title: Genetic variants in platelet factor 4 modulate inflammatory 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 inflammation and platelet activation in the formation of atherosclerotic lesions.
  
  
  RESULTS
  We explored the role of genetic variation in 4 chemokine/chemokine receptor genes (CX3CR1, CX3CL1, CXCR3, and PF4) on systemic inflammation 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 (P(c) 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, P(c)=0.048).
  
  
  CONCLUSIONS
  Our study highlights the importance of PF4 variants in the regulation of platelet activation (PF4) and systemic inflammation (tumor necrosis factor-α) serum biomarkers.
authors: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Pallav
authors: P
authors: Bhatnagar
authors: Xiaochun
authors: X
authors: Lu
authors: Michele K
authors: MK
authors: Evans
authors: Thomas A
authors: TA
authors: Laveist
authors: Alan B
authors: AB
authors: Zonderman
authors: Darryl L
authors: DL
authors: Carter
authors: Dan E
authors: DE
authors: Arking
authors: Craig A
authors: CA
authors: Fletcher
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D054428:Chemokine CX3CL1 / Q000235:genetics; D003710:Demography; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000235:genetics*; D010978:Platelet Factor 4 / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054367:Receptors, CXCR3 / Q000235:genetics; D023062:Receptors, Interleukin-8A / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D015415:Biomarkers; C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; D054367:Receptors, CXCR3; D023062:Receptors, Interleukin-8A; D014409:Tumor Necrosis Factor-alpha; D010978:Platelet Factor 4