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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2009

Open Access 01-12-2009 | Research article

IL6 and CRPhaplotypes are associated with COPD risk and systemic inflammation: a case-control study

Authors: Dilyara G Yanbaeva, Mieke A Dentener, Martijn A Spruit, Jeanine J Houwing-Duistermaat, Daniel Kotz, Valéria Lima Passos, Emiel FM Wouters

Published in: BMC Medical Genetics | Issue 1/2009

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Abstract

Background

Elevated circulating levels of C-reactive protein (CRP), interleukin (IL)-6 and fibrinogen (FG) have been repeatedly associated with many adverse outcomes in patients with chronic obstructive pulmonary disease (COPD). To date, it remains unclear whether and to what extent systemic inflammation is primary or secondary in the pathogenesis of COPD.
The aim of this study was to examine the association between haplotypes of CRP, IL6 and FGB genes, systemic inflammation, COPD risk and COPD-related phenotypes (respiratory impairment, exercise capacity and body composition).

Methods

Eighteen SNPs in three genes, representing optimal haplotype-tagging sets, were genotyped in 355 COPD patients and 195 healthy smokers. Plasma levels of CRP, IL-6 and FG were measured in the total study group. Differences in haplotype distributions were tested using the global and haplotype-specific statistics.

Results

Raised plasma levels of CRP, IL-6 and fibrinogen were demonstrated in COPD patients. However, COPD population was very heterogeneous: about 40% of patients had no evidence of systemic inflammation (CRP < 3 mg/uL or no inflammatory markers in their top quartile). Global test for haplotype effect indicated association of CRP gene and CRP plasma levels (P = 0.0004) and IL6 gene and COPD (P = 0.003). Subsequent analysis has shown that IL6 haplotype H2, associated with an increased COPD risk (p = 0.004, OR = 4.82; 1.64 to 4.18), was also associated with very low CRP levels (p = 0.0005). None of the genes were associated with COPD-related phenotypes.

