TG/HDL-C Ratio Independent of Obesity Associates With Airow Obstruction in Asthmatic Children

There is conicting evidence on the association between dyslipidemia and asthma. This study was to evaluate the correlation between dyslipidemia and pulmonary function parameters in asthmatic children. Asthmatic children (aged 5–18 years old) were measured for fasting serum lipid proles, including low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) and C-Reactive protein (CRP). A pulmonary function test was assessed by spirometry. One Of was followed by (55.71%), non-HDL-C (50%), TG and HDL-C The signicant correlations between % FEV 1 /FVC ratio and the level of serum HDL-C and TC and TG/HDL-C ratio were observed (r=0.215, r=0.831 and r=0.17, p<0.03). There was a signicant negative correlation between the level of CRP and HDL-C, and % FEV1/FVC ratio and TG/HDL-C (r =-0.236, p=0.004 and r=-0.170, p=0.038). Children with airow obstruction (% FEV 1 /FVC ratio<90) had signicantly higher TG, TG/HDL-C ratio, LDL-C/HDL-C ratio but lower HDL-C. After adjusting with other blood lipids, body weight, BMI z-score, and obesity status, multiple logistic regression model demonstrated that only TG/HDL-C ratio was associated with % FEV 1 /FVC ratio<90, OR 2.78; 95% CI 1.5-5.15, p =0.001. Conclusion: The prevalence of dyslipidemia in children with asthma is high. TG/HDL-C ratio is associated with airow obstruction in asthmatic children.


Introduction
The prevalence of dyslipidemia in children has increased in recent years due to the global epidemic of childhood obesity. Among children and adolescents in the United States, approximately 20% of children and adolescents aged 8 to 17 have abnormal lipid values of at least one or more lipid values [1].Dyslipidemia, de ned as abnormal lipid values of total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) levels, or high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG), or non-HDL-C. De nition of pediatric dyslipidemia based on the above normative data of; TC ≥ 200 mg/dL, LDL-C ≥ 130 mg/dL, TG ≥ 100 mg/dL for aged 0 -9 years and ≥ 130 mg/dL for aged 10 -19 years, or non-HDL-C ≥ 145 mg/dL, or below normative level of HDL-C < 40 mg/dL [2].
There is recently con icting evidence on the association between dyslipidemia and asthma. [3,4] The prospective cohort study in children born to mothers with a doctor's diagnosis of asthma has demonstrated the increased airway obstruction in children with high LDL-C. Children with high HDL-C had better lung function and less bronchial responsiveness [3]. While a recent epidemiologic study in China found no associations between serum lipid levels and pediatric asthma [4]. Non-HDL-C and the TG/HDL-C ratio are practical addition lipid measures in evaluating dyslipidemia in children [5]. Non-HDL-C and TG/HDL-C ratio were proposed to be robust markers of cardiometabolic risk in children [5,6]. A recent study has shown the higher prevalence of asthma in children with a higher TG/HDL-C ratio [7]. However, no previous study evaluated the association of non-HDL-C and TG/HDL-C ratio and the degree of air ow limitation in asthmatic children before. The current study was to assess the correlation between dyslipidemia and pulmonary function, measured by spirometry in asthmatic children, and nd the prevalence of dyslipidemia in pediatric asthma.

Materials And Methods
This cross-sectional study was conducted from January 2019 to December 2019. One hundred and fty asthmatic children (aged 5 -18 years old) who regularly followed up at the Pediatric outpatient clinic of Ramathibodi Hospital and having controlled asthma in the past four weeks were enrolled. The diagnosis of asthma and the de nition of controlled asthma are based on Global Initiative for Asthma (GINA) [8].
The exclusion criteria were children with other underlying chronic diseases (Diabetes Mellitus, chronic liver diseases, and chronic kidney diseases). Demographic data, atopic history, medication, number of asthma exacerbations before enrollment were recorded. The Pediatric Asthma Control Test (PACT) and the Pediatric Asthma Quality of Life Questionnaire (PAQLQ) were used to assess asthma control. Ethical approval was provided by the Human Rights and Ethics Committee of the Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand (ID: MURA2019/55). Written informed consent and informed written assent for children aged seven years or older were obtained for all participants and their parents. The current study was registered at the Thai Clinical Trials Registry (No. TCTR20200305005).
Anthropometric measurements, including height and weight, were measured. Body mass index (BMI) and BMI z-score were calculated. Obesity children have de ned as BMI z-score > 2.00 standard deviations (SD) according to the World Health Organization (WHO) Report of the Commission on Ending Childhood Obesity [2]. Blood samples were collected from the subjects after fasting for at least 8 hours. Serum lipid pro les (TC, LDL-C, TG, and HDL-C) and C-Reactive protein (CRP) were measured. Aeroallergen sensitization was evaluated by skin prick test to aeroallergen. Spirometry was performed.

