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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 1  |  Issue : 3  |  Page : 170-177

Association between serum fibroblast growth factor 21 and presence of allostatic load among industrial workers


1 Department of Biochemistry, Regional Occupational Health Centre (Southern), Indian Council of Medical Research, Bengaluru, Karnataka, India
2 Department of Clinical Epidemiology, Indian Council of Medical Research-National Institute of Occupational Health, Ahmadabad, Gujarat, India

Date of Submission09-May-2022
Date of Decision21-Jun-2022
Date of Acceptance10-Aug-2022
Date of Web Publication18-Sep-2022

Correspondence Address:
Dr. Kalahasthi Ravibabu
Department of Biochemistry, Regional Occupational Health Centre (Southern), Indian Council of Medical Research, ICMR Complex, Kannamangala Post, Poojanahalli Road, Devanahalli Taluk, Bengaluru - 562 110, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpdtsm.jpdtsm_39_22

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  Abstract 


BACKGROUND: Fibroblast growth factor 21 (FGF21) mediates metabolic changes and chronic stress. Allostatic load (AL) is an imbalance between repetitive exposure to stress and adaptive response. This study examined the association between FGF21 and the presence of AL among industrial workers.
METHODS: The study is cross-sectional and observational. Parameters data were collected from 169 male industrial workers. AL was assessed using neuroendocrine (cortisol and Dehydroepiandrosterone sulfate), cardiovascular (systolic blood pressure, diastolic blood pressure, and heart rate), metabolic (total cholesterol, triglyceride, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol), and anthropometric (waist-hip ratio and body mass index) measurements. Serum FGF21 was analyzed using the ELISA method. The data were analyzed using SPSS version 20.
RESULTS: The results of the study showed that 43.2% and 56.8% of workers had low and high AL, respectively. Serum (natural logarithm) Ln-FGF21 was significantly elevated in workers with high AL when compared to moderate and low AL. The association between serum FGF21 and AL was analyzed using the linear regression model. The model indicated that age (β = 0.143, P = 0.038) and serum FGF21 (β = 0.162, P = 0.045) were significantly associated with AL. In high AL condition, the receiver operating characteristic area under the curve for Ln-FGF21: 0.656 (95% confidence interval: 0.570–0.742, P = 0.001) was found to be higher as compared to moderate and low AL.
CONCLUSIONS: FGF21 was significantly increased in high AL conditions when compared to low and moderate AL among workers. Therefore, we recommended that FGF21 could be used as a potential biomarker to screen and protect strategy against high AL.

Keywords: Allostatic load, biomarker, fibroblast growth factor 21, industrial workers, lifestyle factors


How to cite this article:
Ravibabu K, Nagaraju R, Balachandar R, Adepu VK. Association between serum fibroblast growth factor 21 and presence of allostatic load among industrial workers. J Prev Diagn Treat Strategies Med 2022;1:170-7

How to cite this URL:
Ravibabu K, Nagaraju R, Balachandar R, Adepu VK. Association between serum fibroblast growth factor 21 and presence of allostatic load among industrial workers. J Prev Diagn Treat Strategies Med [serial online] 2022 [cited 2022 Sep 24];1:170-7. Available from: http://www.jpdtsm.com/text.asp?2022/1/3/170/356288




  Introduction Top


Fibroblast growth factors (FGFs) are a family of proteins that have a role in protecting the cells from damage and suppressing the inflammatory response.[1] FGF19, FGF21, and FGF23 act as endocrine mediators. FGF21 is a polypeptide involved in regulating the metabolism of carbohydrates, lipids, and energy.[2] It also acts as a mediator to stress,[3] endoplasmic reticulum stress,[4] starvation,[5] and nutritional challenges.[6] A higher concentration of FGF21 is related to cardiovascular events,[7],[8] acute myocardial infarction,[9] obesity,[10] Type 1 diabetes mellitus,[11] diabetic retinopathy,[12] and metabolic syndrome.[13],[14]

AL is an imbalance between repetitive exposure to stress and adaptive response.[15] Allostasis is the process of achieving homeostasis through physiological changes in the hypothalamus, pituitary, adrenal glands, and various signal molecules in the body.[16] According to recent research, the AL is linked to higher levels of cortisol in the hair,[17] development of depression,[18] lower health-related quality of life,[19] decreased heart rate variability,[20] work-related stress,[21] and lower Vitamin-D concentration.[22]

