C-Reactive protein gene variants are associated with postoperative C-reactive protein levels after coronary artery bypass surgery

Tjörvi E Perry, Jochen D Muehlschlegel, Kuang-Yu Liu, Amanda A Fox, Charles D Collard, Simon C Body, Stanton K Shernan, CABG Genomics Investigators, Tjörvi E Perry, Jochen D Muehlschlegel, Kuang-Yu Liu, Amanda A Fox, Charles D Collard, Simon C Body, Stanton K Shernan, CABG Genomics Investigators

Abstract

Background: Elevated baseline C-reactive protein (CRP) levels are associated with increased risk for developing cardiovascular disease. Several CRP gene variants have been associated with altered baseline CRP levels in ambulatory populations. However, the influence of CRP gene variants on CRP levels during inflammatory states, such as surgery, is largely unexplored. We describe the association between candidate CRP gene variants and postoperative plasma CRP levels in patients undergoing primary, elective coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB).

Methods: Using a multicenter candidate gene association study design, we examined the association between seventeen candidate CRP single nucleotide polymorphisms (SNPs) and inferred haplotypes, and altered postoperative CRP levels in 604 patients undergoing CABG surgery with CPB. Perioperative CRP levels were measured immediately prior to surgery, post-CPB and on postoperative days (POD) 1-4.

Results: CRP levels were significantly elevated at all postoperative time points when compared with preoperative levels (P < 0.0001). After adjusting for clinical covariates, the minor allele of the synonymous coding SNP, rs1800947 was associated with lower peak postoperative CRP levels (P = 2.4 x 10(-4)) and lower CRP levels across all postoperative time points (P = 4.8 x 10(-5)). rs1800947 remained highly significant after Bonferroni adjustment for multiple comparisons.

Conclusion: We identified a CRP gene SNP associated with lower postoperative CRP levels in patients undergoing CABG surgery with CPB. Further investigation is needed to clarify the significance of this association between CRP gene variants and the acute-phase rise in postoperative CRP levels with regard to the risk of adverse postoperative outcomes.

Figures

Figure 1
Figure 1
Linkage disequilibrium (LD) pattern for candidate CRP gene single nucleotide polymorphisms (SNPs). NCBI hg version 36. *The triallelic rs3091244 SNP is presented as one base pair apart. Numbers within the pattern represent the r2 values, indicating the level of correlation between single nucleotide polymorphisms. SNPs rs3316653, rs3316654, rs2794517, rs3122012, rs3093058, rs2808630, rs3093077, rs2794520, rs876538, rs876537, and rs1572970 are tagSNPs selected using Haploview's Tagger based on a pairwise r2 tagging threshold of 0.8.
Figure 2
Figure 2
Observed and estimated genetic associations of rs1800947, rs3091244 T and Haplotype 4 with postoperative plasma CRP levels. Box plot results are presented for the dominant genetic model. Dark gray denotes null copy, light gray denotes the minor allele of rs180094, rs3091244 T allele and CC haplotype (H4). Column A. Observed genetic effect on postoperative CRP levels. rs1800947 minor allele and H4 were associated with lower plasma CRP levels (POD2-4 P ≤ 0.0095 and P ≤ 0.0037, respectively), rs3091244 T allele was associated with higher plasma CRP levels (POD2 and 3 P ≤ 0.0073). Column B. Bootstrapping estimates for CRP levels using repeated-measure Tobit regression model adjusted for clinical covariates.

