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J Hypertens. Author manuscript; available in PMC 2017 July 01. Published in final edited form as: J Hypertens. 2016 July ; 34(7): 1266–1272. doi:10.1097/HJH.0000000000000936.

SERUM FIBROBLAST GROWTH FACTOR-23 AND INCIDENT HYPERTENSION: THE ATHEROSCLEROSIS RISK IN COMMUNITIES STUDY Amber L. FYFE-JOHSNON1, Alvaro ALONSO1, Elizabeth SELVIN2,3, Julie K. BOWER4, James S. PANKOW1, Sunil K. AGARWAL5, and Pamela L. LUTSEY1

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1Division

of Epidemiology and Community Health, School of Public Health, University of Minnesota

2Department

of Epidemiology, Johns Hopkins Bloomberg School of Public Health

3Welch

Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health

4Division

of Epidemiology, College of Public Health, Ohio State University

5Division

of Cardiology, Icahn School of Medicine at Mount Sinai

Abstract Author Manuscript Author Manuscript

Elevated serum fibroblast growth factor-23 (FGF23), an endogenous hormone, is associated with disturbed mineral homeostasis, cardiovascular disease, and chronic kidney disease. It is unclear whether FGF23 impacts the development of incident hypertension. We investigated the association of serum FGF23 measured at baseline (1990–92) with incident hypertension at two follow-up visits (1993–95 and 1996–98) in 7,948 middle-aged men and women without hypertension at baseline participating in the Atherosclerosis Risk in Communities Study. Incident hypertension was determined by measured blood pressure (DBP ≥ 90 mm Hg, or SBP ≥ 140 mm Hg) and/or self-reported hypertension medication use at follow-up exams. Complementary log-log models that accounted for interval censoring were used to model the association between FGF23 and incident hypertension. During a median follow-up of 5.9 years, 27% (2,152/7,948) participants developed hypertension. A nonlinear association between serum FGF23 and incident hypertension was observed; only persons in the highest decile of serum FGF23 had an increased risk of incident hypertension. After adjustment for demographics, behaviors, and adiposity the hazard ratio for incident hypertension was 1.24 (95% CI: 1.11, 1.39) for the highest decile of FGF23 compared to the lowest quintile. The association was further attenuated in the final model after adjusting for renal function (hazard ratio: 1.21, 95% CI: 1.08, 1.35). In conclusion, high levels (≥ 60.6 pg/mL) of FGF23 are associated with a modestly increased risk of incident hypertension in the general population, independent of kidney function.

Corresponding Author: Amber L. Fyfe-Johnson, ND, Postdoctoral Research Fellow, [email protected], Phone: 612.626.2273, Fax: 612.624.0315, 1300 South 2nd St, Suite 300, Minneapolis, MN 55455. Previous presentations: AHA EPI/Lifestyle 2014, poster presentation Conflicts of interest: None

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Keywords Fibroblast growth factors; fibroblast growth factor-23; hypertension; Atherosclerosis Risk in Communities Study; risk factors

INTRODUCTION

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Approximately 78 million Americans adults have hypertension1; the age-adjusted prevalence approaches 65–75% among persons aged 65 years or older.2,3 Hypertension frequently underlies cardiovascular disease; evidence suggests that hypertension is present in 69% of adults with incident myocardial infarction, 77% with incident stroke, and 74% diagnosed with incident heart failure.1,3 Development of hypertension occurs in conjunction with, (i) the inability of the renal system to maintain mineral homeostasis, and (ii) changes in cardiac and vascular structure.4

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Fibroblast growth factor-23 (FGF23) is a protein produced by osteocytes and osteoblasts. It is principally involved in kidney function and mineral metabolism;5,6 elevated levels have been linked to cardiovascular morbidity and mortality in both the general population7–9 and those with chronic kidney disease.10–12 It is unclear whether FGF23 impacts the development of hypertension, and if so whether the biological mechanism involves mineral metabolism, changes to cardiac or vascular structure, or another explanation. Recent work demonstrates that elevated FGF23 is associated with mineral homeostasis disruption, plasma volume, and hypertension in animal models.13,14 Importantly, in individuals with normal kidney function, FGF23 is a risk factor for mortality, heart failure, and cardiovascular disease events.15,16 Therefore, it appears that FGF23 may have cardiovascular consequences in conjunction with and independent of mineral metabolism. The objective of the current study was to evaluate the association between FGF23 and incident hypertension in the prospective, community-based Atherosclerosis Risk in Communities (ARIC) Study. We hypothesized that elevated serum FGF23 would be positively associated with risk of incident hypertension independent of traditional cardiovascular (CVD) risk factors in the ARIC cohort.

