Analysis of the Role of Interleukin 6 Receptor Haplotypes in the Regulation of Circulating Levels of Inflammatory Biomarkers and Risk of Coronary Heart Disease

Variants at the interleukin 6 receptor (IL6R) gene regulate inflammation and are associated with risk of coronary heart disease (CHD). The aim of the present study was to investigate the effects of IL6R haplotypes on circulating levels of inflammatory biomarkers and risk of CHD. We performed a discovery analysis in SHEEP, a myocardial infarction (MI) case control study (n = 2,774) and replicated our results in two large, independent European populations, PROCARDIS, a CHD case control study (n = 7,998), and IMPROVE (n = 3,711) a prospective cardiovascular cohort study. Two major haplotype blocks (rs12083537A/G and rs4075015A/T—block 1; and rs8192282G/A, rs4553185T/C, rs8192284A/C, rs4240872T/C and rs7514452T/C—block 2) were identified in the IL6R gene. IL6R haplotype associations with C-reactive protein (CRP), fibrinogen, IL6, soluble IL6R (sIL6R), IL6, IL8 and TNF-α in SHEEP, CRP and fibrinogen in PROCARDIS and CRP in IMPROVE as well as association with risk of MI and CHD, were analyzed by THESIAS. Haplotypes in block 1 were associated neither with circulating inflammatory biomarkers nor with the MI/CHD risk. Haplotypes in block 2 were associated with circulating levels of CRP, in all three study populations, with fibrinogen in SHEEP and PROCARDIS, with IL8 and sIL6Rin SHEEP and with a modest, non significant, increase (7%) in MI/CHD risk in the three populations studied. Our results indicate that IL6R haplotypes regulate the circulating levels of inflammatory biomarkers. Lack of association with the risk of CHD may be explained by the combined effect of SNPs with opposite effect on the CHD risk, the sample size as well as by structural changes affecting sIL6R stability in the circulation.

[1]  J. Scheller,et al.  The interleukin-6 receptor Asp358Ala single nucleotide polymorphism rs2228145 confers increased proteolytic conversion rates by ADAM proteases. , 2014, Biochimica et biophysica acta.

[2]  P. Visscher,et al.  A new regulatory variant in the interleukin-6 receptor gene associates with asthma risk , 2013, Genes and Immunity.

[3]  Daniel F. Freitag,et al.  Functional IL6R 358Ala Allele Impairs Classical IL-6 Receptor Signaling and Influences Risk of Diverse Inflammatory Diseases , 2013, PLoS genetics.

[4]  J. Danesh,et al.  Large-scale association analysis identifies new risk loci for coronary artery disease , 2013 .

[5]  Tanya M. Teslovich,et al.  The Metabochip, a Custom Genotyping Array for Genetic Studies of Metabolic, Cardiovascular, and Anthropometric Traits , 2012, PLoS genetics.

[6]  A. Hamsten,et al.  NAMPT (visfatin) and AKT1 genetic variants associate with myocardial infarction. , 2012, Clinica chimica acta; international journal of clinical chemistry.

[7]  Jennifer G. Robinson,et al.  The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis , 2012, The Lancet.

[8]  Mark Woodward,et al.  Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies , 2012 .

[9]  U. de Faire,et al.  The Interaction between Coagulation Factor 2 Receptor and Interleukin 6 Haplotypes Increases the Risk of Myocardial Infarction in Men , 2010, PloS one.

[10]  S. Humphries,et al.  Cross-sectional analysis of baseline data to identify the major determinants of carotid intima-media thickness in a European population: the IMPROVE study. , 2010, European heart journal.

[11]  K L Evans,et al.  Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder , 2009, Molecular Psychiatry.

[12]  Shahrul Mt-Isa,et al.  Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease. , 2009, JAMA.

[13]  I. McInnes,et al.  Role for TNF in atherosclerosis? Lessons from autoimmune disease , 2009, Nature Reviews Cardiology.

[14]  A. Hamsten,et al.  Variants in the coagulation factor 2 receptor (F2R) gene influence the risk of myocardial infarction in men through an interaction with interleukin 6 serum levels , 2009, Thrombosis and Haemostasis.

[15]  P. Ridker,et al.  Novel Loci, Including Those Related to Crohn Disease, Psoriasis, and Inflammation, Identified in a Genome-Wide Association Study of Fibrinogen in 17 686 Women: The Women's Genome Health Study , 2009, Circulation. Cardiovascular genetics.

[16]  F. Hu,et al.  Interleukin-6 Receptor Gene, Plasma C-Reactive Protein, and Diabetes Risk in Women , 2009, Diabetes.

[17]  S. Liggett,et al.  Genetic Variation Within the β1-Adrenergic Receptor Gene Results in Haplotype-Specific Expression Phenotypes , 2008, Journal of cardiovascular pharmacology.

[18]  S. Bandinelli,et al.  A common variant of the interleukin 6 receptor (IL-6r) gene increases IL-6r and IL-6 levels, without other inflammatory effects , 2007, Genes and Immunity.

[19]  D. A. Tregouet,et al.  A new JAVA interface implementation of THESIAS: testing haplotype effects in association studies , 2007, Bioinform..

[20]  R. Collins,et al.  Genome-Wide Mapping of Susceptibility to Coronary Artery Disease Identifies a Novel Replicated Locus on Chromosome 17 , 2006, PLoS genetics.

[21]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[22]  D. Schaid.  Evaluating associations of haplotypes with traits , 2004, Genetic epidemiology.

[23]  Paul Oeth,et al.  MALDI-TOF mass spectrometry , 2004, Molecular biotechnology.

[24]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[25]  P. Bongrand,et al.  The IL-6-Soluble IL-6Rα Autocrine Loop of Endothelial Activation as an Intermediate Between Acute and Chronic Inflammation: an Experimental Model Involving Thrombin , 2001, The Journal of Immunology.

[26]  R S Judson,et al.  Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[27]  C. Hogstedt,et al.  Higher relative, but lower absolute risks of myocardial infarction in women than in men: analysis of some major risk factors in the S heep study , 1999 .

[28]  Koyanagi,et al.  High‐level production of alternatively spliced soluble interleukin‐6 receptor in serum of patients with adult T‐cell leukaemia/HTLV‐I‐associated myelopathy , 1998, Immunology.

[29]  Dana C Crawford,et al.  Definition and clinical importance of haplotypes. , 2005, Annual review of medicine.

[30]  A Ahlbom,et al.  Higher relative, but lower absolute risks of myocardial infarction in women than in men: analysis of some major risk factors in the SHEEP study. The SHEEP Study Group. , 1999, Journal of internal medicine.