Common haplotypes of the C-reactive protein gene and circulating leptin levels influence the interindividual variability in serum C-reactive protein levels

Summary

C-reactive protein (CRP) is a marker of systemic inflammation significantly associated with an increased risk of cardiovascular disease in the general population. The aim of our current work was to study those clinical and genetic variables potentially associated with interindividual variability in serum CRP levels. A random sample of 844 participants (450 women, mean age 55 years) from a study carried out on the general Spanish population (The Segovia Study) was studied. Our results showed that age, gender, waist circumference, leptin, impaired glucose tolerance and smoking were the clinical variables significantly associated with variations in serum CRP levels. Among those, leptin showed the strongest association, explaining 11% of the interindividual variability in circulating CRP levels (p < 0.001). To study the effect of genetic variants on serum CRP levels, 10 SNPs within the CRP locus were genotyped in 756 participants. Four of these SNPs (rs1417938, rs1800947, rs1130864, rs1205) were significantly associated with CRP levels after adjustment for clinical variables. Among the common haplotypes inferred from eight SNPs, two (CCATGCCT, p = 0.025; CTATCCTT, p = 0.004) explained 2.9% of the total variation in serum CRP. The results here reported show that 2.9% of the total variation in circulating CRP levels seems to be explained by genetics variations within CRP locus. Furthermore, serum leptin levels are strongly associated with serum CRP levels in our Spanish population.

Keywords

C-reactive protein - genetic - inflammation - population - leptin

• References

• 1 Combes V, Simon AC, Grau GE. et al. In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant. J Clin Invest 1999; 104: 93-102.
• 2 Kagawa H, Komiyama Y, Nakamura S. et al. Expression of functional tissue factor on small vesicles of lipopolysaccharide-stimulated human vascular endothelial cells. Thromb Res 1998; 91: 297-304.
• 3 Abid Hussein MN, Meesters EW, Osmanovic N. et al. Antigenic characterization of endothelial cell-derived microparticles and their detection ex vivo. J Thromb Haemost 2003; 1: 2434-2443.
• 4 Minagar A, Jy W, Jimenez JJ. et al. Elevated plasma endothelial microparticles in multiple sclerosis. Neurology 2001; 56: 1319-1324.
• 5 Gonzalez-Quintero VH, Jimenez JJ, Jy W. et al. Elevated plasma endothelial microparticles in preeclampsia. Am J Obstet Gynecol 2003; 189: 589-593.
• 6 Nieuwland R, Berckmans RJ, McGregor S. et al. Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood 2000; 95: 930-935.
• 7 Mallat Z, Hugel B, Ohan J. et al. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques. Circulation 1999; 99: 348-353.
• 8 Abid Hussein MN, Nieuwland R, Hau CM. et al. Cell-derived microparticles contain caspase 3 in vitro and in vivo. J Thromb Haemost 2005; 3: 888-896.
• 9 Sebbagh M, Renvoize C, Hamelin J. et al. Caspase- 3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nat Cell Biol 2001; 3: 346-352.
• 10 Zoellner H, Hofler M, Beckmann R. et al. Serum albumin is a specific inhibitor of apoptosis in human endothelial cells. J Cell Sci 1996; 109: 2571-2580.
• 11 Hamilton KK, Hattori R, Esmon CT. et al. Complement proteins C5b-9 induce vesiculation of the endothelial plasma membrane and expose catalytic surface for assembly of the prothrombinase enzyme complex. J Biol Chem 1990; 265: 3809-3814.
• 12 Coleman ML, Sahai EA, Yeo M. et al. Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 2001; 3: 339-345.
• 13 Miyoshi H, Umeshita K, Sakon M. et al. Calpain activation in plasma membrane bleb formation during tert-butyl hydroperoxide-induced rat hepatocyte injury. Gastroenterology 1996; 110: 1897-1904.
• 14 van Berkel AM, van MJ, Groen AK. et al. Mechanisms of biliary stent clogging: confocal laser scanning and scanning electron microscopy. Endoscopy 2005; 37: 729-734.
• 15 Janicke RU, Sprengart ML, Wati MR. et al. Caspase- 3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 1998; 273: 9357-9360.
• 16 Zheng TS, Schlosser SF, Dao T. et al. Caspase-3 controls both cytoplasmic and nuclear events associated with Fas-mediated apoptosis in vivo. Proc Natl Acad Sci USA 1998; 95: 13618-13623.
• 17 de Gassart A, Geminard C, Fevrier B. et al. Lipid raft-associated protein sorting in exosomes. Blood 2003; 102: 4336-4344.
• 18 O’Connell DJ, Rozenvayn N, Flaumenhaft R. Phosphatidylinositol 4,5-bisphosphate regulates activationinduced platelet microparticle formation. Biochemistry 2005; 44: 6361-6370.
• 19 Hasmim M, Vassalli G, Alghisi GC. et al. Expressed isolated integrin beta1 subunit cytodomain induces endothelial cell death secondary to detachment. Thromb Haemost 2005; 94: 1060-1070.