The Library

Does high C-reactive protein concentration increase atherosclerosis? : the Whitehall II Study

Tools

Kivimäki, Mika, Lawlor, Debbie A., Smith, George Davey, Kumari, Meena, Donald, Ann, Britton, A. (Annie), Casas, Juan P., Shah, Tina, Brunner, Eric, Timpson, Nicholas J., Halcox, Julian P. J., Miller, Michelle A., Dr., Humphries, Steve E., Deanfield, John, Marmot, Michael G. and Hingorani, Aroon. (2008) Does high C-reactive protein concentration increase atherosclerosis? : the Whitehall II Study. PLOS One, Vol.3 (No.8). e3013. ISSN 1932-6203

Preview

PDF
WRAP_MIller_journal.pone.0003013.pdf - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Download (158Kb)

Official URL: http://dx.doi.org/10.1371/journal.pone.0003013

Abstract

Background: C-reactive protein (CRP), a marker of systemic inflammation, is associated with risk of coronary events and subclinical measures of atherosclerosis. Evidence in support of this link being causal would include an association robust to adjustments for confounders (multivariable standard regression analysis) and the association of CRP gene polymorphisms with atherosclerosis (Mendelian randomization analysis). Methodology/Principal Findings: We genotyped 3 tag single nucleotide polymorphisms (SNPs) [+1444T>C (rs1130864); +2303G>A (rs1205) and +4899T>G (rs 3093077)] in the CRP gene and assessed CRP and carotid intima-media thickness (CIMT), a structural marker of atherosclerosis, in 4941 men and women aged 50–74 (mean 61) years (the Whitehall II Study). The 4 major haplotypes from the SNPs were consistently associated with CRP level, but not with other risk factors that might confound the association between CRP and CIMT. CRP, assessed both at mean age 49 and at mean age 61, was associated both with CIMT in age and sex adjusted standard regression analyses and with potential confounding factors. However, the association of CRP with CIMT attenuated to the null with adjustment for confounding factors in both prospective and crosssectional analyses. When examined using genetic variants as the instrument for serum CRP, there was no inferred association between CRP and CIMT. Conclusions/Significance: Both multivariable standard regression analysis and Mendelian randomization analysis suggest that the association of CRP with carotid atheroma indexed by CIMT may not be causal.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology R Medicine > RC Internal medicine
Divisions:	Faculty of Medicine > Warwick Medical School > Clinical Sciences Research Institute (CSRI) Faculty of Medicine > Warwick Medical School > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	C-reactive protein, Atherosclerosis -- Risk factors, Atherosclerosis -- Genetic aspects
Journal or Publication Title:	PLOS One
Publisher:	Public Library of Science
ISSN:	1932-6203
Date:	20 August 2008
Volume:	Vol.3
Number:	No.8
Page Range:	e3013
Identification Number:	10.1371/journal.pone.0003013
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	British Academy (BA), Medical Research Council (Great Britain) (MRC), British Heart Foundation, Great Britain. Health and Safety Executive, Great Britain. Dept. of Health (DoH), National Heart, Lung, and Blood Institute, National Institute on Aging (NIA), United States. Agency for Health Care Policy and Research, John D. and Catherine T. MacArthur Foundation, Suomen Akatemia [Academy of Finland]
Grant number:	HL36310 (NHLBI), AG13196 (NIA), HS06516 (AHCPR), 117604 (SA), PG2005/014 (BHF), FS/02/086/14760 (BHF)
References:	1. Verma S, Devaraj S, Jialal I (2006) Is C-reactive protein an innocent bystander or proatherogenic culprit? C-reactive protein promotes atherothrombosis. Circulation 113: 2135–2150. 2. Pepys MB, Hawkins PN, Kahan MC, Tennent GA, Gallimore JR, et al. (2005) Proinflammatory effects of bacterial recombinant human C-reactive protein are caused by contamination with bacterial products, not by C-reactive protein itself. Circ Res 97: e97–103. 3. Koenig W, Khuseyinova N (2007) Biomarkers of atherosclerotic plaque instability and rupture. Arterioscler Thromb Vasc Biol 27: 15–26. 4. Danesh J, Collins R, Appleby P, Peto R (1998) Association of fibrinogen, Creactive protein, albumin, or leukocyte count with coronary heart disease: metaanalyses of prospective studies. JAMA 279: 1477–1482. 5. Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, et al. (2004) Creactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 350: 1387–1397. 6. Lawlor DA, Davey Smith G, Rumley A, Lowe GD, Ebrahim S (2005) Associations of fibrinogen and C-reactive protein with prevalent and incident coronary heart disease are attenuated by adjustment for confounding factors. British Women’s Heart and Health Study. Thromb Haemost 93: 955–963. 