Genetic variants in platelet factor 4 modulate infilammatory and platelet activation biomarkers

Abstract

Background: African Americans suffer from higher prevalence and severity of atherosclerosis compared with whites, highlighting racial and ethnic disparities in cardiovascular disease. Previous studies have pointed to the role of vascular infilammation and platelet activation in the formation of atherosclerotic lesions. Methods and Results: We explored the role of genetic variation in 4 chemokine/chemokine receptor genes (CX3CR1, CX3CL1, CXCR3, and PF4) on systemic infilammation and platelet activation serum biomarkers (fractalkine, platelet P-selectin, platelet factor 4 [PF4], and tumor necrosis factor-α). In total, 110 single nucleotide polymorphisms were tested among 1042 African Americans and 763 whites. The strongest association with serum PF4 levels was observed for rs168449, which was significant in both racial groups (P value: African Americans=0.0017, whites=0.014, combined=1.2×10 -4), and remained significant after permutation-based multiple corrections (Pc value: combined=0.0013). After accounting for the effect of rs168449, we identified another significant single nucleotide polymorphism (rs1435520), suggesting a second independent signal regulating serum PF4 levels (conditional P value: African Americans=0.02, whites=0.02). Together, these single nucleotide polymorphisms explained 0.98% and 1.23% of serum PF4 variance in African Americans and whites, respectively. Additionally, in African Americans, we found an additional PF4 variant (rs8180167), uncorrelated with rs168449 and rs1435520, associated with serum tumor necrosis factor-α levels (P=0.008, Pc=0.048). Conclusions: Our study highlights the importance of PF4 variants in the regulation of platelet activation (PF4) and systemic infilammation (tumor necrosis factor-α) serum biomarkers. © 2012 American Heart Association, Inc.