C-reactive protein modifies the association of plasma leptin with coronary calcium in asymptomatic overweight individuals

Abstract

Evidence suggests putative interactions of leptin and C-reactive protein (CRP) in the pathogenesis of adiposity-related atherosclerotic cardiovascular disease (CVD). Therefore, we investigated whether CRP levels modify the relationship of leptin levels with coronary artery calcium (CAC). We examined 1,460 asymptomatic individuals from two community-based cross-sectional studies coordinated at a single, university-based research center. We focused on subjects who were overweight or obese (BMI ≥25) given greater biologic plausibility in this setting. In multivariable CAC models, we analyzed the interaction of log-transformed plasma leptin levels with higher CRP levels as defined by three cut-points: two clinically based (2 mg/l, 3 mg/l) and one dataset specific (sex-specific upper quartile). The association of plasma leptin with CAC was modified by higher CRP regardless of cut-point (interaction term P values all <0.01 in fully adjusted models). Leptin levels were associated with CAC in those with high, but not low CRP levels (e.g., tobit ratio for a 1 unit increase in ln(leptin) (95% CI): 2.18 (1.29-3.66) if CRP level ≥3 mg/l; N = 461 vs. 0.94 (0.67-1.31) if CRP levels <3 mg/l; N = 999) in fully adjusted models. No interaction with CRP was present in control analyses with adiponectin, BMI and waist circumference. In conclusion, in asymptomatic overweight and obese adults, increased leptin levels were independently associated with increased CAC in the presence of high, but not low CRP levels, supporting a leptin-CRP interface in atherosclerosis risk.

Figure 1

Association of leptin levels with coronary calcium at high and low C-reactive protein levels. Tobit ratios for the increase in coronary artery calcium (CAC) score for a one unit increase in ln(leptin) demonstrating an independent positive association of leptin with CAC at high, but not low C-reactive protein (CRP) levels. Basic model included age, sex, race, type 2 diabetes mellitus, and waist circumference. Full model further adjusted for apolipoprotein B, ln(triglycerides), high-density lipoprotein cholesterol, systolic blood pressure, diastolic blood pressure, family history of premature cardiovascular disease, menopause, active smoking, alcohol use, exercise, adiponectin, ln(interleukin-6), and medications (same as Table 2). UQ = sex-specific upper quartile of CRP levels (≥6.5 mg/l in women; ≥2.6 mg/l in men).

Figure 2

Association of waist circumference with coronary calcium at high and low C-reactive protein levels. Tobit ratios for the increase in coronary artery calcium (CAC) score for a one standard deviation increase in waist circumference (5.30) in basic and full models (same adjustment as Figure 1 with waist circumference transitioned to independent variable of interest) demonstrating the absence of interaction across C-reactive protein (CRP) cut-points.