7. Kivima¨ki M, Lawlor DA, Juonala M, Davey Smith G, Elovainio M, et al. (2005) Lifecourse socioeconomic position, C-reactive protein, and carotid intima-media thickness in young adults: the Cardiovascular Risk in Young Finns Study. Arterioscler Thromb Vasc Biol 25: 2197–2202. 8. Wang TJ, Nam BH, Wilson PW, Wolf PA, Levy D, et al. (2002) Association of C-reactive protein with carotid atherosclerosis in men and women: the Framingham Heart Study. Arterioscler Thromb Vasc Biol 22: 1662–1667. 9. Lorenz MW, Karbstein P, Markus HS, Sitzer M (2007) High-Sensitivity Creactive Protein Is Not Associated With Carotid Intima-Media Progression. The Carotid Atherosclerosis Progression Study. Stroke 38: 1774–1779. 10. Bots ML (2006) Carotid intima-media thickness as a surrogate marker for cardiovascular disease in intervention studies. Cur Med Res Opinion 22: 2181–2190. 11. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M (2007) Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 115: 459–467. 12. Davey Smith G, Lawlor DA, Harbord R, Timpson N, Rumley A, et al. (2005) Association of C-Reactive Protein With Blood Pressure and Hypertension. Life Course Confounding and Mendelian Randomization Tests of Causality. Arterioscler Thromb Vasc Biol 25: 1051–1056. 13. Lowe GDO, Pepys MB (2006) C-reactive protein and cardiovascular disease: weighing the evidence. Current Atherosclerosis Reports 8: 421–428. 14. Dhingra R, Gona P, Nam BH, D’Agostino RB Sr, Wilson PW, et al. (2007) Creactive protein, inflammatory conditions, and cardiovascular disease risk. Am J Med 120: 1054–1062. 15. Davey Smith G, Ebrahim S (2003) ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 32: 1–22. 16. Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G (2007) Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology. Stat Med 27: 1133–1163. 17. Hingorani A, Humphries S (2005) Nature’s randomised trials. Lancet 366: 1906–1908. 18. Davey Smith G, Lawlor DA, Harbord R, Timpson N, Day I, et al. (2007) Clustered environments and randomized genes: A fundamental distinction between conventional and genetic epidemiology. PLoS Med 4: e352. 19. Casas JP, Shah T, Cooper J, Hawe E, McMahon AD, et al. (2003) Insight into the nature of the CRP-coronary event association using Mendelian randomization. Int J Epidemiol 35: 922–931. 20. Timpson NJ, Lawlor DA, Harbord RM, Gaunt TR, Day IN, et al. (2005) Creactive protein and its role in metabolic syndrome: Mendelian randomisation study. Lancet 366: 1954–1959. 21. Kivima¨ki M, Lawlor DA, Davey Smith G, Eklund C, Hurme M, et al. (2007) Variants in the CRP gene as a measure of lifelong differences in average Creactive protein levels: the Cardiovascular Risk in Young Finns Study, 1980– 2001. Am J Epidemiol 166: 760–764. 22. Kivima¨ki M, Lawlor DA, Eklund C, Davey Smith G, Hurme M, et al. (2007) Mendelian randomization suggests no causal association between C-reactive protein and carotid intima-media thickness in the young Finns study. Arterioscler Thromb Vasc Biol 27: 978–979. 23. Bots ML, Hofman A, Grobbee DE (2007) Increased common carotid intimamedia thickness. Adaptive response or a reflection of atherosclerosis? Findings from the Rotterdam Study. Stroke 28: 2442–2447. 24. Lange LA, Carlson CS, Hindorff LA, Lange EM, Walston J, et al. (2006) Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. JAMA 296: 2703–2711. 25. Lawlor DA, Harbord RM, Timpson NJ, Lowe GDO, Rumley A, et al. (2008) The assocation of C-reactive protein and CRP genotype with coronary heart disease: Findings from five studies with 4,610 cases amongst 18,637 participants. PLoS ONE. In press. 26. Verzilli C, Shah T, Casas JP, Chapman J, Sandhu M, et al. (2008) Bayesian meta-analysis of genetic association studies with different sets of markers. Am J Hum Genet 82: 859–872. 27. Pai JK, Mukamal KJ, Rexrode KM, Rimm EB (2008) C-reactive protein (CRP) gene polymorphisms, CRP levels, and risk of incident coronary heart disease in two nested case-control studies. PLoS ONE 3: e1395. 28. CRP CHD Genetics Collaboration (2008) Collaborative pooled analysis of data on C-reactive protein gene variants and coronary disease: judging causality by Mendelian randomization. Eur J Epidemiol 23: 531–540. 29. Davey Smith G, Ebrahim S (2005) What can mendelian randomisation tell us about modifiable behavioural and environmental exposures? BMJ 330: 1076–1079. 30. Zee RY, Ridker PM (2002) Polymorphism in the human C-reactive protein (CRP) gene, plasma concentrations of CRP, and the risk of future arterial thrombosis. Atherosclerosis 162: 217–219. 