Interleukin‐8 (IL‐8) as a Potential Mediator of an Association Between Trimethylamine N‐Oxide (TMAO) and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) among African‐Americans at Risk for Cardiovascular Disease

Abstract

Trimethylamine N‐Oxide (TMAO) is a microbial metabolite derived from the hepatic‐gut axis and linked to inflammation and cardiovascular disease (CVD). Studies have shown that TMAO is linked to CVD and its risk factor hyperlipidemia by enhanced macrophage foam cell formation or alterations in reverse cholesterol transport. Other mechanisms have not been reported to date. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is a largely hepatic expressed protein that blocks Low Density Lipoprotein (LDL) receptor recycling, leading to hyperlipidemia. The primary objective of this study was to investigate a potential relationship between TMAO and PCSK9 in order to explore a novel mechanism linking TMAO and CVD risk. We hypothesized that TMAO and PCSK9 would have a direct association among a sample of African American adults, a population at increased risk for CVD, and that this relationship would be mediated by inflammatory cytokines.African‐American adults at risk for CVD living in the Washington, DC area were recruited to participate in a cross‐sectional community‐based study that involved clinical examination and collection of fasting blood samples. Serum samples were analyzed for clinical CVD risk factors. Fasting levels of inflammatory cytokines (interleukin (IL)‐1 beta, tumor necrosis factor‐alpha, and interleukin‐8), TMAO, and PCSK9 were measured using Luminex and ELISA, respectively. Univariate and multivariate linear regression analyses and structural equation mediation analyses were conducted using STATA. All models were adjusted for body mass index (BMI) and atherosclerotic CVD risk score (ASCVD).The participant sample (n = 60) included a majority of self‐identified African‐American women (93.33%), who presented as obese (Mean BMI = 33). A significant association between TMAO and PCSK9 was identified in both unadjusted (β = 0.30, p = 0.02) and adjusted (β = 0.31, p =0.02) models. Both TMAO and PCSK9 were significantly associated with IL‐8 (TMAO: β = 0.45, p = 0.00; PCSK9: β = 0.23, p = 0.05) in adjusted models. Mediation analysis indicated that 34.77% of the relationship between TMAO and PCSK9 was explained by IL‐8 (Figure 1).Our findings indicate a potential PCSK9 involved pathway for TMAO and CVD risk. Furthermore, our results suggest this pathway is mediated by the inflammatory cytokine, IL‐8. Future studies may identify the role of dietary or stress‐related factors that could increase IL‐8 and potentially influence the TMAO‐PCKSK9 relationship.