Elevated serum fibroblast growth factor 21 is associated with hypertension in community-dwelling adults

Abstract

Fibroblast growth factor 21 (FGF21), a recently discovered endocrine factor, plays an important role in glucose and lipid metabolism and may contribute to the development of atherosclerosis and coronary heart disease. The present cross sectional study examined the relationship of FGF21 with hypertension in 744 community-dwelling adults who participated in the Baltimore Longitudinal Study of Aging.

Fibroblast growth factor 21 (FGF21) is a recently discovered hormone that has been implicated in abnormal glucose metabolism, insulin resistance, and dyslipidemia in adults.^1,2 FGF21 is a member of the family of fibroblast growth factors (FGF), but is atypical in that it lacks a heparin-binding domain, which allows FGF21 to leave the tissues of origin and circulate freely as an endocrine factor. FGF-21 is expressed in the liver, white adipose tissue and the pancreas. FGF21 binds to the cell surface receptor FGFR complex formed with β-klotho to stimulate glucose uptake in adipocytes.^1,2 In animal models, systemic administration of FGF21 increases energy expenditure, reduces body weight, and improves lipid profiles by lowering LDL cholesterol and increasing HDL cholesterol.^1,2

In contrast to the observations in animal models, in humans, elevated circulating FGF21 is associated with the metabolic syndrome,³ and dyslipidemia,⁴ which suggests that FGF21 expression might be dysregulated due to abnormalities in FGF21 secretion or circulating FGF21 isoforms, or FGF21 resistance in peripheral tissues. In adults without diagnosed diabetes, elevated plasma FGF21 is associated with abnormal glucose metabolism, insulin resistance, and reduced whole body insulin sensitivity.⁵ In adults with type 2 diabetes, elevated FGF21 is associated with the presence of carotid artery plaques.⁶ The combination of dyslipidemia and hypertension is associated with an increased risk of atherosclerosis and cardiovascular disease. The underlying causes of hypertension include abnormalities in the renin-angiotensin system, dysregulation in sodium handling, and genetic predisposition, but much of the basic pathophysiology remains obscure.⁷ In obese women, elevated FGF21 was associated with increased arterial stiffness, as measured by brachial-ankle pulse wave velocity.⁸ Arterial stiffness and hypertension have been shown to have a bidirectional association.⁹ The relationship of circulating FGF21 with hypertension has not been characterized. Our previous investigations suggested an association between FGF21 and hypertension, but these findings were preliminary.⁵ We hypothesized that serum FGF21 is independently associated with hypertension and that FGF21 may be related to hypertension through dyslipidemia. To address this hypothesis, we investigated the relationship of FGF21 with hypertension in community-dwelling adults.

The study subjects consisted of participants in the Baltimore Longitudinal Study of Aging (BLSA) who were seen between April 2002 and August 2007. The BLSA is a prospective open cohort study of community-dwelling volunteers, largely from the Baltimore/Washington area. The study was established in 1958 and is described in detail elsewhere.¹⁰ BLSA participants return every two years to the Gerontology Research Center in Baltimore, Maryland, for 2.5 days of medical, physiological, and psychological examinations. Height was measured to the nearest 0.5 cm. Weight was measured to the nearest 0.1 kg. Body mass index (BMI) was calculated as kg/m². Smoking status was ascertained by a questionnaire that classified each subject as a non-smoker, former smoker, or current smoker. Diagnosis of hypertension was based upon self-report of physician diagnosis of hypertension and corroboration with current treatment (diuretics, antihypertensive medications) or blood pressure >140/90 mm Hg. Metabolic syndrome was defined according to recent consensus criteria.¹¹ The BLSA has continuing approval from the Institutional Review Board (IRB) of the MedStar Research Institute. The protocol for the present study was also approved by the IRB of the Johns Hopkins School of Medicine.

Blood samples were drawn from the antecubital vein between 7 and 8 AM after an overnight fast. Serum creatinine, glucose, cholesterol, and triglycerides were measured as described elsewhere.⁵ Chronic kidney disease (stage 3) and fasting plasma glucose were categorized as described elsewhere.⁵ Samples were stored continuously at −70° C until the time of analysis of serum FGF21. Serum FGF21 was measured using ELISA (Quantikine Human FGF-21 ELISA, R & D Systems, Minneapolis, MN). The samples were analyzed at Johns Hopkins Hospital in the laboratory of one of the investigators (R.D.S.). The intra-assay and inter-assay coefficients of variability were 2.8% and 7.0%. The assay has a minimum limit of detection of 4.6 pg/mL. No samples were below the lower limit of detection.

Continuous variables were reported as median (25^th, 75^th percentile). Serum FGF21 was highly skewed and log-transformed to obtain a normal distribution. Multivariate logistic regression models were used to examine the relationship of log serum FGF21 (per 1 standard deviation [SD]), demographic, anthropometric, and clinical characteristics with hypertension. Covariates included in the multivariable models were traditional risk factors for hypertension (age, race, smoking, body mass index). Diabetes and eGFR included in the multivariate models because these two variables are known to be associated with higher FGF21 levels. All analyses were conducted using SAS (version 9.1.3, SAS Institute, Cary, NC) with type I error of 0.05.

Overall, the median (25^th, 75^th percentile) serum FGF21 concentration was 227 (127, 371) pg/mL. Of the 744 adults, 235 (31.6%) had hypertension. The characteristics of the 744 participants in the study overall and by the presence or absence of hypertension are shown in Table 1. Age, race, BMI, waist circumference, metabolic syndrome, use of angiotensin converting enzyme inhibitors, FGF21, triglycerides, fasting plasma glucose, eGFR, chronic kidney disease, and diabetes were significantly associated with hypertension. Male gender, current smoking, angiotensin receptor blocker use, total cholesterol, HDL cholesterol, LDL cholesterol, and C-reactive proteins were not associated with hypertension. No participants were taking fibrate medications. Median (25^th, 75^th percentile) FGF21 concentrations in subjects taking or not taking ACE inhibitors, respectively, was 278 (165, 468) and 220 (123, 353) pg/mL (P <0.0001).

