Firstly, in this study, we found that after adjusting for gender and age, the HTW phenotype had a higher risk of Elevated BP, High TC, Low HDL-C and High LDL-C compared to the NTNW phenotype. After gender stratification, similar results were obtained for boys, however, the HTW phenotype was a risk factor for elevated BP and low HDL-C in girls. Secondly, further studies showed that the HTW phenotype increased the risk of CVRFC ≥ 2 and CVRFC ≥3 compared to the NTNW phenotype. Moreover, similar results were obtained for both sexes when stratified by gender. Finally, ROC curve analysis showed that TG combining WC performed better than TG or WC alone in detecting CVRFC ≥ 2 and CVRFC ≥3.
A one-year cohort study of children and adolescents showed that the HTW phenotype was a risk factor for longitudinal changes in SBP during follow-up13. Another study showed that the HTW phenotype was a strong predictor of incident hypertension, those with HTW phenotype were 2.3 times more likely to develop hypertension than those with NTNW phenotype after adjusting for gender and age14. The results of other study also suggest that the HTW phenotype is independently associated with the risk of cardiovascular disease, with a higher prevalence of hypertension in the HTW phenotype compared to the NTNW phenotype8. Those are consistent with the results of the present study. Esmaillzadeh et al. suggest that adolescents with the HTW phenotype are not significantly associated with the development of IFG compared to adolescents with the NTNW phenotype15. This is similar to our results. However, another study of children and adolescents identified that after adjusting for confounding variables, an increase in fasting glucose mean of 3.87 mg/dl (95%CI: 1.68-6.05) at one-year follow-up in those with the HTW phenotype13. Several studies in adults have also shown that the HTW phenotype is associated with IFG and even with the incident of type 2 diabetes6,16,17. This difference may be related to differences in study populations and regions, as well as the lower prevalence of IFG in adolescents in this population. Further explanation of the association between the HTW phenotype and glucose in adolescent is still needed in more studies. The study of Esmaillzadeh et al. showed that adolescents with the HTW phenotype were significantly more likely to have high TC (OR=2.9; 95%CI:2.0-4.2), high LDL-C (OR=1. 8; 95% CI: 1.3-2.7) and low HDL-C (OR=1.6; 95%CI:1.3-2.0) after controlling for potential confounding variables15. Kelishadi et al. similarly showed that HTW was associated with high TC in children and adolescents aged 10-18 years18. Adult studies have also found that individuals with the HTW phenotype have a greater chance of having low HDL-C and LDL-C compared to individuals with the NTNW phenotype8,19,20. We obtained similar results in boys, but in girls the HTW phenotype was associated with low HDL-C, but not with high TC and high HDL-C. This difference may be related to differences in gender and sex hormone levels, but more definitive underlying mechanisms need to be further investigated.
The clustering of CVRFs among adolescents is known to be associated with accelerated atherosclerosis and an increased risk of many chronic diseases, such as hypertension, hyperglycaemia and dyslipidaemia in adulthood21–23. Therefore, after confirming the association of the HTW phenotype with individual CVRFs, our study further analyzed its association with CVRFC and results presented that the HTW phenotype was related with an increased risk of CVRFC ≥2(OR=6.64; 95%CI:4.08-10.80) and CVRFC ≥3(OR=11.74; 95%CI:5.95-23.13) in adolescents. Previous studies in adolescents have shown that the HTW phenotype is a stronger risk factor for CVRFC ≥1 (OR=1.4; 95%CI:1.1-1.7) and CVRFC≥2(OR=2.2; 95%CI:1.6-3.0) compared to adolescents with the NTNW phenotype after adjusting for potential confounding variables15. This is similar to the results of our study. Another adult study showed that hypertensive adults with the HTW phenotype were significantly more likely to have all CVRFs compared to the NTNW group, and in particular for 8.35 times more likely to have CVRFC ≥3 (95% CI: 5. 92-11.79)9. Esmaillzadeh et al. also presented a clustering of metabolic abnormalities in adolescents with the HTW phenotype and suggested this phenotype as a simple marker to identify adolescents at risk for metabolic syndrome(MetS) and other metabolic abnormalities15. The findings of Kelishadi et al. suggest that the HTW phenotypes could be used in place of all MetS component measures as a screening index for identifying children and adolescents at high risk of cardiometabolic disease in primary care settings and large epidemiological studies18.
Some adult studies have also shown that the HTW phenotype is independently associated with CVRFs and suggest that the HTW phenotype may be a simple and useful tool to screen individuals for future cardiovascular disease risk6,8,19. Liu et al. showed that the HTW phenotypes is a reliable tool for identifying MetS, with an AUC of 0.843 (0.824-0.862) in men and 0.839 (0.813-0.865) in women24. Another study showed an AUC of 0.81 for TG*WC to predict metabolic syndrome25. In present study, TG combining WC predicted AUC of 0.690 and 0.697 for CVRFC ≥ 2 and CVRFC ≥ 3 in boys and 0.684 and 0.695 for CVRFC ≥ 2 and CVRFC ≥ 3 in girls, respectively. Lee et al. also concluded that the combination of TG and WC has been illustrated as the best indicator of overall MetS in both genders26. Other study has further confirmed that the HTW phenotype can be used as a simple and clinically useful method to identify adolescents at increased cardiometabolic risk27. A number of other studies have similarly shown that individuals with the HTW phenotype have a significantly more unfavourable cardiometabolic profile than those with the NTNW phenotype and that HTW is effective in identifying cardiometabolic risk7,28. These findings suggest that the HTW phenotype is not only strongly associated with individual cardiovascular risk factors, but also has important implications for the identification of metabolic syndromes and cardiovascular risk factor clustering.
Regarding the HTW phenotype increased risk of cardiovascular risk factors may be associated with insulin resistance and endothelial dysfunction. First, the increase in WC, a proxy for visceral adiposity, reflects to some extent the accumulation of visceral adipose tissue. In the case of central obesity, visceral adipocytes release excess fatty acids and pro-inflammatory adipocytokines such as leptin and tumour necrosis factor alpha into the portal circulation, leading to increased hepatic adiposity and insulin resistance, which further activates the renin-angiotensin-aldosterone system, increasing sympathetic activity, enhancing procoagulant activity, and inducing endothelial dysfunction, leading to hypertension and other cardiovascular diseases29–31. And a recent study found that high TG and high WC is a state of insulin resistance in adolescents32. Besides, a Meta-analysis showed a significant correlation between the HTW phenotype and insulin resistance16. When the body has both abdominal obesity and high triglycerides, there may be a superimposed effect on insulin resistance. Insulin resistance has been identified as a major cause of increased cardiovascular risk factors33. However, the underlying mechanisms regarding the relationship between HTW and cardiovascular risk factors remain unclear and require further elaboration in more studies.
Our study provides a reference for understanding the association of the HTW phenotype with individual cardiovascular risk factors and cardiovascular risk factors clustering. However, there are several limitations of the study that should be noted. Firstly, this cross-sectional study limits the causal interpretation of the observed associations. Secondly, this study did not assess some confounding factors such as lifestyle and physical activity, which may have influenced our results. Thirdly, the results cannot be generalised to other populations due to the age and ethnicity limitations of the participants.