31. Brull DJ, Serrano N, Zito F, Jones L, Montgomery HE, et al. (2003) Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease. Arterioscler Thromb Vasc Biol 23: 2063–2069. 32. Russell AI, Cunninghame Graham DS, Shepherd C, Roberton CA, Whittaker J, et al. (2004) Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus. Hum Mol Genet 13: 137–147. 33. Carlson CS, Aldred SF, Lee PK, Tracy RP, Schwartz SM, et al. (2005) Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels. Am J Hum Genet 77: 64–77. 34. Kovacs A, Green F, Hansson LO, Lundman P, Samnega° rd A, et al. (2005) A novel common single nucleotide polymorphism in the promoter region of the Creactive protein gene associated with the plasma concentration of C-reactive protein. Atherosclerosis 178: 193–198. 35. Szalai AJ, Alarcon GS, Calvo-Alen J, Toloza SM, McCrory MA, et al. (2005) Systemic lupus erythematosus in a multiethnic US Cohort (LUMINA): Association between C-reactive protein (CRP) gene polymorphisms and vascular events. Rheumatology (Oxford) 44: 864–868. 36. Miller DT, Zee RY, Suk Danik J, Kozlowski P, Chasman DI, et al. (2005) Association of common CRP gene variants with CRP levels and cardiovascular events. Ann Hum Gen 69: 623–638. 37. Suk HJ, Ridker PM, Cook NR, Zee RY (2005) Relation of polymorphism within the C-reactive protein gene and plasma CRP levels. Atherosclerosis 178: 139–145. 38. Kathiresan S, Larson MG, Vasan RS, Guo CY, Gona P, et al. (2006) Contribution of clinical correlates and 13 C-reactive protein gene polymorphisms to interindividual variability in serum C-reactive protein level. Circulation 113: 1415–1423. 39. Staiger D, Stock JH (1997) Instrumental Variables Regression with Weak Instruments. Econometrica: Journal of the Econometric Society 65: 557–586. 40. Cardon LR, Palmer LJ (2003) Population stratification and spurious allelic association. Lancet 361: 598–604. 41. Knowler WC, Williams RC, Pettitt DJ, Steinberg AG (1988) Gm3;5,13,14 and type 2 diabetes mellitus: an association in American Indians with genetic admixture. Am J Hum Genet 43: 520–526. 42. Gelernter J, Goldman D, Risch N (1993) The A1 allele at the D2 dopamine receptor gene and alcoholism. A reappraisal. JAMA 269: 1673–1677. 43. Szalai AJ, Wu J, Lange EM, McCrory MA, Langefeld CD (2005) Singlenucleotide 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 83: 440–447. 44. Timpson NJ, Davey Smith G, Ebrahim S (2006) Letter by Timpson et al regarding article, ‘‘Contribution of clinical correlates and 13 C-reactive protein gene polymorphisms to interindividual variability in serum C-reactive protein level’’. Circulation 114: e256. 45. Ridker PM, Pare G, Parker A, Zee RY, Danik JS, et al. (2008) 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 82: 1185–1192. 46. Debat V, David P (2006) Mapping phenotypes: canalization, plasticity and developmental stability. Trends in Ecology & Evolution 16: 555–561. 47. Reilly MP, Wolfe ML, Localio AR, Rader DJ (2003) C-reactive protein and coronary artery calcification: The Study of Inherited Risk of Coronary Atherosclerosis (SIRCA). Arterioscler Thromb Vasc Biol 23: 1851–1856. 48. de Maat MP, Trion A (2004) C-reactive protein as a risk factor versus risk marker. Curr Opin Lipidol 15: 651–657. 49. Esposito K, Pontillo A, Di Palo C, Giugliano G, Masella M, et al. (2003) Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA 289: 1799–1804. 50. O’Brien KD, Brehm BJ, Seeley RJ, Bean J, Wener MH, et al. (2005) Dietinduced weight loss is associated with decreases in plasma serum amyloid a and C-reactive protein independent of dietary macronutrient composition in obese subjects. J Clin Endocrin Metabol 90: 2244–2249. 51. Tzoulaki I, Ja¨ rvelin MR, Hartikainen AL, Leinonen M, Pouta A, et al. (2008) Size at birth, weight gain over the life course, and low-grade inflammation in young adulthood: northern Finland 1966 birth cohort study. Eur Heart J 29: 1049–1056. 52. Yeh ET, Willerson JT (2003) Coming of age of C-reactive protein: using inflammation markers in cardiology. Circulation 107: 370–371. 53. Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, et al. (2006) Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 440: 1217–1221. 54. Marmot MG, Davey Smith G, Stansfeld S, Patel C, North F, et al. (1991) Health inequalities among British civil servants: the Whitehall II study. Lancet 337: 1387–1393. 55. Rose GA, Blackburn H, Gillum RF, Prineas RJ (1982) Cardiovascular Survey Methods. 2nd ed. Geneva: World Health Organization. 165 p. 56. Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas AM, et al. (1994) Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation 90: 583–612.
URI:	http://wrap.warwick.ac.uk/id/eprint/4436