title: Analysis of the role of interleukin 6 receptor haplotypes in the regulation of circulating levels of inflammatory biomarkers and risk of coronary heart disease.
abstract: 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.
authors.affiliation: Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine (IMM), Stockholm, Sweden; Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd University Hospital, Stockholm, Sweden.
authors.forename: Bruna
authors.initials: B
authors.lastname: Gigante
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, all at Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rona J
authors.initials: RJ
authors.lastname: Strawbridge
authors.affiliation: Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine (IMM), Stockholm, Sweden.
authors.forename: Ilais Moreno
authors.initials: IM
authors.lastname: Velasquez
authors.affiliation: Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine (IMM), Stockholm, Sweden.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Golabkesh
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, all at Karolinska Institutet, Stockholm, Sweden.
authors.forename: Angela
authors.initials: A
authors.lastname: Silveira
authors.affiliation: Department of Cardiovascular Medicine, The Wellcome Trust Centre of Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Anuj
authors.initials: A
authors.lastname: Goel
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy; Centro Cardiologico Monzino, IRCCS, Milan Italy.
authors.forename: Damiano
authors.initials: D
authors.lastname: Baldassarre
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Veglia
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy; Centro Cardiologico Monzino, IRCCS, Milan Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tremoli
authors.affiliation: Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.affiliation: Department of Cardiovascular Medicine, The Wellcome Trust Centre of Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, all at Karolinska Institutet, Stockholm, Sweden; Dept of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.affiliation: Centre for Cardiovascular Genetics, University College London, United Kingdom.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.affiliation: Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine (IMM), Stockholm, Sweden; Dept of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: de Faire
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D003327:Coronary Disease / Q000097:blood / Q000235:genetics*; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019947:Receptors, Interleukin-6 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D015415:Biomarkers; C508603:IL6R protein, human; D016209:Interleukin-8; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D005340:Fibrinogen; D002097:C-Reactive Protein