© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Genotype at a promoter polymorphism of the interleukin-6 gene is associated with baseline levels of plasma C-reactive protein
aDepartment of Medicine and Therapeutics, University of Aberdeen, Aberdeen, UK
bDepartment of Cardiovascular Medicine, Oxford University, Oxford, UK
cInstitut Pasteur, Paris, France
dCentre National de Genotypage, Evry, France
eNuffield Department of Medicine, Oxford University, Oxford, UK
fInstitute of Human Genetics, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, UK
b.d.keavney{at}ncl.ac.uk
* Corresponding author. Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle-upon-Tyne NE1 3BZ, UK. Tel.: +44-191-2227-149; fax: +44-191-2220-723
Objective: Baseline concentrations of plasma C-reactive protein (CRP) are associated with coronary heart disease. Interleukin-6 (IL-6) regulates CRP gene expression; a promoter polymorphism (–174G/C) of the IL-6 gene has been shown to influence IL-6 transcription but the relationship between genotype at this polymorphism and circulating levels of inflammatory markers remains unclear. We hypothesised that plasma CRP would be a heritable phenotype that would be influenced by genotype at this polymorphism. Methods: We measured baseline plasma CRP and determined genotypes at the –174G/C polymorphism of the IL-6 gene in 588 members of 98 nuclear families. The heritability of plasma CRP and the association of plasma CRP with genotype were determined using variance components methods. Results: Baseline CRP levels were highly heritable (h2=0.39, P<0.0000001). Presence of the –174C allele was associated with higher baseline CRP levels, both in the whole population (P=0.01), and in the founders only (n=128, P=0.001). Family-based analyses confirmed the association (P=0.02) suggesting that it arises from chromosomal proximity or identity of the typed polymorphism with a genetic variant influencing baseline CRP levels. Conclusions: Baseline plasma CRP is a significantly heritable cardiovascular risk factor. Levels are associated with genotype at the –174G/C polymorphism of the IL-6 gene.
KEYWORDS Atherosclerosis; Cytokines; Epidemiology; Infection/inflammation; Sequence (DNA/RNA/prot)
1 M.A.V. and F.R.G. contributed equally to this work.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Aker, C. Bantis, P. Reis, N. Kuhr, C. Schwandt, B. Grabensee, P. Heering, and K. Ivens Influence of interleukin-6 G-174C gene polymorphism on coronary artery disease, cardiovascular complications and mortality in dialysis patients Nephrol. Dial. Transplant., September 1, 2009; 24(9): 2847 - 2851. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Shen and J. M. Ordovas Impact of Genetic and Environmental Factors on hsCRP Concentrations and Response to Therapeutic Agents Clin. Chem., February 1, 2009; 55(2): 256 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Corella, J. I. Gonzalez, M. Bullo, P. Carrasco, O. Portoles, J. Diez-Espino, M. I. Covas, V. Ruiz-Gutierrez, E. Gomez-Gracia, F. Aros, et al. Polymorphisms Cyclooxygenase-2 -765G>C and Interleukin-6 -174G>C Are Associated with Serum Inflammation Markers in a High Cardiovascular Risk Population and Do Not Modify the Response to a Mediterranean Diet Supplemented with Virgin Olive Oil or Nuts J. Nutr., January 1, 2009; 139(1): 128 - 134. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fornage, Y. A. Chiang, E. S. O'Meara, B. M. Psaty, A. P. Reiner, D. S. Siscovick, R. P. Tracy, and W.T. Longstreth Jr Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain: The Cardiovascular Health Study Stroke, July 1, 2008; 39(7): 1952 - 1959. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kolz, W. Koenig, M. Muller, M. Andreani, S. Greven, T. Illig, N. Khuseyinova, D. Panagiotakos, G. Pershagen, V. Salomaa, et al. DNA variants, plasma levels and variability of C-reactive protein in myocardial infarction survivors: results from the AIRGENE study Eur. Heart J., May 2, 2008; 29(10): 1250 - 1258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Edberg, J. Wu, C. D. Langefeld, E. E. Brown, M. C. Marion, G. McGwin Jr, M. Petri, R. Ramsey-Goldman, J. D. Reveille, S. G. Frank, et al. Genetic variation in the CRP promoter: association with systemic lupus erythematosus Hum. Mol. Genet., April 15, 2008; 17(8): 1147 - 1155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Baker, T. Rahman, D. Hall, P. J Avery, B. M Mayosi, J. M C Connell, M. Farrall, H. Watkins, and B. Keavney The C-532T polymorphism of the angiotensinogen gene is associated with pulse pressure: A possible explanation for heterogeneity in genetic association studies of AGT and hypertension Int. J. Epidemiol., December 1, 2007; 36(6): 1356 - 1362. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. G. Hage and A. J. Szalai C-Reactive Protein Gene Polymorphisms, C-Reactive Protein Blood Levels, and Cardiovascular Disease Risk J. Am. Coll. Cardiol., September 18, 2007; 50(12): 1115 - 1122. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Lange, C. S. Carlson, L. A. Hindorff, E. M. Lange, J. Walston, J. P. Durda, M. Cushman, J. C. Bis, D. Zeng, D. Lin, et al. Association of Polymorphisms in the CRP Gene With Circulating C-Reactive Protein Levels and Cardiovascular Events JAMA, December 13, 2006; 296(22): 2703 - 2711. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. Crawford, C. L. Sanders, X. Qin, J. D. Smith, C. Shephard, M. Wong, L. Witrak, M. J. Rieder, and D. A. Nickerson Genetic Variation Is Associated With C-Reactive Protein Levels in the Third National Health and Nutrition Examination Survey Circulation, December 5, 2006; 114(23): 2458 - 2465. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. P. Hersh, D. T. Miller, D. J. Kwiatkowski, and E. K. Silverman Genetic determinants of C-reactive protein in COPD Eur. Respir. J., December 1, 2006; 28(6): 1156 - 1162. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Imrie, M. Freel, B. M. Mayosi, E. Davies, R. Fraser, M. Ingram, H. J. Cordell, M. Farrall, P. J. Avery, H. Watkins, et al. Association between Aldosterone Production and Variation in the 11{beta}-Hydroxylase (CYP11B1) Gene J. Clin. Endocrinol. Metab., December 1, 2006; 91(12): 5051 - 5056. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Wang, S. C. Hunt, Q. Xu, Y. E. Chen, M. A. Province, J. H. Eckfeldt, J. S. Pankow, and Q. Song 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, December 1, 2006; 291(6): H2752 - H2757. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Lakka, T. Rankinen, T. Rice, A. S. Leon, D. C. Rao, J. S. Skinner, and C. Bouchard Quantitative trait locus on chromosome 20q13 for plasma levels of C-reactive protein in healthy whites: the HERITAGE Family Study Physiol Genomics, October 11, 2006; 27(2): 103 - 107. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ladenvall, K. Jood, C. Blomstrand, S. Nilsson, C. Jern, and P. Ladenvall Serum C-Reactive Protein Concentration and Genotype in Relation to Ischemic Stroke Subtype Stroke, August 1, 2006; 37(8): 2018 - 2023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Biolo, A. Amoroso, S. Savoldi, A. Bosutti, M. Martone, D. Pirulli, F. Bianco, S. Ulivi, S. Bertok, M. Artero, et al. Association of interferon-{gamma} +874A polymorphism with reduced long-term inflammatory response in haemodialysis patients Nephrol. Dial. Transplant., May 1, 2006; 21(5): 1317 - 1322. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. B. Sansbury, A. W. Bergen, K. L. Wanke, B. Yu, N. E. Caporaso, N. Chatterjee, L. Ratnasinghe, A. Schatzkin, T. A. Lehman, A. Kalidindi, et al. Inflammatory cytokine gene polymorphisms, nonsteroidal anti-inflammatory drug use, and risk of adenoma polyp recurrence in the polyp prevention trial. Cancer Epidemiol. Biomarkers Prev., March 1, 2006; 15(3): 494 - 501. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. McCaffery, N. Frasure-Smith, M.