Conclusion

Our findings suggest that common genetic variation in CRP and IL6 genes may contribute to heterogeneity of COPD population associated with systemic inflammation.
Appendix
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Literature
1.
GOLD: Executive Summary: Global Strategy for the Diagnosis, Management, and Prevention of COPD. Summary of GOLD recommendations for the diagnosis, management, and prevention of COPD, with citations from the scientific literature. 2006, 1-32.
2.
Donaldson GC, Seemungal TA, Patel IS, Bhowmik A, Wilkinson TM, Hurst JR, Maccallum PK, Wedzicha JA: Airway and systemic inflammation and decline in lung function in patients with COPD. Chest. 2005, 128 (4): 1995-2004. 10.1378/chest.128.4.1995.CrossRefPubMed
3.
Gan WQ, Man SF, Senthilselvan A, Sin DD: Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax. 2004, 59 (7): 574-580. 10.1136/thx.2003.019588.CrossRefPubMedPubMedCentral
4.
Garrod R, Marshall J, Barley E, Fredericks S, Hagan G: The relationship between inflammatory markers and disability in chronic obstructive pulmonary disease (COPD). Prim Care Respir J. 2007, 16 (4): 236-240. 10.3132/pcrj.2007.00047.CrossRefPubMed
5.
Pinto-Plata VM, Mullerova H, Toso JF, Feudjo-Tepie M, Soriano JB, Vessey RS, Celli BR: C-reactive protein in patients with COPD, control smokers and non-smokers. Thorax. 2006, 61 (1): 23-28. 10.1136/thx.2005.042200.CrossRefPubMed
6.
Schols AM, Buurman WA, Staal van den Brekel AJ, Dentener MA, Wouters EF: Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. Thorax. 1996, 51 (8): 819-824. 10.1136/thx.51.8.819.CrossRefPubMedPubMedCentral
7.
Broekhuizen R, Wouters EF, Creutzberg EC, Schols AM: Elevated CRP levels mark metabolic and functional impairment in advanced COPD. Thorax. 2006, 61 (1): 17-22. 10.1136/thx.2005.041996. Epub 2005 Jul 29CrossRefPubMed
8.
Watz H, Waschki B, Boehme C, Claussen M, Meyer T, Magnussen H: Extrapulmonary effects of chronic obstructive pulmonary disease on physical activity: a cross-sectional study. Am J Respir Crit Care Med. 2008, 177 (7): 743-751. 10.1164/rccm.200707-1011OC.CrossRefPubMed
9.
de Torres JP, Cordoba-Lanus E, Lopez-Aguilar C, Muros de Fuentes M, Montejo de Garcini A, Aguirre-Jaime A, Celli BR, Casanova C: C-reactive protein levels and clinically important predictive outcomes in stable COPD patients. Eur Respir J. 2006, 27 (5): 902-907.PubMed
10.
Yarnell JW, Sweetnam PM, Rumley A, Lowe GD: Lifestyle factors and coagulation activation markers: the Caerphilly Study. Blood Coagul Fibrinolysis. 2001, 12 (8): 721-728. 10.1097/00001721-200112000-00015.CrossRefPubMed
11.
de Maat MP, Bladbjerg EM, Hjelmborg JB, Bathum L, Jespersen J, Christensen K: Genetic influence on inflammation variables in the elderly. Arterioscler Thromb Vasc Biol. 2004, 24 (11): 2168-2173. 10.1161/01.ATV.0000143856.01669.e7.CrossRefPubMed
12.
Dupuis J, Larson MG, Vasan RS, Massaro JM, Wilson PW, Lipinska I, Corey D, Vita JA, Keaney JF, Benjamin EJ: Genome scan of systemic biomarkers of vascular inflammation in the Framingham Heart Study: evidence for susceptibility loci on 1q. Atherosclerosis. 2005, 182 (2): 307-314. 10.1016/j.atherosclerosis.2005.02.015.CrossRefPubMed
13.
Pankow JS, Folsom AR, Cushman M, Borecki IB, Hopkins PN, Eckfeldt JH, Tracy RP: Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study. Atherosclerosis. 2001, 154 (3): 681-689. 10.1016/S0021-9150(00)00586-4.CrossRefPubMed
14.
Yang Q, Tofler GH, Cupples LA, Larson MG, Feng D, Lindpaintner K, Levy D, D'Agostino RB, O'Donnell CJ: A genome-wide search for genes affecting circulating fibrinogen levels in the Framingham Heart Study. Thromb Res. 2003, 110 (1): 57-64. 10.1016/S0049-3848(03)00288-3.CrossRefPubMed
15.
Hersh CP, Miller DT, Kwiatkowski DJ, Silverman EK: Genetic determinants of C-reactive protein in COPD. Eur Respir J. 2006, 28 (6): 1156-1162. 10.1183/09031936.00147805.CrossRefPubMed
