Complement and Cardiovascular Risk in Adolescents

Study Overview
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Brief Summary
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This study evaluates how genetic variations in complement, a part of the immune system, affect cardiovascular risk in adolescents.

Detailed Description
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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.

Official Title
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Complement and Cardiovascular Risk in Adolescents

Conditions
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Type 2 Diabetes, Cardiovascular Disease

Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Healthy Adolescents<br>Healthy non Hispanic white adolescents | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complement C3 Genotype | Genetic C3F genotype allele presence | Baseline | 
| C4 Copy Number | C4A or C4B gene copy numbers | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BMI | Body mass index | Baseline | 
| Waist Circumference | Waist circumference at narrowest point | Baseline | 
| Body Fat | Percent body fat BodPod | Baseline | 
| Endothelial Function | reactive hyperemia response to upper arm occlusion | 8 min | 
| Vascular Stiffness | augmentation index of reflected blood pressure wave | baseline | 
| Endothelin 1 |  | baseline | 
| Inflammation | IL6 | baseline | 
| Clotting | PAI1 | baseline | 
| Insulin Sensitivity | Oral glucose tolerance test | baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Complement, endothelial function, insulin sensitivity, adolescents, inflammation