-P. Dube, P. Theroux, G. A. Rouleau, Q. Duan, and F. Lesperance Common genetic vulnerability to depressive symptoms and coronary artery disease: a review and development of candidate genes related to inflammation and serotonin. Psychosom Med, March 1, 2006; 68(2): 187 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Liu, Y. Berthier-Schaad, M. D. Fallin, N. E. Fink, R. P. Tracy, M. J. Klag, M. W. Smith, and J. Coresh IL-6 Haplotypes, Inflammation, and Risk for Cardiovascular Disease in a Multiethnic Dialysis Cohort J. Am. Soc. Nephrol., March 1, 2006; 17(3): 863 - 870. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P.S. Sie, F. A. Sayed-Tabatabaei, H.-H. S. Oei, A. G. Uitterlinden, H. A.P. Pols, A. Hofman, C. M. van Duijn, and J. C.M. Witteman Interleukin 6 -174 G/C Promoter Polymorphism and Risk of Coronary Heart Disease: Results from the Rotterdam Study and a Meta-Analysis Arterioscler Thromb Vasc Biol, January 1, 2006; 26(1): 212 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Grimm, L. Six, C. Tomovski, P. Speiser, E. Joura, R. Zeillinger, G. Sliutz, A. Reinthaller, and L. A. Hefler A Common Interleukin-6 Promoter Polymorphism in Patients With Vulvar Cancer Reproductive Sciences, December 1, 2005; 12(8): 617 - 620. [Abstract] [PDF]
|
|
|
|
 |
|
 H. Bruunsgaard Physical activity and modulation of systemic low-level inflammation J. Leukoc. Biol., October 1, 2005; 78(4): 819 - 835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Mayosi, P. J. Avery, M. Baker, N. Gaukrodger, H. Imrie, F. R. Green, M. Farrall, H. Watkins, and B. Keavney Genotype at the -174G/C Polymorphism of the Interleukin-6 Gene Is Associated With Common Carotid Artery Intimal-Medial Thickness: Family Study and Meta-Analysis Stroke, October 1, 2005; 36(10): 2215 - 2219. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Hefler, C. Grimm, T. Lantzsch, D. Lampe, S. Leodolter, H. Koelbl, G. Heinze, A. Reinthaller, D. Tong-Cacsire, C. Tempfer, et al. Interleukin-1 and Interleukin-6 Gene Polymorphisms and the Risk of Breast Cancer in Caucasian Women Clin. Cancer Res., August 15, 2005; 11(16): 5718 - 5721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Di Napoli, M. Schwaninger, R. Cappelli, E. Ceccarelli, G. Di Gianfilippo, C. Donati, H. C.A. Emsley, S. Forconi, S. J. Hopkins, L. Masotti, et al. Evaluation of C-Reactive Protein Measurement for Assessing the Risk and Prognosis in Ischemic Stroke: A Statement for Health Care Professionals From the CRP Pooling Project Members Stroke, June 1, 2005; 36(6): 1316 - 1329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Campa, R. J. Hung, D. Mates, D. Zaridze, N. Szeszenia-Dabrowska, P. Rudnai, J. Lissowska, E. Fabianova, V. Bencko, L. Foretova, et al. Lack of Association between Polymorphisms in Inflammatory Genes and Lung Cancer Risk Cancer Epidemiol. Biomarkers Prev., February 1, 2005; 14(2): 538 - 539. [Full Text] [PDF]
|
|
|
|
|
|
B. Keavney, B. Mayosi, N. Gaukrodger, H. Imrie, M. Baker, R. Fraser, M. Ingram, H. Watkins, M. Farrall, E. Davies, et al. Genetic Variation at the Locus Encompassing 11-{beta} Hydroxylase and Aldosterone Synthase Accounts for Heritability in Cortisol Precursor (11-Deoxycortisol) Urinary Metabolite Excretion J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 1072 - 1077. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Huber, C. Grimm, S. Jirecek, R. Zeillinger, K. Heim, P. Husslein, and L. Hefler An lnterleukin-6 Gene Promoter Polymorphism and Unexplained Late Intrauterine Fetal Death: A Multicenter Study Reproductive Sciences, January 1, 2005; 12(1): 33 - 36. [Abstract] [PDF]
|
|
|
|
|
|
