Results from this study suggest that the lipid profile of nonobese prepubertal children with DS is less favorable than that of their siblings, with higher concentrations of TC, LDL, and TG and lower concentrations of HDL after adjustment for important confounding factors. Our findings of increased TC, LDL, TG, and decreased HDL in individuals with DS are similar to 1 previous report by Zamorano et al20
in Chile in 1991. In that study, lipid profiles of 72 children with DS were compared with 66 controls without DS. Children with DS were found to have higher TG, TC, LDL, and lower HDL compared with controls. Weight, BMI, age, and gender were not controlled for in that study. Other studies of lipid and lipoprotein concentrations in individuals with DS have produced varying results ranging from no significant difference in cholesterol, triglycerides, and lipoprotein levels between DS and non-DS groups to reports of increased serum cholesterol, triglycerides and oxidatively modified LDL.4–8,21
Our study is the first to use exclusively sibling controls to show all measured lipid parameters to be less favorable in the DS group after adjustment for important confounding factors.
Our findings of less favorable lipid profiles in the DS group are also significant in light of a recent study on obesity in children with DS. In that study, the authors concluded that, given the high rates of obesity in children with DS, obesity laboratory assessment protocols for the general pediatric population should also be applied to children with DS.22
Although current DS health supervision guidelines encourage the monitoring of BMI and emphasize education to prevent obesity, there are no specific recommendations for obesity-related laboratory assessment.23
The mechanism by which individuals with DS develop a less favorable lipid profile than their siblings is unclear, but, based on our results, this mechanism does not appear to be explained by overall adiposity, as measured by BMI. Differences observed in lipid profile may be related to fat distribution, but, because the current study was not designed to answer this question, anatomic distribution of fat was not measured. In the general population, increased waist circumference and waist-to-height ratio are associated with an unfavorable lipid profile; however, to our knowledge, no studies of adipose tissue distribution in individuals with DS have been performed. In addition, there is a known association between hypothyroidism and hyperlipidemia, and many individuals with DS have hypothyroidism; however, hypothyroidism requiring treatment was one of the exclusion criteria for this study. In their epidemiological study, Hill et al13
postulated that the excess mortality from cardiovascular disease (CVD) in DS may be related to unrecognized congenital heart defect, increased BMI, and tendency toward diabetes mellitus in persons with DS. However, these conditions were excluded or adjusted for in our study, suggesting that an unfavorable lipid profile may also play a role in the increased CVD mortality of individuals with DS.
Hyperglycemia and insulin resistance are also known to be related to dyslipidemia. Hyperglycemia can cause increased oxidative stress, glycosylation of proteins such as LDL cholesterol (making it more atherogenic), decreased nitric oxide production, and increased coagulability, leading to endothelial injury and increased atherogenic risk.24
In addition, insulin resistance at the level of the adipocyte can increase free fatty acids, and result in increased small, dense LDL cholesterol.25
In a previous publication by our group, we compared obesity-related hormones between the same 2 study groups (children with DS and sibling controls).26
We found no significant difference in glucose (83.4 ± 7.7 mg/dL in the DS group and 80.5 ± 11.0 mg/dL in the sibling group, P
= .095) or insulin (10 ± 10.3 μU/mL in DS group vs 7.7 ± 2.2 μU/mL in the sibling group, P
= .3) between the 2 groups in the unadjusted comparison. When the comparison was adjusted for age, gender, race, and ethnicity, the difference in insulin was still not significant (P
= .1), but the difference in glucose became statistically significant (P
= .007). Despite the statistical significance, the authors do not believe the difference between 83.4 mg/dL and 80.5 mg/dL to be clinically significant. They are both well within the normal fasting glucose range. Although the relationship between glucose and the risk for diabetes is considered to be a continuum (even if glucose is in the normal range), the authors do not know of any such data for the relationship between glucose and dyslipidemia.
Given our study design and results, congenital heart defects, hypothyroidism, weight status, glucose, and insulin levels are unlikely to explain the difference in lipid profile in these children with DS compared with their siblings, and the question of whether overexpression of chromosome 21 directly influences lipid profile can be raised. In a study screening for additional familial combined hyperlipidemia genes, a locus conferring susceptibility to elevated apoB levels was identified on chromosome 21.27
A study performed on fetuses with DS was suggestive of abnormalities of lipid metabolism in utero, before other factors could influence lipid levels. DS fetuses were also found to have increased TC and increased apolipoprotein A levels compared with controls.28
Another possible mechanism for increased dyslipidemia in children with DS involves leptin, a hormone secreted by adipose tissue that correlates with percentage of fat mass in humans.29
In a previous study, we found that children with DS had increased leptin levels for percentage of body fat when compared with their siblings, suggesting increased leptin resistance at the same fat level with DS.26
Leptin is also significantly associated with total cholesterol and triglycerides, even after adjusting for BMI.30
Therefore, it is possible that increased leptin resistance in DS may play a role in the lipid profile of the children with DS observed here.
The strengths of this study included the use of biological siblings as a control group, reducing the effect of potential familial and environmental factors, as well as the recruitment bias of healthy controls. The limitations of this study include its relatively small sample size and exclusion of individuals with DS who have comorbid disease, which reduces the generalizability to most children with DS. This design, however, decreased the risk of confounding by these conditions and increased the chances to identify an effect of DS alone. Because there is no national DS registry, our sample of patients with DS does not represent a population-based sample of all persons with DS. We acknowledge the possibility that the families willing to participate in our study may have children with more complex medical needs. We acknowledge the possibility that families willing to participate in our study may have children with more complex medical needs. Additional limitations include the failure to control for blood sugar levels, insulin levels, or hemoglobin A1c because blood sugar, insulin, and hemoglobin A2c can potentially affect lipid levels.