Complement C3 and C4, but not their regulators or activated products, are associated with incident metabolic syndrome: the CODAM study

PURPOSE: We investigated the associations of components of the alternative (C3, C3a, Bb, factor D [FD], factor H [FH], properdin) and the classical complement pathway (C4, C1q, C1-inhibitor [C1-INH]) with prevalent and incident metabolic syndrome in a cohort with a moderately increased risk of cardiometabolic disease. METHODS: The study cohort was comprised of 574 participants (61% men, age 59.6 ± 7.0 years) at baseline and 489 participants after 7-year follow-up. Multiple logistic regression analyses were done to investigate the associations of concentrations of baseline plasma complement (standardized values) with prevalent and incident (in those without metabolic syndrome at baseline, n = 189) metabolic syndrome. RESULTS: C3 (odds ratio (OR) = 1.48 [95% confidence interval: 1.02; 2.14]) and C4 (OR = 1.95 [1.32; 2.88]), but none of the other complement components were associated with incident metabolic syndrome (n = 40 cases). Notably, in the cross-sectional analyses, we did observe higher levels of C3a (OR = 1.25 [1.03; 1.52]), FH (OR = 2.93 [2.24; 3.83]), and properdin (OR = 1.88 [1.50; 2.34]), in addition to C3 (OR = 3.60 [2.73; 4.75]) and C4 (OR = 1.39 [1.13; 1.69]), in those with the metabolic syndrome compared to those without, while no association was observed for FD, Bb, C1q, or C1-INH. CONCLUSIONS: In the cross-sectional analyses, the effects sizes (standardized regression coefficients) for C3 and C4 were similar to those of (some of) the regulators and activators, yet only C3 and C4 were associated with incident disease. These findings suggest a role for C3 and C4, but not their regulators or activated products, in the development of the metabolic syndrome.