M. P.M. de Maat, E. M. Bladbjerg, J. von Bornemann Hjelmborg, L. Bathum, J. Jespersen, and K. Christensen Genetic Influence on Inflammation Variables in the Elderly Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 2168 - 2173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. R. Harding, S. Dhamrait, A. Whitelaw, S. E. Humphries, N. Marlow, and H. E. Montgomery Does Interleukin-6 Genotype Influence Cerebral Injury or Developmental Progress After Preterm Birth? Pediatrics, October 1, 2004; 114(4): 941 - 947. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. O. Obisesan, C. Leeuwenburgh, T. Phillips, R. E. Ferrell, D. A. Phares, S. J. Prior, and J. M. Hagberg C-Reactive Protein Genotypes Affect Baseline, but not Exercise Training-Induced Changes, in C-Reactive Protein Levels Arterioscler Thromb Vasc Biol, October 1, 2004; 24(10): 1874 - 1879. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. H. Gibbons, C. C. Liew, M. O. Goodarzi, J. I. Rotter, W. A. Hsueh, H. M. Siragy, R. Pratt, and V. J. Dzau Genetic Markers: Progress and Potential for Cardiovascular Disease Circulation, June 29, 2004; 109(25_suppl_1): IV-47 - IV-58. [Full Text] [PDF]
|
|
|
|
|
|
J. R. Greenfield, K. Samaras, A. B. Jenkins, P. J. Kelly, T. D. Spector, J. R. Gallimore, M. B. Pepys, and L. V. Campbell Obesity Is an Important Determinant of Baseline Serum C-Reactive Protein Concentration in Monozygotic Twins, Independent of Genetic Influences Circulation, June 22, 2004; 109(24): 3022 - 3028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Keavney Commentary: Katan's remarkable foresight: genes and causality 18 years on Int. J. Epidemiol., February 1, 2004; 33(1): 11 - 14. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Campa, S. Zienolddiny, V. Maggini, V. Skaug, A. Haugen, and F. Canzian Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer Carcinogenesis, February 1, 2004; 25(2): 229 - 235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. MacGregor, J. R. Gallimore, T. D. Spector, and M. B. Pepys Genetic Effects on Baseline Values of C-Reactive Protein and Serum Amyloid A Protein: A Comparison of Monozygotic and Dizygotic Twins Clin. Chem., January 1, 2004; 50(1): 130 - 134. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.M. Hirschfield and M.B. Pepys C-reactive protein and cardiovascular disease: new insights from an old molecule QJM, November 1, 2003; 96(11): 793 - 807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Kluft and M. P.M. de Maat Genetics of C-Reactive Protein: New Possibilities and Complications Arterioscler Thromb Vasc Biol, November 1, 2003; 23(11): 1956 - 1959. [Full Text] [PDF]
|
|
|
|
|
|
D. Harding, S. Dhamrait, A. Millar, S. Humphries, N. Marlow, A. Whitelaw, and H. Montgomery Is Interleukin-6 -174 Genotype Associated With the Development of Septicemia in Preterm Infants? Pediatrics, October 1, 2003; 112(4): 800 - 803. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Landi, V. Moreno, L. Gioia-Patricola, E. Guino, M. Navarro, J. de Oca, G. Capella, and F. Canzian Association of Common Polymorphisms in Inflammatory Genes Interleukin (IL)6, IL8, Tumor Necrosis Factor {alpha}, NFKB1, and Peroxisome Proliferator-activated Receptor {gamma} with Colorectal Cancer , Cancer Res., July 1, 2003; 63(13): 3560 - 3566. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Hefler, C. Grimm, S. Ackermann, S. Malur, A. R. Radjabi-Rahat, S. Leodolter, M. W. Beckmann, R. Zeillinger, H. Koelbl, and C. B. Tempfer An Interleukin-6 Gene Promoter Polymorphism Influences the Biological Phenotype of Ovarian Cancer Cancer Res., June 15, 2003; 63(12): 3066 - 3068. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Jerrard-Dunne, M. Sitzer, P. Risley, D. A. Steckel, A. Buehler, S. von Kegler, and H. S. Markus Interleukin-6 Promoter Polymorphism Modulates the Effects of Heavy Alcohol Consumption on Early Carotid Artery Atherosclerosis: The Carotid Atherosclerosis Progression Study (CAPS) Stroke, February 1, 2003; 34(2): 402 - 407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Mayosi, B. Keavney, A. Kardos, C. H. Davies, P. J. Ratcliffe, M. Farrall, and H. Watkins Electrocardiographic measures of left ventricular hypertrophy show greater heritability than echocardiographic left ventricular mass Eur. Heart J., December 2, 2002; 23(24): 1963 - 1971. [Abstract] [PDF]
|
|
|
|
 |
|
 P J Sheridan and D C Crossman Critical review of unstable angina and non-ST elevation myocardial infarction Postgrad. Med. J., December 1, 2002; 78(926): 717 - 726. [Abstract] [Full Text] [PDF]
|
|