In this 14-year-old population, a strikingly high proportion, 29%, fell into a high-risk group with features of metabolic syndrome, i.e., higher BMI, insulin resistance (HOMA), SBP, and triglycerides and lower HDL cholesterol levels. The high-risk group also exhibited substantially higher levels of inflammatory markers, which are independently associated with cardiovascular disease and diabetes in adults. Importantly, only overweight adolescents within the high-risk group had raised inflammatory markers.
Cluster analysis (10
) of the individual metabolic syndrome components was used to avoid definitions relying on arbitrary cutoffs, previously shown to be inconsistent for diagnosing metabolic syndrome in adolescence (19
). The prevalence of metabolic syndrome by conventional cutoffs was low in this population (2%) compared with that in other adolescent Western cohorts, including the National Health and Nutrition Examination Survey, with prevalence ranging from 2 to 9% using multiple definitions. Meanwhile, the cluster approach, with the use of continuous variables, revealed almost 15 times the prevalence (29%) of children at risk. Despite the far higher prevalence of children identified at risk by cluster analysis, the high- and low-risk groups appeared to be distinct populations with wide separation of 99% CI for each of the metabolic syndrome components (). Therefore, this approach is powerful for public health research into cardiovascular risk in a population, as it allows identification of larger numbers at risk.
High adiposity was the strongest independent predictor of the inflammatory markers, accounting for 17–28% of the variance in CRP, uric acid, ALT, and GGT, not dissimilar to the result seen for CRP in other adolescent studies (20
). However, an important point was disclosed by this study. Adiposity was exclusively associated with the highest levels of inflammatory markers when it was part of the high-risk cluster, i.e., children with increased adiposity in isolation showed levels of CRP similar to those in leaner children, best illustrated by division of the clusters according to binary groupings of their components (). This approach helps dissect out highly collinear data.
The NHANES study, using an arbitrary metabolic syndrome definition, showed that being overweight with metabolic syndrome was associated with higher CRP than being overweight without the syndrome (21
). However, in contrast with our findings, NHANES showed that CRP was high in the few individuals with normal weight who had the syndrome. Our approach with cluster analysis probably yielded different subpopulations. In the present study, the use of cluster analysis rather than the restrictive definitions of metabolic syndrome used elsewhere to assess associations with inflammatory markers enabled us to identify a broader section of the adolescent population at risk of cardiovascular and metabolic disease.
Increased levels of GGT, CRP, and uric acid in the high-risk cluster in our study are also notable; each has been shown to be a strong predictor of adult cardiovascular disease (3
), independent of the individual components of the metabolic cluster.
The association between aminotransferases and the metabolic cluster is consistent with persistent elevation of ALT and GGT in those with elevated cardiovascular risk in the Bogalusa study (5
). Because GGT predicts both type 2 diabetes (7
) and cardiovascular mortality in adults (6
), this association further emphasizes the heightened potential for premature ill health for the 14 year olds in the metabolic cluster.
There were noteworthy differences between the markers we investigated and their relationship to metabolic syndrome components. Specifically, 1) HDL cholesterol was related to CRP and uric acid, 2) SBP was related to uric acid, and 3) HOMA was related to the aminotransferases. These results suggest that each inflammatory marker evolves via different pathways.
Aminotransferases were predicted by HOMA levels in our study. Therefore, liver inflammation is associated with adiposity and insulin resistance in adolescents, as in adults with nonalcoholic fatty liver disease (NAFLD) (22
). This finding implies that a large proportion of 14 year olds (29% in the high-risk cluster) are at risk of developing NAFLD and its sequelae, bearing in mind that the incidence of NAFLD will increase as the current overweight youth reach adulthood.
Uric acid is associated with the prevalence of the metabolic syndrome (8
). However, our results indicate that uric acid has different associations with other inflammatory markers. Uric acid was independently associated with SBP and HDL cholesterol. The relation between uric acid and blood pressure is consistent with that in studies showing elevated uric acid with hypertension in adults, in youth (23
), and in women with preeclampsia, for which hypertension is a hallmark. In contrast, an association between uric acid and HDL cholesterol, independent of adiposity, has not previously been reported in youth, although it was hinted at by the independent association between uric acid and the triglyceride–to–HDL cholesterol ratio in 352 middle-aged men (24
). In our study, not only did HDL cholesterol independently predict uric acid, but also the highest levels of uric acid occurred in the high-risk cluster with low HDL cholesterol (data not shown). The explanation for this association is unclear, but, if causal, it may be related to the anti-inflammatory effects of HDL cholesterol (25
Caution is needed in postulating causation from a cross-sectional study. It is possible that in using stepwise regression for identifying predictors of the markers, the variables selected may be surrogates, appearing in the model when measured with less error or in place of unmeasured variables. However, lack of adult confounders in our young population may be advantageous in clarifying causal pathways. We believe that the metabolic cluster in our adolescents signals disease processes early in evolution before other downstream effects. Discrepancies between adolescent and adult studies may relate to secondary effects of advanced vascular disease and pathological changes concomitant with aging or complicating effects of lifestyle factors such as smoking. Our study helps in understanding the critical early steps in the pathogenesis of inflammation and the metabolic syndrome. The biomarkers studied are on pathways of inflammation, along with cytokines such as interleukin-6 and tumor necrosis factor-α, previously shown to be closely related to adiposity. Longitudinal data will be available for a high proportion of adolescents with future follow-ups and will be of considerable interest in unraveling the evolution of cardiovascular risk during the transition to adulthood.
In summary, cluster analysis demonstrates that approximately 30% of 14-year-old predominantly Caucasian Australian children exhibit early features of the metabolic syndrome accompanied by a range of inflammatory markers. In addition to emphasizing the magnitude of the problem in a proximate adolescent population, the findings extend current understanding in several ways. The results suggest that adiposity in isolation is insufficient to cause inflammation but requires the synergistic effect of other features of the metabolic syndrome cluster, particularly insulin resistance and dyslipidemia. Furthermore, different associations of metabolic syndrome components with inflammatory markers suggest that the metabolic syndrome is likely to be a heterogeneous condition produced via different pathways, with implications for adult pathological conditions such as diabetes, NAFLD, and hypertension. We previously reported the effect of perinatal factors and early weight gain on cardiovascular risk in 8 year olds from this cohort (10
). The results from these 14 year-olds highlight the need for effective childhood intervention to prevent obesity, diabetes, adult cardiovascular disease, and NAFLD.