Industrial workers demonstrated higher increments of psychological, physical, and occupational stress.[23],[24],[25] In underdeveloped countries, preventing work-related stress is a major challenge.[26] Work-related stress is also considered the second-largest task in occupational safety.[27] AL condition is repeated chronic exposure to stress and FGF21 acts as a mediator for metabolic changes due to stress. Thus, an assenting association between the duo could yield a biomarker for measuring chronic repetitive stress. Given a literature review, the physiological role of FGF21 in AL with contemplation of lifestyle factors has been needed to explore. The proposed study is intended to examine the association between serum FGF21 and AL among workers with contemplation of lifestyle factors.


  Methods Top


This study adopted a cross-sectional and observational design in an industrial setting. The sample size was estimated based on the target workers, which were 200 workers. A confidence level of 99% and a margin of error of 5% were assumed. The response distribution of 50% was considered. The sample frame was calculated as 154 workers. We enrolled 169 male industrial workers engaged in the manufacturing processes. Participants were recruited, and data were collected during the years 2020–2021 in India.

The study protocol was approved by the Regional Occupational Health Centre's institutional ethics committee in accordance with the National Ethical Guidelines for biomedical and health research involving human participants in India (IEC No: ROHCS/142/1/dated 16.01.2020).

Informed written consent was obtained from all participants before enrollment. Consented participants without a medical history of dyslipidemia, hypertension, thyroid dysfunction, congenital or metabolic disorders were included in the study. The pretested questionnaires were used to collect the demographic details.

Anthropometrics

Body mass index

With a light-weight outfit and no footwear, the subject's height and weight were measured in meters and kilograms, respectively, using a nonextendable metallic measuring tape and a precalibrated weighing machine. Following the body mass index (BMI) was calculated as a measure of a person's weight (in kilograms) by height (in square meters), represented as kilogram/meter2.

The waist and hip ratio (WHR) was calculated as the ratio of the waist circumference (WC) to the hip circumference (HC). The WC measurement was taken mid-way between the ribs and the iliac crest, while the HC measurement was taken as the maximum value measured at the buttocks. The WHR was computed using WC and HC values, as described.[28]

Cardiovascular activity

The blood pressure (systolic blood pressure [SBP], diastolic blood pressure [DBP], and heart rate) of the subjects were monitored using a HEM-7112 digital monitor after they had rested for 5 min in a sitting position. It was decided to utilize the average of the two values.[29]

Blood collection

From each subject, three milliliters of fasting whole venous blood was taken and transferred to vacutainer tubes obtained from M/s Labtech disposables (India). Serum was separated by centrifugation at 4°C for 10 min at 4,000 RPM. The serum was later used to determine the neuroendocrine activity (cortisol and DHEA-S), metabolic (triglyceride [TG], cholesterol, and HDL-C), and FGF21 concentrations.

Neuroendocrine parameters

Cortisol

The level of serum cortisol was determined using an ELISA kit (Catalog. No. CO368S, Calbiotech, USA) as per the protocol of the manufacturer. The absorbance of samples and standards was measured by using the Lisa Scan EM microplate reader, India, at 450 nm. The detection range of protocol was noted as 0–500 ng/mL, and the sensitivity is 1.16 ng/mL.

DHEA-S

The level of serum DHEA-S was estimated using the competitive ELISA kit (Catalog. no. DH291S, Calbiotech, USA) as per the protocol of the manufacturer. The absorbance of samples and standards was measured by using the Lisa Scan EM microplate reader, India, at 450 nm. The detection range of this procedure is 0–10 μg/ml, and the sensitivity is 0.023 μg/ml.

Metabolic parameters

Serum TG level was determined using the Prietest diagnostic kit method developed by Fossati and Prencipe, 1982[30] with Trinder reaction, 1969[31] (Catalog no. TRIG 05 10; Robonik, India). The recorded absorbance of samples was correlated with TG concentration. The minimum detection limit of this method is 1 mg/dL.

