES adversity and stroke. The strongest mediating associations for CHD included PTPRS, SCG3, and MMP12. The strongest mediating associations for stroke included NCAN, FAM20B, and APLP1. SPARCL1 and CDCP1 remained the strongest mediators of the association between SES adversity and CHD, after adjusting for potential confounders and traditional cardiovascular risk factors. CONCLUSION: We identified several biomarkers that characterize the biologic risk of SES adversity on CHD and stroke.

Aged↗

PubMed2026

Proteomics Analysis of Plasma for Risk of Sepsis: Findings from the Atherosclerosis Risk in Communities Study.

BACKGROUND: Sepsis is a life-threatening complication of infection with high mortality. A high-throughput analysis of circulating blood proteins may provide mechanistic insight and potent therapeutic targets for the prevention of sepsis. METHODS: We used multivariable Cox regression analysis to examine the association of 4955 plasma proteins, measured by SomaScan, with the risk of incident sepsis among 11 065 participants of the Atherosclerosis Risk in Communities (ARIC) Study (visit 3 in 1993 to 1995; mean age, 60.1 years, 54.4% female, 21.0% Black). Proteins (false discovery rate [FDR] of P < 0.05) discovered at visit 3 were replicated using data at visit 5 (n = 4869 in 2011 to 2013: mean age, 75.5 years) and in the Cardiovascular Health Study (CHS) (n = 3512 in 1992 to 1993; mean age, 74.5 years). Canonical pathways were identified by enrichment analyses. RESULTS: At ARIC visit three, 669 proteins were associated with the risk of sepsis; 175 were replicated at visit 5. Of these, 90 were validated in the CHS. The top 20 proteins ranked by P value were relevant to acute inflammatory signaling in innate immunity. Pathway analyses implicated activation of pro-inflammatory pathways (e.g., cytokine storm signaling) as well as inhibition of anti-inflammatory pathways (e.g., liver X receptor/retinoid X receptor [LXR/RXR] activation), which also play relevant roles in lipid metabolism. CONCLUSIONS: In this analysis, levels of acute inflammatory proteins measured during routine visits were associated with the subsequent incidence of sepsis. An increased risk of sepsis associated with the inhibition of anti-inflammatory pathways, such as LXR/RXR warrants further mechanistic investigation.

Humans↗

PubMed2026

Plasma proteomics and incident coronary heart disease.

BACKGROUND: Systematic profiling of plasma proteins in population studies offers a complementary approach to discovery of novel risk factors and may provide new insights into the causes of coronary heart disease. METHODS: To explore relationships between the circulating proteome and coronary heart disease (CHD), we evaluated associations of 4780 plasma proteins with incident CHD in the Cardiovascular Health Study (CHS, N=2856, 575 CHD events) and replicated significant associations in the Atherosclerosis Risk in Communities Study (ARIC, N = 10456; 1375 events). RESULTS: We find that 11 proteins significantly associate with incident CHD after adjusting for risk factors; and eight significantly replicated in ARIC. Several proteins correlate with carotid intimal medial thickness and CHD associations are attenuated in participants without subclinical atherosclerosis. Macrophage metalloelastase (MMP12) is the strongest observed association (Hazard Ratio, 1.31; 95% Confidence Interval, 1.19-1.44). Mendelian randomization (MR) identifies a causal relationship between higher MMP12 and lower CHD (Odds Ratio, OR 0.94) and ischemic stroke (OR 0.90) risk, while reverse MR found that genetic propensity to CHD increased MMP12. Taken together, multivariable MR confirms a direct protective effect of higher plasma MMP12 on CHD risk and a genetic effect of atherosclerosis and CHD on elevating MMP12. CONCLUSIONS: Proteomic analyses reveal associations with incident CHD and genomic evidence suggests that therapeutic MMP12 inhibition may confer adverse cardiovascular effects.

Journal Article↗

PubMed2025

Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants.

BACKGROUND: Genome-wide association studies have identified several hundred susceptibility single nucleotide variants for coronary artery disease (CAD). Despite single nucleotide variant-based genome-wide association studies improving our understanding of the genetics of CAD, the contribution of structural variants (SVs) to the risk of CAD remains largely unclear. METHOD AND RESULTS: We leveraged SVs detected from high-coverage whole genome sequencing data in a diverse group of participants from the National Heart Lung and Blood Institute's Trans-Omics for Precision Medicine program. Single variant tests were performed on 58 706 SVs in a study sample of 11 556 CAD cases and 42 907 controls. Additionally, aggregate tests using sliding windows were performed to examine rare SVs. One genome-wide significant association was identified for a common biallelic intergenic duplication on chromosome 6q21 (P=1.54E-09, odds ratio=1.34). The sliding window-based aggregate tests found 1 region on chromosome 17q25.3, overlapping USP36, to be significantly associated with coronary artery disease (P=1.03E-10). USP36 is highly expressed in arterial and adipose tissues while broadly affecting several cardiometabolic traits. CONCLUSIONS: Our results suggest that SVs, both common and rare, may influence the risk of coronary artery disease.

Humans↗