Abstract
Introduction: Macrophages play important roles in atherosclerotic plaque formation and stability. CD163 is a macrophage specific receptor involved in the clearance and endocytosis of hemoglobin-haptoglobin complexes; soluble CD163 (sCD163) may be a useful biomarker to assess macrophage activation. We are not aware of epidemiologic studies of sCD163 levels and cardiovascular disease (CVD) risk. Also it is not known whether common genetic variants are associated with sCD163. Methods: We tested whether sCD163 was associated with carotid intima-media thickness (IMT) and incident clinical events (overall mortality, coronary heart disease [CHD], myocardial infarction [MI], stroke, and congestive heart failure [CHF]) in 4,577 Cardiovascular Health Study (CHS) participants (95% white, 5% black; age range 65-100 y). We used linear regression with adjustment for sex, age, race, study site, current smoking, BMI, hypertension status, systolic blood pressure (SBP) and LDL cholesterol to test for association between sCD163 and IMT. We used 2 Cox proportional hazards models for incident events analyses: (1) adjusting for sex, age, race, study site, and current smoking; (2) model 1 plus BMI, hypertension status, SBP, LDL-cholesterol, C-reactive protein (CRP), interleukin-6 (IL6), and fibrinogen. We also performed a genome-wide association study (GWAS) for sCD163 in 2,769 unrelated CHS white participants, using Hapmap 2 imputed SNPs. Results: sCD163 was positively associated with female sex, white race, age, BMI, SBP, CRP, IL6 and fibrinogen, negatively associated with current smoking status (p&lt0.0001), and not associated with LDL cholesterol or hypertension status. After adjustment for traditional CVD risk factors, sCD163 was positively associated with carotid IMT (p=0.027). In model 1, increased sCD163 levels were associated with overall mortality (p&lt0.0001), incident CHD (p=0.0034), incident stroke (p=0.016), and incident CHF (p&lt0.0001), but not incident MI (p=0.069). None of the model 2 analyses resulted in significant associations (all p&gt0.05). Five variants upstream of chromosome 2q gene MGAT5 (top result rs4954118, p=7.1x10-14) and a single variant (rs314253, p=6.0x10-13) on chromosome 17p between ASGR1 and DLG4 were significantly (p&lt5x10-8) associated with sCD163. The top result near the CD163 gene was for upstream variant rs6488429 (p=8.2x10-5). Conclusions: sCD163 was associated with carotid IMT after accounting for established CVD risk factors. There were associations of sCD163 with mortality and incident clinical CVD, although associations were attenuated after adjustment for other risk factors. Additional studies are needed to evaluate whether results are similar in younger age groups and other populations. The significant results in the GWAS for sCD163 implicate novel molecular pathways that warrant future fine-mapping and functional studies.
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