Cholesterol from high-density lipoproteins (HDL): Serum HDL-C levels were quantified by prescribed method[32] using commercial kits (Catalog no. HDC PPT 02 50; Robonik, India). In this technique, the HDLs were separated from chylomicrons, very low-density lipoproteins (LDLs), and LDLs using phosphotungstic acid and magnesium ions. The separated HDLs were used to measure cholesterol with the Prietest diagnostic kit established on the principle of Trinder reaction (Catalog No. CHO 02 50; Robonik, India). The end product obtained from this reaction is quinonimine, which is generated through the interactions of 4-aminoantipyrine, phenol, and H2O2. The absorbance of the sample was recorded using the Robonik Prietest Touch Biochemistry Analyzer, India. The minimum detection concentration of this approach is 4 mg/dL.

Total cholesterol

The serum total cholesterol levels were determined using the Allain et al. technique.[33] In this approach, cholesterol was measured using a Prietest diagnostic kit established on the principle of Trinder reaction (Catalog No. CHO 02 50; Robonik, India). The end product obtained from this reaction is quinonimine, which is generated through the interactions of 4-aminoantipyrine, phenol, and H2O2. The absorbance of the sample was recorded using the Robonik Prietest Touch Biochemistry Analyzer, India. The minimum detection concentration of this approach is 4 mg/dL.

Low-density lipoprotein-cholesterol

The level of LDL-C was estimated using the individual values of TG, cholesterol, and HDL-C.[34]

LDL-C = (Total cholesterol) − (HDL-C) − (TG/5).

Fibroblast growth factor 21

The concentration of serum FGF21 was measured using an ELISA kit (Catalog No. ELH-FGF21, Ray Bio, USA) as per the protocol instruction of the manufacturer. The absorbance of samples and standards was measured using the Lisa Scan EM microplate reader, India, at 450 nm. The changes in optical density in the samples are proportional to the concentration of FGF21. Human FGF21 has a detection range of 8.19–2000 Pg/mL and a minimum detectable concentration of 8 Pg/mL. The reproducibility of kit parameters found to be as intra-assay CV% is <10 and inter-assay CV% is <12.

Assessment of allostatic load

The creation of AL was done by using the physiological dysregulation of cardiovascular activity (SBP, DBP, and HR), metabolic (TG, total cholesterol, HDL-C and LDL-C), neuroendocrine (cortisol, and DHEA-S), and anthropometrics (BMI and WHR). The highest risk quartile method was used to determine the AL. The people count falling in the highest risk quartile of a value is assigned as 1, and the people count falling in less than the high-risk quartile of a value are allotted as 0. The AL score was calculated by summing the 11 dichotomous scores of each of the 11 markers. The value of the AL score ranged from 0 to 11 points.

Statistical analysis

The data were analyzed using the Statistical Package for the Social Sciences (SPSS) version 20 (IBM Corp, Armonk, Newyork, USA). The data were presented as mean ± standard deviation (SD) for continuous variables and proportion for categorical variables. The normality test of serum FGF21 was analyzed using Kolmogorov–Smirnov and Shapiro–Wilk test and found to deviate from the normal distribution. For analysis, the values of FGF21 were converted using a natural logarithm (Ln). For the comparison of data between AL categories among workers, a Student's t-test was utilized. The influence of AL on serum FGF21 was evaluated using an ANOVA test. To compare allostatic categories within the categorical variables of serum FGF21, a one-way ANOVA with a post hoc test (LSD) approach was utilized. To determine the association between Ln-FGF21 and the occurrence of AL, a general linear regression model was used. The results of the model are reported as unstandardized coefficients (B), standard error (SE), standardized coefficients (β) and P value. The capacity of FGF21 to predict the existence of AL categories was assessed using a receiver operating characteristic curve-area under the curve (ROC-AUC) analysis. The probability value of notable findings is <0.05.