References

    1. Armani A, Becker RC. The biology, utilization, and attenuation of C-reactive protein in cardiovascular disease: part I. Am Heart J. 2005;149:971–976. doi: 10.1016/j.ahj.2004.12.031.
    1. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003;111:1805–1812.
    1. Agrawal A. CRP after 2004. Mol Immunol. 2005;42:927–930. doi: 10.1016/j.molimm.2004.09.028.
    1. Kaplan MH, Volanakis JE. Interaction of C-reactive protein complexes with the complement system. I. Consumption of human complement associated with the reaction of C-reactive protein with pneumococcal C-polysaccharide and with the choline phosphatides, lecithin and sphingomyelin. J Immunol. 1974;112:2135–2147.
    1. Mold C, Gewurz H, Du Clos TW. Regulation of complement activation by C-reactive protein. Immunopharmacology. 1999;42:23–30. doi: 10.1016/S0162-3109(99)00007-7.
    1. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000;102:2165–2168.
    1. Agrawal A, Cha-Molstad H, Samols D, Kushner I. Transactivation of C-reactive protein by IL-6 requires synergistic interaction of CCAAT/enhancer binding protein beta (C/EBP beta) and Rel p50. J Immunol. 2001;166:2378–2384.
    1. Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A, Hutchinson WL, Pepys MB. C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation. 1999;99:237–242.
    1. Mendall MA, Strachan DP, Butland BK, Ballam L, Morris J, Sweetnam PM, Elwood PC. C-reactive protein: relation to total mortality, cardiovascular mortality and cardiovascular risk factors in men. Eur Heart J. 2000;21:1584–1590. doi: 10.1053/euhj.1999.1982.
    1. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–843. doi: 10.1056/NEJM200003233421202.
    1. Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation. 1998;98:731–733.
    1. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med. 2000;343:1139–1147. doi: 10.1056/NEJM200010193431602.
    1. Mendall MA, Patel P, Ballam L, Strachan D, Northfield TC. C reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study. Bmj. 1996;312:1061–1065.
    1. MacGregor AJ, Gallimore JR, Spector TD, Pepys MB. Genetic effects on baseline values of C-reactive protein and serum amyloid a protein: a comparison of monozygotic and dizygotic twins. Clin Chem. 2004;50:130–134. doi: 10.1373/clinchem.2003.028258.
    1. Retterstol L, Eikvar L, Berg K. A twin study of C-Reactive Protein compared to other risk factors for coronary heart disease. Atherosclerosis. 2003;169:279–282. doi: 10.1016/S0021-9150(03)00192-8.
    1. Suk HJ, Ridker PM, Cook NR, Zee RY. Relation of polymorphism within the C-reactive protein gene and plasma CRP levels. Atherosclerosis. 2005;178:139–145. doi: 10.1016/j.atherosclerosis.2004.07.033.
    1. Chen J, Zhao J, Huang J, Su S, Qiang B, Gu D. -717A>G polymorphism of human C-reactive protein gene associated with coronary heart disease in ethnic Han Chinese: the Beijing atherosclerosis study. J Mol Med. 2005;83:72–78. doi: 10.1007/s00109-004-0585-5.
    1. Crawford DC, Sanders CL, Qin X, Smith JD, Shephard C, Wong M, Witrak L, Rieder MJ, Nickerson DA. Genetic variation is associated with C-reactive protein levels in the Third National Health and Nutrition Examination Survey. Circulation. 2006;114:2458–2465. doi: 10.1161/CIRCULATIONAHA.106.615740.
    1. Miller DT, Zee RY, Suk Danik J, Kozlowski P, Chasman DI, Lazarus R, Cook NR, Ridker PM, Kwiatkowski DJ. Association of common CRP gene variants with CRP levels and cardiovascular events. Ann Hum Genet. 2005;69:623–638. doi: 10.1111/j.1529-8817.2005.00210.x.
    1. Reiner AP, Barber MJ, Guan Y, Ridker PM, Lange LA, Chasman DI, Walston JD, Cooper GM, Jenny NS, Rieder MJ, et al. Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein. Am J Hum Genet. 2008;82:1193–1201. doi: 10.1016/j.ajhg.2008.03.017.
    1. Ridker PM, Pare G, Parker A, Zee RY, Danik JS, Buring JE, Kwiatkowski D, Cook NR, Miletich JP, Chasman DI. Loci related to metabolic-syndrome pathways including LEPR, HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study. Am J Hum Genet. 2008;82:1185–1192. doi: 10.1016/j.ajhg.2008.03.015.
    1. Collard CD, Shernan SK, Fox AA, Bernig T, Chanock SJ, Vaughn WK, Takahashi K, Ezekowitz AB, Jarolim P, Body SC. The MBL2 'LYQA secretor' haplotype is an independent predictor of postoperative myocardial infarction in whites undergoing coronary artery bypass graft surgery. Circulation. 2007;116:I106–112.
    1. Hage FG, Szalai AJ. C-reactive protein gene polymorphisms, C-reactive protein blood levels, and cardiovascular disease risk. J Am Coll Cardiol. 2007;50:1115–1122. doi: 10.1016/j.jacc.2007.06.012.
    1. de Bakker PI, Yelensky R, Pe'er I, Gabriel SB, Daly MJ, Altshuler D. Efficiency and power in genetic association studies. Nat Genet. 2005;37:1217–1223. doi: 10.1038/ng1669.
