Cytokines, C-Reactive Protein, and Risk of Incident Hypertension in the REGARDS Study

Abstract

Background: Hypertension is a highly prevalent cardiovascular disease risk factor that may be related to inflammation. Whether adverse levels of specific inflammatory cytokines relate to hypertension is unknown. The present study sought to determine whether higher levels of IL (interleukin)-1β, IL-6, TNF (tumor necrosis factor)-α, IFN (interferon)-γ, IL-17A, and CRP (C-reactive protein) are associated with a greater risk of incident hypertension.

Methods: The REGARDS study (Reasons for Geographic and Racial Difference in Stroke) is a prospective cohort study that recruited 30 239 community-dwelling Black and White adults from the contiguous United States in 2003 to 2007 (visit 1), with follow-up 9 years later in 2013 to 2016 (visit 2). We included participants without prevalent hypertension who attended follow-up 9 years later and had available laboratory measures and covariates of interest. Poisson regression estimated the risk ratio of incident hypertension by level of inflammatory biomarkers.

Results: Among 1866 included participants (mean [SD] aged of 62 [8] years, 25% Black participants, 55% women), 36% developed hypertension. In fully adjusted models comparing the third to first tertile of each biomarker, there was a greater risk of incident hypertension for higher IL-1β among White (1.24 [95% CI, 1.01-1.53]) but not Black participants (1.01 [95% CI, 0.83-1.23]) and higher TNF-α (1.20 [95% CI, 1.02-1.41]) and IFN-γ (1.22 [95% CI, 1.04-1.42]) among all participants. There was no increased risk with IL-6, IL-17A, or CRP.

Conclusions: Higher levels of IL-1β, TNF-α, and IFN-γ, representing distinct inflammatory pathways, are elevated in advance of hypertension development. Whether modifying these cytokines will reduce incident hypertension is unknown.

Keywords: C-reactive protein; biomarkers; cytokines; hypertension; inflammation; prospective studies.

Figure 1.

Inclusion flowchart. Counts are unweighted except where specified. Missing dietary scores were assigned a value of poor and are not considered missing in this flowchart. BioMedioR indicates Biomarkers as Mediators of Racial Disparities in Risk Factors; BMI, body mass index; BP, blood pressure; CRP, C-reactive protein; IFN, interferon; IL, interleukin; and TNF, tumor necrosis factor.

Figure 2.

Distribution of cytokines and CRP (C-reactive protein) at baseline. Density histograms. IL (interleukin)-1β was undetectable in 24.7% of the sample (25.9% of Black and 24.4% of White participants) and was assigned a value of 0.0090 for purpose of this histogram. IL-1β was race stratified because of an IL-1β–race interaction on incident hypertension. IL-17A is sex-stratified because of an IL-17A–sex interaction on incident hypertension. CRP indicates C-reactive protein; IFN, interferon; and TNF, tumor necrosis factor.

Figure 3.

Relative risk (RR) of incident hypertension by level of cytokines and CRP (C-reactive protein). RR is relative risk of incident hypertension in each model. P value represents a linear P test across tertiles. The base model is unadjusted. Model 1 is adjusted for age, sex, race, and systolic blood pressure (SBP). Model 2 adds education and income to model 1. Model 3 adds body mass index (BMI) and waist circumference to model 1. Model 4 adds exercise intensity, alcohol use, smoking status, prevalent diabetes, and diet to model 1. Model 5 combines all covariates in models 1 to 4. DM indicates diabetes mellitus; IFN, interferon; IL, interleukin; and TNF, tumor necrosis factor.