  Results Top


The information on the demographics of industrial workers is tabulated in [Table 1]. The average age of industrial workers was 35.3 years, with the mean height and weight found to be 165.1 cm and 63.6 kg, respectively. The mean BMI (±) SD was 23.3 ± 3.6. The mean waist and HCs of workers were found to be 35.6 and 36.0 inches, respectively, and the WHR was found to be 1.0 ± 0.1. Regarding educational qualifications, 13% of workers were illiterate, while 20.7%, 34.3%, 24.9%, and 7.1%, respectively, studied up to primary, secondary, preuniversity, and university levels. The majority of the subjects was married and consumed a nonvegetarian diet. About 56.8% of workers had the habit of chewing tobacco products, while 18.9% and 34.3% had smoking and alcohol consumption habits, respectively.
Table 1: Demographical details of industrial workers

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In [Table 2], the parameters and cutoff values are used to create an allostatic load (AL) among workers are shown. A total of eleven biomarkers such as neuroendocrine mediators (cortisol and DHAE-S), cardiovascular activity (SBP, DBP, and HR), metabolic (TG, cholesterol, HDL-C, and LDL-C), and anthropometrics (BMI and WHR) were used to construct the AL. The methodology adopted for constructing the AL includes quartile distributions, logistic regression, factor analysis, z-scores, and grade of membership.[35] In the present study, we created the AL among workers using the quartile distribution method, which was the first method used in the aging and the National Health and Nutrition Examination Survey.[36] Jung et al. reported the total average AL score was 2.6 (1.7SD), with the highest being seven and the lowest being zero among office workers, from eleven biomarker measurements.[37] We created an AL score from eleven biomarker measurements. The average total score was 2.9 (1.97SD), with the highest being nine and the lowest being zero. The study participants were divided into two groups based on their total average score: Low AL (≤2.9) and high AL (>2.9).
Table 2: Cutoff values of allostatic load parameters among industrial workers

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The allostatic score distribution based on deregulated components among industrial workers are presented in [Table 3]. The comparison of biomarker measurements and serum FGF21 between AL categories is presented in [Table 4]. Biomarkers measurements such as BMI (P = 0.001), WHR (P = 0.001), SBP (P = 0.001), DBP (P = 0.001), HR (P = 0.001), TG (P = 0.001), cholesterol (P = 0.001), LDL-C (P = 0.001), cortisol (P = 0.001), DHEA (s) (P = 0.039), and FGF21 (P = 0.035) were significantly increased in workers with high AL category as compared to low AL. In contrast, serum HDL-C levels were decreased (P = 0.491) in the high AL.
Table 3: Allostatic parameters distribution based on deregulated components among industrial workers

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Table 4: Comparison of parameters and fibroblast growth factor 21 among industrial workers with high and low allostatic load category

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Univariate analysis of AL categories that affected serum FGF21 among workers is presented in [Table 5]. The result of the model indicated that a higher AL was noted with an increased level of serum FGF21. The post hoc comparison (LSD) method was evaluated to determine the effect of various categories within categorical variables on serum FGF21. We found significantly increased levels of serum FGF21 in the high AL category (>3) when compared to the low (0–1) and moderate (2–3) categories of AL. The comparison between the moderate and low AL categories found no significant difference.
Table 5: Univariate analysis of allostatic load categories that affect serum fibroblast growth factor 21 among workers

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Linear regression analyses of variables that affect serum FGF21 among workers are presented in [Table 6]. In this model, The AL score was used as continuous dependent variables, and age, alcohol consumption (yes = 1 and no = 0), smoking habits (yes = 1 and no = 0), educational status, marital status (married and unmarried), diet (vegetarian and non-vegetarian), and chewing of tobacco products were used as independent variables. The model was statistically significant (F = 3.547, P = 0.001) and explained 15.1% variation. The independent variables such as age (β = 0.186, P = 0.038) and serum FGF21 (β = 0.162, P = 0.045) were significantly associated with AL. The variables of alcohol consumption, smoking habits, educational status, marital status, diet, and chewing of tobacco products were not predicted significantly.
Table 6: Association between serum natural logarithm fibroblast growth factor 21 levels and allostatic load among workers

