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Thromb Haemost 2014; 111(06): 1102-1111
DOI: 10.1160/TH13-10-0831
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Distinct associations of complement C3a and its precursor C3 with atherosclerosis and cardiovascular disease

The CODAM study
Elisabeth Hertle
1   Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
,
Marleen M. van Greevenbroek
1   Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
,
Ilja C. Arts
2   Department of Epidemiology and School for Public Health and Primary Care (CAPHRI) and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
,
Carla J. van der Kallen
1   Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
,
Stefan L. Geijselaers
1   Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
,
Edith J. Feskens
3   Division of Human Nutrition, Section Nutrition and Epidemiology, Wageningen University, Wageningen, The Netherlands
,
Eugene H. Jansen
4   National Institute of Public Health and the Environment (RIVM), Laboratory for Health Protection Research, Bilthoven, The Netherlands
,
Casper G. Schalkwijk
1   Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
,
Coen D. Stehouwer
1   Department of Internal Medicine and CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
› Author Affiliations Financial support: This work was supported by grants from the Netherlands Organization for Scientific Research (940–35–034), the Dutch Diabetes Research Foundation (98.901) and the Dutch Heart Foundation (NHS2010B194).
Further Information

Publication History

Received: 09 October 2013

Accepted after major revision: 13 January 2014

Publication Date:
02 December 2017 (online)

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Summary

Complement C3 is a novel risk factor for cardiovascular disease (CVD), but the underlying mechanism is currently unknown. We determined the associations of the anaphylatoxin C3a, the activation product of C3, and of C3 itself with estimates of atherosclerosis and CVD. We studied associations of C3a and C3 with carotid intima-media thickness (cIMT), ankle-arm blood pressure index (AAIx) and CVD in cross-sectional analyses among 545 participants of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study (62% men, 59.4 ± 6.9 years) and examined effect modification by smoking. We conducted linear and logistic regression analyses with adjustments for age, sex, glucose metabolism status, lipids, adiposity, renal function, blood pressure, pack-years smoked, physical activity, use of medication and investigated mediation by inflammation. C3a was independently associated with cIMT (β=0.032 mm, [95% confidence interval: 0.004; 0.060]) and AAIx (β=−0.022, [−0.043; −0.001]), but C3 was not. Effect modification by smoking was only observed for CVD (Psmoking*C3a=0.008, Psmoking*C3=0.018), therefore these associations were stratified for smoking behaviour. Both C3a (odds ratio [OR] =2.96, [1.15; 7.62]) and C3 (OR =1.98, [1.21; 3.22]) were independently associated with CVD in heavy smokers. The association of C3 with CVD was independent of C3a. Low-grade inflammation did partially explain the association of C3a with AAIx, but not the other observed associations. This suggests that C3a and C3 have distinct roles in pathways leading to CVD. C3a may promote atherosclerosis and additionally advance CVD in heavy smokers. Conversely, C3 may be associated with CVD in heavy smokers via pathways other than atherosclerosis.

Keywords

Complement - C3 - C3a - atherosclerosis - cardiovascular disease

 

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