METHODS Study Population

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The Atherosclerosis Risk in Communities (ARIC) Study is a longitudinal prospective cohort study initiated in 1987–89. Originally, 15,792 men and women ages 45–64 years of age were recruited from 4 U.S. communities: Minneapolis suburbs, Minnesota; Jackson, Mississippi; Washington County, Maryland; and Forsyth County, North Carolina.17 Five follow-up visits were conducted: visit 2 (1990–92), visit 3 (1993–95), visit 4 (1996–98), and visit 5 (2011– 13). FGF23 was first measured at visit 2, thus visit 2 is baseline for the present analysis. Of the 14,348 participants attending visit 2, we excluded participants with prevalent hypertension (defined as measured systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg and/or self-reported antihypertensive medication use) at visit 2 (n=5,163), individuals who were neither African American nor white, and African J Hypertens. Author manuscript; available in PMC 2017 July 01.

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Americans from the Minnesota and Maryland centers due to small sample sizes (n=91), individuals with FGF23 values >200 pg/mL (n=12) or missing FGF23 values (n=751), and those missing hypertension classification at visits 3 and 4 (n=383). Our final sample size was 7,948 observations. No exclusions were made for missing covariates. Written informed consent was collected from all study participants; all affiliated institutional review boards approved the study protocol. FGF23 and other covariates

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FGF23—All participants were instructed to fast overnight prior to blood specimen collection at study visit 2 (1990–92). Blood samples were processed, shipped, and stored at −70°C until laboratory assays were performed.17 In 2012–2013, intact serum FGF23 was measured in stored specimens collected at ARIC visit 2 by enzyme-linked immunosorbent assay (Kainos Laboratories, Inc., Tokyo, Japan). Serum samples were incubated in microtiter plates previously coated with a capture antibody. A detection antibody was then added to form a sandwich complex between serum FGF23 that had bound to the detection antibody on the plate. The microtiter plate was then washed and incubated with a tetramethylbenzidine substrate solution. Finally, a spectrophotometric plate reader determined the optical density of each well and sample intact FGF23 concentrations were calculated from a standard curve. The inter-assay (process) coefficient of variation for FGF23 based on ARIC blind duplicate samples (split-specimens collected at the time of blood draw) was 16.6% and the coefficient of variation from internal laboratory quality control samples was 8.8%; internal lab quality control was based on a standard blood pool which had a serum FGF23 concentration of 41.4 pg/ml. Blind duplicates were performed over the full range of ARIC participants.

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Self-reported variables—Questionnaires were administered to all participants at each ARIC visit. Age, sex, and race were determined based on self-report. Education was categorized as less than a high school diploma, a high school diploma, or beyond a high school diploma; physical activity was calculated using the Baecke questionnaire for sports during leisure time (both carried forward from visit 1).18 Smoking status and alcohol intake were categorized as current, former, or never users.

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Objectively measured variables—Body mass index (kg/m2) and waist-to-hip ratio (cm) were calculated from objective height (meters), weight (kg), and girth of waist and hip (cm) collected by trained ARIC study staff using standardized protocols.17 High-density lipoprotein cholesterol (HDL, mg/dL), low-density lipoprotein cholesterol (LDL, Friedewald equation, mg/dL),19 and triglycerides (mg/dL) were measured as previously reported.17 High-sensitivity C-reactive protein, parathyroid hormone, phosphorous, sodium, and calcium were measured in 2012–2013 in stored visit 2 serum (all mg/dL, Roche Diagnostics, Indianapolis, IN). Cystatin C was measured using a Roche Modular P Chemistry analyzer and Gentian cystatin C reagent; serum creatinine was determined using a modified kinetic Jaffé reaction. Kidney function (estimated glomerular filtration rate; eGFR) was derived using the CKD-EPI 2012 equation which incorporates both creatinine and cystatin C20. We modeled eGFR in two ways: continuously ml/min/1.73m2 and categorically as ≥90, ≥60 to

Serum fibroblast growth factor-23 and incident hypertension: the Atherosclerosis Risk in Communities (ARIC) Study.

Elevated serum fibroblast growth factor-23 (FGF23), an endogenous hormone, is associated with disturbed mineral homeostasis, cardiovascular disease, a...
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