Complement and Cardiovascular Risk in Adolescents

Cardiometabolic diseases usually do not produce significant mortality and morbidity until
adulthood. There is clear evidence, however, that these diseases have their origins in
childhood and adolescence. With the rising incidence of obesity associated with poorer eating
and less physical activity in children and adolescents it is important that the investigators
study these diseases early in their course if the investigators are to prevent future
cardiometabolic disease. While obesity clearly increases cardiometabolic risk, not all obese
subjects are at increased risk; approximately 25-30% of obese adults and adolescents are
metabolically healthy. The complement system is key physiological component in controlling
inflammation and recent studies have indicated complement plays an important role in
increasing obesity and cardiometabolic risk. Adults with proven cardiometabolic disease or at
future risk for cardiometabolic disease have increased levels of the complement components
C3, C3a-desArg, and C4 compared to healthy, not at risk, control subjects, independent of
obesity. Increased C3 or C3a-desArg levels in adolescents are associated with increased
cardiometabolic risk independent of obesity. Two specific single nucleotide polymorphisms
(SNPs) in the intron for C3, rs11569562 and rs2250656, both with A>G polymorphisms, are
associated with increased serum C3 levels, and increases in a variety of cardiovascular risk
factors. No one has investigated how C3 polymorphisms affect risk factors in adolescents. The
C4 gene has significant copy number variation and increased copy number is associated with
increased C4 levels. The relationship of C4 gene copy number to cardiometabolic risk has not
been studied in adults or adolescents. The short-term objectives of this study are to explore
differences in cardiometabolic risk factors in overweight and obese adolescents with C3
polymorphisms and also to explore how C4 gene copy number variation affects risk factors. The
investigators overall hypothesis is that variations in C3 polymorphisms, C4 gene copy number
or both will have significant impact on cardiometabolic health in overweight and obese
adolescents. Both traditional and nontraditional cardiometabolic risk markers, including
measures of body habitus, blood pressure, lipids, vascular function, insulin secretion and
sensitivity, inflammation, and clotting will be investigated in 100 overweight and obese
adolescents. The investigators proposed study will help us understand the role of complement
and its genetics in the development of cardiometabolic risk and in potentially developing
genetic biomarkers for adolescents at increased risk.

Inclusion Criteria:

- Healthy adolescents age 12 to 18 years

- Medication free for 2 weeks except oral contraceptives in females

- Non Hispanic white

Exclusion Criteria:

- Chronic medications except for contraceptives in females.

- History of autoimmune disease either endocrine or connective tissue type

- History of hematologic or renal disease, malignancy or other chronic disease

- Hispanic ethnicity,

- African-American or Asian race