16.
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 (22): 2703-2711. 10.1001/jama.296.22.2703.CrossRefPubMed
17.
Qi L, van Dam RM, Meigs JB, Manson JE, Hunter D, Hu FB: Genetic variation in IL6 gene and type 2 diabetes: tagging-SNP haplotype analysis in large-scale case-control study and meta-analysis. Hum Mol Genet. 2006, 15 (11): 1914-1920. 10.1093/hmg/ddl113.CrossRefPubMed
18.
Siemes C, Visser LE, Coebergh JW, Splinter TA, Witteman JC, Uitterlinden AG, Hofman A, Pols HA, Stricker BH: C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: the Rotterdam Study. J Clin Oncol. 2006, 24 (33): 5216-5222. 10.1200/JCO.2006.07.1381.CrossRefPubMed
19.
Uitte de Willige S, de Visser MC, Houwing-Duistermaat JJ, Rosendaal FR, Vos HL, Bertina RM: Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen gamma' levels. Blood. 2005, 106 (13): 4176-4183. 10.1182/blood-2005-05-2180.CrossRefPubMed
20.
Davey Smith G, Ebrahim S: 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?. Int J Epidemiol. 2003, 32 (1): 1-22. 10.1093/ije/dyg070.CrossRef
21.
Yanbaeva D, Dentener M, Spruit M, Kruijs Van de A, Derks A, Wouters E: Variation in C-reactive protein gene and COPD: tagging SNPs analysis in a case-control study. 17th ERS Annual Congress: September 15–19, 2007 2007; Stockholm, Sweden: Eur Respir J. 2007, 456s-
22.
Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, et al: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007, 176 (6): 532-555. 10.1164/rccm.200703-456SO.CrossRefPubMed
23.
Kotz D, Wesseling G, Huibers MJ, van Schayck OC: Efficacy of confrontational counselling for smoking cessation in smokers with previously undiagnosed mild to moderate airflow limitation: study protocol of a randomized controlled trial. BMC Public Health. 2007, 7: 332-10.1186/1471-2458-7-332.CrossRefPubMedPubMedCentral
24.
Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA: Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet. 2002, 70 (2): 425-434. 10.1086/338688.CrossRefPubMed
25.
Reitz C, Berger K, de Maat MP, Stoll M, Friedrichs F, Kardys I, Witteman JC, Breteler MM: CRP gene haplotypes, serum CRP, and cerebral small-vessel disease: the Rotterdam Scan Study and the MEMO Study. Stroke. 2007, 38 (8): 2356-2359. 10.1161/STROKEAHA.107.482661.CrossRefPubMed
26.
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 (1): 64-77. 10.1086/431366.CrossRefPubMedPubMedCentral
27.
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 (Pt 6): 623-638. 10.1111/j.1529-8817.2005.00210.x.CrossRefPubMed
28.
Walter RE, Wilk JB, Larson MG, Vasan RS, Keaney JF, Lipinska I, O'Connor GT, Benjamin EJ: Systemic inflammation and COPD: the Framingham Heart Study. Chest. 2008, 133 (1): 19-25. 10.1378/chest.07-0058.CrossRefPubMed
29.
Lee TM, Lin MS, Chang NC: Usefulness of C-reactive protein and interleukin-6 as predictors of outcomes in patients with chronic obstructive pulmonary disease receiving pravastatin. Am J Cardiol. 2008, 101 (4): 530-535. 10.1016/j.amjcard.2007.09.102.CrossRefPubMed
30.
Gould JM, Weiser JN: Expression of C-reactive protein in the human respiratory tract. Infect Immun. 2001, 69 (3): 1747-1754. 10.1128/IAI.69.3.1747-1754.2001.CrossRefPubMedPubMedCentral
31.
Dong Q, Wright JR: Expression of C-reactive protein by alveolar macrophages. J Immunol. 1996, 156 (12): 4815-4820.PubMed
32.
Ramage L, Proudfoot L, Guy K: Expression of C-reactive protein in human lung epithelial cells and upregulation by cytokines and carbon particles. Inhal Toxicol. 2004, 16 (9): 607-613. 10.1080/08958370490464599.CrossRefPubMed
33.
Yende S, Waterer GW, Tolley EA, Newman AB, Bauer DC, Taaffe DR, Jensen R, Crapo R, Rubin S, Nevitt M, et al: Inflammatory markers are associated with ventilatory limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects. Thorax. 2006, 61 (1): 10-16. 10.1136/thx.2004.034181.CrossRefPubMed