Pulmonary function test assessments
Spirometer, pre-and post-bronchodilator with 400 mcg of salbutamol inhalation were evaluated. The percentage of bronchodilator response (%∆) was calculated from the absolute difference value obtained before and after salbutamol inhalation, then divided by the absolute values before salbutamol, and the result was multiplied by 100. The spirometry was performed using Spiromaster PC-10; Chest M.I., Co Ltd, Tokyo, Japan. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV 1 ), %FEV 1 /FVC ratio, and forced expiratory ow at 25-75% of FVC (FEF 25-75 ) were measured.

Statistical analysis
Statistical analysis was performed using SPSS software, version 18. Differences between groups were examined using Chi-square test, student t-test, Mann-Whitney Test, one-way ANOVA, or Kruskal-Wallis test. Correlation analyses were performed using Pearson correlation. Logistic regression analysis was performed to investigate the relationship between the blood lipids and the risk of having air ow obstruction de ned as %FEV 1 /FVC ratio <90 based on GINA guideline [8].

Results
One hundred-fty asthmatic children were enrolled with the mean (SD) age of 11.82  Table 1.

Correlations between CRP and Lipid Pro le
A Pearson correlation analysis was performed to analyze the correlation between CRP and lipid pro le. HDL-C was signi cantly negative correlated with CRP value (r = -0.236, p = 0.004) ( Figure 1D).
However, there were no signi cant correlations between the level of CRP and other lipid pro les.

Comparison of spirometry between dyslipidemia and non-dyslipidemia children
There were no signi cant differences in the baseline characteristics between children with or without dyslipidemia (Table 2). There were no signi cant differences in spirometry parameters between subjects with dyslipidemia and those with normal lipid pro les ( Table 2).
Comparison of spirometry parameters between obese and non-obese children Obese children had signi cantly higher FVC % predicted, FEV 1 % predicted but lower % FEV 1 /FVC. Obese children also had signi cantly more %D of FEV 1 and FVC. Obese children also had a signi cantly higher CRP level than those having a normal weight. No signi cant differences in ACT/PACT and PAQLQ scores were observed. Interestingly, only the TG level was signi cantly different between obese asthmatic children and non-obese asthmatic children (Table 3).
Subgroup analysis comparison in lung function parameters between children with or without dyslipidemia and obesity or non-obesity Comparison among children with obesity and dyslipidemia, obesity and non-dyslipidemia, dyslipidemia and non-obesity, and non-dyslipidemia and non-obesity demonstrated that FVC % predicted and FVC %D were signi cant differences among groups. The obesity with dyslipidemia and nondyslipidemia groups had a signi cantly higher value of FVC %predicted and FEV 1 %predicted than those of the non-obesity group. There were no signi cant differences in FOT parameters among these four groups. Further analysis of TG/HDL-C ratio abnormality(TG/HDL-C > 2.5) and obesity in children demonstrated that FVC % predicted, FVC %D, % FEV 1 /FVC were signi cant differences among groups.
Children who had abnormal TG/HDL-C ratio and non-obesity had the lowest % FEV 1 /FVC ( Table 4).
Comparison of lipid pro les between children with air ow obstruction and without air ow obstruction Baseline characteristics and blood lipids of children who had air ow obstruction (% FEV 1 /FVC ratio < 90) and children with no air ow obstruction (% FEV 1 /FVC ratio > 90) were compared. Children who had air ow obstruction had signi cantly higher TG, TG/HDL-C, LDL-C/HDL-C but lower HDL-C. However, children with air ow obstruction had signi cantly higher body weight, BMI, BMI z-score, and more obesity than those with no air ow obstruction (Table 5). Multiple logistic regression analysis demonstrated only TG/HDL-C ratio was associated with % FEV 1 /FVC ratio < 90, odd ratio 2.78; 95% con dent interval (CI) 1.5-5.15, p =0.001. The model was adjusted for age, body weight, height, BMI, obesity status, and blood lipid parameters.

