Complement C3 and C4 Genetics and Cardiometabolic Risk in Adolescents

Abstract

Background: Although not usually manifest until adulthood, evidence indicates that cardiometabolic disease has its origins in pediatrics. If we are truly to decrease cardiometabolic disease we must understand the pathophysiology of cardiometabolic risk in childhood. Individuals with the F polymorphism of the complement C3 gene have increased rates of myocardial infarction and athereosclerosis. Individuals with increased gene copy number of the complement C4 long and A genes have decreased longevity. Methods: C3 F vs. S genotype and C4A, C4B, C4L and C4s gene copy number were measured in 59 non-Hispanic white subjects (29 female, age=15.3±1.7 years, BMI=22.4.1±5.9 kg/m2,, mean±SD). Endothelial function (reactive hyperemia (RH), venous occlusion plethysmography), arterial stiffness (augmentation index (AI), arterial tonometry), lipids, interleukin-6 (IL-6), c-reactive protein, plasminogen activator inhibitor 1 (PAI1) insulin sensitivity and secretion (oral glucose tolerance test) were used to assess cardiometabolic risk. BMI percentile, waist circumference and percent body fat (air displacement) were measured to assess adiposity. Results: Forty percent of subjects had at least one C3F allele. These subjects were found to have increased waist circumference (78±18 vs. 70±11 cm, p=0.029) and higher HDL levels (55±14 vs. 46±11 mg/dl, p=0.024) compared to those with only the S allele. Increased C4L (r=0.34, p=0.017) and C4A (r=0.33, p=0.019) gene copy number were associated with decreased endothelial function. Multiple linear regression including percent body fat and either C4L or C4A showed that both relationships became more significant. Conclusions: In adolescent the C3 F polymorphism gene is associated with increased central obesity but surprisingly increased HDL. Increased C4L and C4A gene copy are associated with decreased endothelial function. This could explain their association with deceased longevity. Disclosure R.P. Hoffman: None. M.M. Copenhaver: None. C. Yu: None.