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ROC-AUC analysis was used to predict FGF21 on low, moderate, and high AL categories. [Figure 1]a, [Figure 1]b, [Figure 1]c represents the prediction of FGF21 on low, moderate, and high AL categories. In high AL category, the AUC of the ROC curve for Ln-FGF21 was 0.656 (95% CONFIDENCE INTERVAL [CI]: 0.570–0.742, P = 0.001), in moderate AL category, it was 0.414 (95% CI: 0.372–0.501, P = 0.058), and in low AL score, it was identified that 0.420 (95% CI: 0.320–0.519, P = 0.119).The prediction of FGF21 on low and moderate AL was found to be a null hypothesis (AUC < 0.5). The difference in the AUC of the ROC curve of FGF21 between the higher AL and lower AL categories is 0.236 and found to be significant (Z = 3.53 and P = 0.001). The difference in the AUC of the ROC curve of FGF21 between the high AL and moderate AL category is 0.242 and found to be statistically significant (Z = 3.83 and P = 0.001).
Figure 1: (a) Represents prediction of Ln-FGF21 with low AL among workers. (b) The prediction of Ln-FGF21 with moderate AL among workers. (c) represents the prediction of Ln-FGF21 with high AL among workers. AUC: Area under the curve, AL: Allostatic load, FGF21: Fibroblast growth factor 21, CI: Confidence interval

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  Discussion Top


The current study investigated the association between AL and serum FGF21 levels in industrial workers with lifestyle factors. AL is an integrated score of biological and clinimetric.[38] It is used as an early marker of stress in healthy people.[26] Zhang et al. reported a significant relationship between AL and all causes of mortality.[39] As per literature, 48.6% of the US adult population had AL.[40] In the present study, we reported that 56.8% of workers had high (>2.9) AL. The proportion of AL noted in this study was 1.17% higher than in the US adult population. The 10.3% of the male population had an AL component score in the range of 5–9 as noted by Zhang et al.[39] In the current study, we reported 20.1% of workers in a similar range, which was 9.8% higher than in the population-based study.

FGF21 protection effect was impaired due to increased levels of endothelial dysfunction, oxidative stress, lipid accumulation, and inflammation.[41] It prevents neurodegeneration via NF-kB andAMPKα/AKT pathways by regulating oxidative stress and inflammation.[42] Recent studies have linked the higher levels of FGF21 to diabetes,[43] epigenetic genes in metabolic pathways,[44] acute ischemic stroke patients,[41] cognitive parameters,[45] chronic kidney disease,[46] metabolic.[47] The authors of these studies were concluded that the higher level of FGF21 is due to deregulations of blood pressure, carbohydrate, and lipid metabolism. In the current study, we constructed the AL using the deregulations of blood pressure, metabolic, neuroendocrine, and body measurements. In this study, we reported significantly higher levels of serum FGF21 in workers with high AL. Furthermore, we also assessed the effects of low, moderate, and high AL categories on serum FGF21 levels among workers. The results of the model indicated that high AL had significantly higher levels of serum FGF21 as compared to low and moderate AL.

Previous studies were observed that the higher concentration of FGF21 was associated with unstable angina pectoris,[7] aortic stiffness,[48] risk of diabetic retinopathy and sight-threatening diabetic retinopathy,[49] poor neurological outcome,[50] and microalbuminuria.[51] We observed a significant association between FGF21 and AL among workers with linear regression analysis.

Furthermore, many previous studies assessed the prediction of FGF21 on the risks of unstable angina pectoris,[7] missed abortion,[52] dilated caridomyopathy,[53] atherosclerosis,[54] diabetic,[55] and mitochondrial disease[56] using ROC-AUC analysis. In the present study, we used ROC-AUC analysis for the prediction of FGF21 on the existence of AL categories. In high AL, the ROC-AUC of FGF21 was significantly predicted as compared to low and moderate AL categories. The difference in ROC-AUC of FGF21 in the high AL category was found to be significant as compared to the low and moderate AL categories. Based on study findings, we recommend FGF21 as a potential marker against high AL conditions.


  Conclusions Top


FGF21 was significantly increased in high AL conditions when compared to low and moderate AL among workers. Therefore, we recommended that FGF21 could be used as a potential biomarker to screen and protect strategy against high AL.

Limitation of the study

Based on the baseline value of FGF21 and AL, we recommend a large database be built to find the association between FGF21 and exposure to specific stress factors.

Acknowledgments

The authors are thankful to the Director, ICMR-National Institute of Occupational Health for his support and encouragement to conduct this study. Authors also thankful to Mrs. Thara, senior technical officer and Mr. Rajeev Yadav, Technician C for their assistance to the collection of data and samples.

Financial support and sponsorship

ICMR –National Institute of Occupational Health Meghani Nagar, Ahmadabad-380016, Gujarat, India.

Conflicts of interest

There are no conflicts of interest.



 
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