Discussion
We have demonstrated the association of TG/HDL-C ratio and air ow obstruction in asthmatic children as de ned by the FEV 1 /FVC ratio < 90. In contrast, no similar association was shown with other blood lipids. A recent crossectional study in Korean adolescents has shown the greater prevalence of asthma in children who had a high TG/HDL-C ratio. [7] A study in adults demonstrated that elevated serum TG and low HDL-C were associated with self-reported wheezing after adiposity adjustment [9]. A recent study in children showed the association of a high HDL level and the improvement of speci c airway resistance and decreased bronchial responsiveness [3]. A study in adults with asthma demonstrated the association of HDL and FEV 1 % predicted [10]. A recent meta-analysis has also shown the association of low HDL and pediatric asthma compared with the non-asthma group [11].
We found that obese asthmatic children had a greater FVC %predicted & FEV 1 %predicted and had a lower % FEV 1 /FVC. The increase in FEV 1 and FVC in obese children may explain by the airway dysanapsis, the incongruence between the growth of the lung tissue and airway caliber [12]. Obesity has a signi cant effect on lung function in children. [13] However, we found that the obesity group had a greater FVC %∆ and FEV 1 %∆ value than the non-obesity group, which represents more bronchodilator reversibility of air ow obstruction in obese asthmatic children.
Apart from higher TG/HDL-C ratio, asthmatic children who had evidence of air ow obstruction (% FEV 1 /FVC ratio < 90) were more obese and higher LDL/HDL-C ratio than those who had no air ow obstruction (% FEV 1 /FVC ratio > 90). However, multiple logistic regression model adjusted with age, body weight, BMI, obesity status, blood lipids found only TG/HDL-C ratio was signi cantly associated with having air ow obstruction (% FEV 1 /FVC ratio < 90) [ OR 2.78; 95% CI 1.5-5.15, p =0.001. This result would suggest that the TG/HDL-C ratio, irrespective of obesity, seems to have an association with having air ow obstruction (% FEV 1 /FVC ratio < 90) in asthmatic children. High TG and low HDL-C may have a role in systemic in ammation in asthmatic patients. A study in adults demonstrated the negative correlation of HDL-C, and positive correlation of TG with blood eosinophils, a marker of in ammation in asthmatic patients [14]. We also found that children who had abnormal HDL also had a signi cantly higher CRP level, the systemic in ammatory marker. In contrast, children who had abnormal LDL, cholesterol, or triglyceride did not have a higher CRP level. An in-vitro study of Th-cell and monocyte subsets has shown that HDL was inversely associated with monocyte activation and Th1 polarization in obese asthmatic children [15]. Additionally, dysfunctional HDL could modulate T cells through inhibiting T reg and promoting proin ammatory Th1 and Th17 cell production [16]. As a result, children with a high TG/HDL-C ratio may have chronic in ammation resulting in more air ow obstruction, as demonstrated in lower FEV 1 /FVC. Intervention to lower TG and increase HDL-C may lessen the systemic in ammation and result in improved lung functions. However, further controlled study with more sample size is needed to strengthen our ndings.
The prevalence of dyslipidemia in the current study is much higher (46%) than in the previous report in Thai children (11.8%) [17]. Interestingly, 55 out of 70 dyslipidemia of our enrolled children (78.57%) were not obese. Only 23 children (18.11%) among 150 children met the criteria for the diagnosis of obesity. We have found that children who had air ow obstruction (% FEV 1 /FVC < 90) had higher TG, TG/HDL, LDL-C/HDL-C ratio, lower HDL-C, and more obese. However, after the multiple logistic regression analysis, we found that only TG/HDL was associated with % FEV 1 /FVC < 90. This result would suggest that dyslipidemia, especially TG/HDL-C ratio and obesity, impacts the pulmonary function test on the different mechanism.
Our study has limitations in that we did not have a control group who are non-asthmatic and non-dyslipidemia. Nevertheless, a recent study in Korean adolescents demonstrated a higher TG/HDL-C ratio in asthma than non-asthma [7]. Besides, only 5% of our enrolled children had obesity but having normal lipid pro les. The study sample size in the current study may not be large enough to differentiate the effect of obesity and dyslipidemia on pulmonary functions parameter in asthmatic children.

Conclusions
The prevalence of dyslipidemia in asthmatic children is higher than in general children. The majority of dyslipidemia asthmatic children are not obese. Abnormal TG/HDL-C but not other blood lipids are associated with air ow obstruction ( %FEV 1 /FVC <90) irrespectively from obesity. Intervention for improving the level of TG/HDL-C ratio may bene t lung function parameters in asthmatic children.