34.
Broekhuizen R, Grimble RF, Howell WM, Shale DJ, Creutzberg EC, Wouters EF, Schols AM: Pulmonary cachexia, systemic inflammatory profile, and the interleukin 1beta -511 single nucleotide polymorphism. Am J Clin Nutr. 2005, 82 (5): 1059-1064.PubMed
35.
Hsieh MH, Chong IW, Hwang JJ, Lee CH, Ho CK, Yu ML, Huang CT, Lee CY, Wu MT, Christiani DC: Lack of associations between several polymorphisms in cytokine genes and the risk of chronic obstructive pulmonary diseases in Taiwan. Kaohsiung J Med Sci. 2008, 24 (3): 126-137. 10.1016/S1607-551X(08)70140-2.CrossRefPubMed
36.
Crul T, Spruit MA, Gayan-Ramirez G, Quarck R, Gosselink R, Troosters T, Pitta F, Decramer M: Markers of inflammation and disuse in vastus lateralis of chronic obstructive pulmonary disease patients. Eur J Clin Invest. 2007, 37 (11): 897-904. 10.1111/j.1365-2362.2007.01867.x.CrossRefPubMed
37.
Debigare R, Maltais F, Cote CH, Michaud A, Caron MA, Mofarrahi M, Leblanc P, Hussain SN: Profiling of mRNA expression in quadriceps of patients with COPD and muscle wasting. Copd. 2008, 5 (2): 75-84.CrossRefPubMed
38.
Barreiro E, Schols AM, Polkey MI, Galdiz JB, Gosker HR, Swallow EB, Coronell C, Gea J: Cytokine profile in quadriceps muscles of patients with severe COPD. Thorax. 2008, 63 (2): 100-107. 10.1136/thx.2007.078030.CrossRefPubMed
39.
Tabassum F, Kumari M, Rumley A, Lowe G, Power C, Strachan DP: Effects of socioeconomic position on inflammatory and hemostatic markers: a life-course analysis in the 1958 British birth cohort. Am J Epidemiol. 2008, 167 (11): 1332-1341. 10.1093/aje/kwn055.CrossRefPubMed
40.
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 (23): 2458-2465. 10.1161/CIRCULATIONAHA.106.615740.CrossRefPubMed
41.
Fabbri LM, Rabe KF: From COPD to chronic systemic inflammatory syndrome?. Lancet. 2007, 370 (9589): 797-799. 10.1016/S0140-6736(07)61383-X.CrossRefPubMed
42.
Sevenoaks MJ, Stockley RA: Chronic Obstructive Pulmonary Disease, inflammation and co-morbidity – a common inflammatory phenotype?. Respir Res. 2006, 7: 70-10.1186/1465-9921-7-70.CrossRefPubMedPubMedCentral
43.
Broekhuizen R, Howell W, Shale D, Creutzberg EC, Wouters EF, Schols AM: Pulmonary cachexia, systemic inflammatory profile, and the interleukin 1beta -511 single nucleotide polymorphism. Am J Clin Nutr. 2005, 82: 1059-1064.PubMed
44.
Cordoba-Lanus EdTJ-P, Lopez-Aguilar , Rodriguez-Perez M-C, Maca-Meyer N, Montejo-de-Garcini A, Aguirre-Jaime A, Perez-Mendez L, Casanova C: Association of IL-6 gene polymorphism and COPD in a Spanish population. Respiratory Medicine. 2008, 102: 1805-1811. 10.1016/j.rmed.2008.06.012.CrossRefPubMed
45.
Seifart CDA, Plagens A, Seifart U, Clostermann U, Muller B, et al: TNF-alpha, TNF-beta, IL-6, and IL-10 promoter polymorphisms in patients with chronic obstructive pulmonary disease. Tissue Antigens. 2005, 65: 93-100. 10.1111/j.1399-0039.2005.00343.x.CrossRefPubMed
46.
Wilk JB, Walter RE, Laramie JM, Gottlieb DJ, O'Connor GT: Framingham Heart Study genome-wide association: results for pulmonary function measures. BMC Med Genet. 2007, 8 (Suppl 1): S8-10.1186/1471-2350-8-S1-S8.CrossRefPubMedPubMedCentral
47.
Sin DDMS: Interleukin-6: a red herring or a real catch in COPD?. Chest. 2008, 133: 4-6. 10.1378/chest.07-2085.CrossRefPubMed
Metadata
Title
IL6 and CRPhaplotypes are associated with COPD risk and systemic inflammation: a case-control study
Authors
Dilyara G Yanbaeva
Mieke A Dentener
Martijn A Spruit
Jeanine J Houwing-Duistermaat
Daniel Kotz
Valéria Lima Passos
Emiel FM Wouters
Publication date
01-12-2009
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2009
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/1471-2350-10-23

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