    1. Stephens M, Scheet P. Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am J Hum Genet. 2005;76:449–462. doi: 10.1086/428594.
    1. Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001;68:978–989. doi: 10.1086/319501.
    1. Imai K, King G, Lau O. Toward A Common Framework for Statistical Analysis and Development. Journal of Computational and Graphical Statistics. 2008;17:892–913. doi: 10.1198/106186008X384898.
    1. Canty A, Ripley B. Boot: Bootstrap R (S-Plus) Functions. Version 12–36. 2009.
    1. Davison AC, Hinkley DV. Bootstrap Methods and their Application. New York, NY: Cambridge University Press; 1997.
    1. R Development Core Team . R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2008.
    1. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–575. doi: 10.1086/519795.
    1. Carlson CS, Aldred SF, Lee PK, Tracy RP, Schwartz SM, Rieder M, Liu K, Williams OD, Iribarren C, Lewis EC, et al. Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels. Am J Hum Genet. 2005;77:64–77. doi: 10.1086/431366.
    1. Davey Smith G, Lawlor DA, Harbord R, Timpson N, Rumley A, Lowe GD, Day IN, Ebrahim S. Association of C-reactive protein with blood pressure and hypertension: life course confounding and mendelian randomization tests of causality. Arterioscler Thromb Vasc Biol. 2005;25:1051–1056. doi: 10.1161/01.ATV.0000160351.95181.d0.
    1. Eklund C, Kivimaki M, Islam MS, Juonala M, Kahonen M, Marniemi J, Lehtimaki T, Viikari J, Raitakari OT, Hurme M. C-reactive protein genetics is associated with carotid artery compliance in men in The Cardiovascular Risk in Young Finns Study. Atherosclerosis. 2008;196:841–848. doi: 10.1016/j.atherosclerosis.2007.01.027.
    1. Russell AI, Cunninghame Graham DS, Shepherd C, Roberton CA, Whittaker J, Meeks J, Powell RJ, Isenberg DA, Walport MJ, Vyse TJ. Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus. Hum Mol Genet. 2004;13:137–147. doi: 10.1093/hmg/ddh021.
    1. Kolz M, Koenig W, Muller M, Andreani M, Greven S, Illig T, Khuseyinova N, Panagiotakos D, Pershagen G, Salomaa V, et al. DNA variants, plasma levels and variability of C-reactive protein in myocardial infarction survivors: results from the AIRGENE study. Eur Heart J. 2008;29:1250–1258. doi: 10.1093/eurheartj/ehm442.
    1. Lange LA, Carlson CS, Hindorff LA, Lange EM, Walston J, Durda JP, Cushman M, Bis JC, Zeng D, Lin D, et al. Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. JAMA. 2006;296:2703–2711. doi: 10.1001/jama.296.22.2703.
    1. Brull DJ, Serrano N, Zito F, Jones L, Montgomery HE, Rumley A, Sharma P, Lowe GD, World MJ, Humphries SE, et al. Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease. Arterioscler Thromb Vasc Biol. 2003;23:2063–2069. doi: 10.1161/01.ATV.0000084640.21712.9C.
    1. Shen LX, Basilion JP, Stanton VP., Jr Single-nucleotide polymorphisms can cause different structural folds of mRNA. Proc Natl Acad Sci USA. 1999;96:7871–7876. doi: 10.1073/pnas.96.14.7871.
    1. Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM. A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science. 2007;315:525–528. doi: 10.1126/science.1135308.
    1. Kathiresan S, Larson MG, Vasan RS, Guo CY, Gona P, Keaney JF, Jr, Wilson PW, Newton-Cheh C, Musone SL, Camargo AL, et al. Contribution of clinical correlates and 13 C-reactive protein gene polymorphisms to interindividual variability in serum C-reactive protein level. Circulation. 2006;113:1415–1423. doi: 10.1161/CIRCULATIONAHA.105.591271.
    1. Kovacs A, Green F, Hansson LO, Lundman P, Samnegard A, Boquist S, Ericsson CG, Watkins H, Hamsten A, Tornvall P. A novel common single nucleotide polymorphism in the promoter region of the C-reactive protein gene associated with the plasma concentration of C-reactive protein. Atherosclerosis. 2005;178:193–198. doi: 10.1016/j.atherosclerosis.2004.08.018.
    1. Suk Danik J, Chasman DI, Cannon CP, Miller DT, Zee RY, Kozlowski P, Kwiatkowski DJ, Ridker PM. Influence of genetic variation in the C-reactive protein gene on the inflammatory response during and after acute coronary ischemia. Ann Hum Genet. 2006;70:705–716. doi: 10.1111/j.1469-1809.2006.00272.x.
    1. Wang Q, Hunt SC, Xu Q, Chen YE, Province MA, Eckfeldt JH, Pankow JS, Song Q. Association study of CRP gene polymorphisms with serum CRP level and cardiovascular risk in the NHLBI Family Heart Study. Am J Physiol Heart Circ Physiol. 2006;291:H2752–2757. doi: 10.1152/ajpheart.01164.2005.
    1. Szalai AJ, Wu J, Lange EM, McCrory MA, Langefeld CD, Williams A, Zakharkin SO, George V, Allison DB, Cooper GS, et al. Single-nucleotide polymorphisms in the C-reactive protein (CRP) gene promoter that affect transcription factor binding, alter transcriptional activity, and associate with differences in baseline serum CRP level. J Mol Med. 2005;83:440–447. doi: 10.1007/s00109-005-0658-0.

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