Table 1.

Characteristics of 744 adults overall and by presence or absence of hypertension in the Baltimore Longitudinal Study of Aging

Characteristic*		Entire group (n = 744)	With hypertension (n = 235)	Without hypertension (n = 509)	P†
Age, years, %	<50	15.5	20.0	5.5	<0.0001
	50–59	22.6	25.3	16.6
	60–69	26.5	25.2	29.4
	70–79	23.8	18.7	34.9
	≥80	11.7	10.8	13.6
Male gender, %		49.9	54.5	47.7	0.09
Race, white, %		65.7	55.7	70.3	<0.0001
Current smoking, %		4.6	4.6	4.5	0.92
Body mass index (kg/m2), %	<18.5	0.7	0.6	0.9	<0.0001
	18.5–24.9	34.8	40.3	23.0
	25.0–29.9	38.2	36.9	40.8
	≥30	26.3	22.2	35.3
Waist circumference, cm		92.0 (82.9, 100.4)	90.2 (81.2, 91.8)	95.4 (88.1, 97.3)	0.0008
Metabolic syndrome, %		25.4	37.5	16.7	<0.0001
On angiotensin receptor blockers, %		1.1	1.7	0.8	0.26
On angiotensin converting enzyme inhibitors, %		14.6	34.9	5.3	<0.0001
Serum fibroblast growth factor 21(pg/mL)		227 (127, 371)	269 (161, 457)	208 (117, 335)	<0.0001
Total cholesterol, mg/dL		193 (171, 216)	193 (173, 216)	192 (164, 216)	0.15
HDL cholesterol, mg/dL		55 (46, 68)	54 (47, 69)	56 (45, 66)	0.16
LDL cholesterol, mg/dL		115 (83, 138)	110 (90, 133)	117 (95, 139)	0.05
Triglycerides, mg/dL		89 (66, 123)	95 (69, 133)	87 (65, 119)	0.03
C-reactive protein, μg/mL		1.17 (0.75, 2.34)	1.25 (0.87, 2.51)	1.10 (0.64, 2.29)	0.17
Fasting plasma glucose, mg/dL, %	≤99	73.5	60.8	79.4	<0.0001
	100–125	23.1	33.2	18.5
	>125	3.4	6.0	2.1
Estimated glomerular filtration rate, mL/(min·1.73m2)		77.2 (64.4, 90.2)	72.6 (59.1, 85.6)	79.5 (65.9, 91.2)	<0.0001
Chronic kidney disease, %		19.2	26.4	15.9	0.0008
Diabetes, %		5.9	12.3	2.9	<0.0001

^*Values are median (25^th, 75^th percentile) for continuous variables, and % for categorical variables.

^†Kruskal Wallis test used for continuous variables, chi-square test used for categorical variables.

Log FGF21 (per 1 SD increase, 0.77) was significantly associated with hypertension in multivariable logistic regression models adjusting for age, race, smoking, and BMI (Odds Ratio [O.R.] 1.25, 95% Confidence Interval [C.I.] 1.03–1.51, P = 0.02), additionally for eGFR (O.R. 1.23, 95% C.I. 1.01–1.48, P = 0.03), and finally with addition of diabetes (O.R. 1.22, 95% C.I. 1.01–1.48, P = 0.04).

The Spearman correlation between serum FGF21 and triglycerides was 0.31 (P <0.0001). When triglycerides were added to the preceding model, the association between log FGF21 (per 1 SD increase) changed (O.R. 1.17, 95% C.I., 0.96–1.43, P = 0.13). We also explored alternative multivariate models for log FGF21 (per 1 SD increase) and hypertension adjusting for age, race, smoking, eGFR, and fasting plasma glucose (O.R. 1.20, 95% C.I. 0.99, 1.46, P = 0.06), or adjusting for age, race, smoking, eGFR, diabetes, and dyslipidemia (O.R. 1.23, 95% C.I. 1.01, 1.48, P = 0.04). Log FGF21 (per 1 SD increase) was also associated with metabolic syndrome (O.R. 2.02, 95% C.I. 1.52, 2.68, P <0.0001), adjusting for age, race, smoking, eGFR, BMI, and diabetes.

The present study shows that serum FGF21 levels are independently associated with hypertension in community-dwelling adults. To our knowledge, this is the first study to show that elevated serum FGF21 is independently associated with hypertension in adults. Whether elevated serum FGF21 is causally related to hypertension cannot be determined from this cross-sectional observational study. It is interesting to note that in an intervention study involving forty nondiabetic obese women, three months of supervised exercise training fives times per week led to significant reductions in systolic and diastolic blood pressure, arterial stiffness, and circulating FGF21 levels.⁸ In 72 patients with end-stage renal disease, angiotensin receptor blocker treatment for six months reduced serum FGF21 concentrations by 13%.¹² These findings suggest a possible link between the renin-angiotensin system and FGF21.

The strengths of this study include the relatively large sample size of community-dwelling adults, the rigorously timed and standardized collection of fasting serum samples for FGF21 measurements, and the adjustment of the multivariable analysis for renal function. A limitation of the study is the cross-sectional design, as the direction of the association of elevated circulating FGF21 and hypertension is not known. As with any epidemiological study, it is not possible to measure all potential confounders, and there may be other unmeasured factors that influence the association between FGF21 and hypertension. Further studies are needed to address the biological mechanism(s) that could explain the association between FGF21 and hypertension.