title: Gene-centric analysis identifies variants associated with interleukin-6 levels and shared pathways with other inflammation markers.
abstract: BACKGROUND- Inflammatory cytokine interleukin-6 (IL-6), a possible risk factor for coronary heart disease, has an estimated heritability of >60%, but to date few genetic variants influencing IL-6 levels are known. METHODS AND RESULTS- We used the ITMAT-Broad-Care (IBC) HumanCVD disease BeadChip in the Whitehall II study (N=4911) and British Women's Heart and Health Study (N=3445) to identify single-nucleotide polymorphisms associated with circulating IL-6 levels. Twenty-two single-nucleotide polymorphisms from 7 loci (IL6R/TDRD10, HLA-DRB1, BUD13, SEZ6L, IL1RN, TRIB3, and ABO) were associated with IL-6 (P<10(-5)), although none were associated with the IL6 gene itself. With the exception of TRIB3, all loci have been previously reported in genome-wide association studies for autoimmune and cardiovascular diseases. Fourteen single-nucleotide polymorphisms in the IL6R region in high-linkage disequilibrium (r(2)>0.9) with a nonsynonymous variant, rs2228145, were also associated with IL-6 and C-reactive protein concentration (P<10(-5)). An IL-6-specific weighted allele score explained 2% of the variance of log IL-6 levels (P=2.4410(-22)) in Whitehall II and 1% (P=1.910(-8)) in British Women's Heart and Health Studies. CONCLUSIONS- Multiple common genetic variants of modest effect influence IL-6 concentration. Several loci contain single-nucleotide polymorphisms, exhibiting overlapping associations with autoimmune and cardiovascular disorders and other circulating biomarkers. Genetic variants associated with IL-6 provide important tools for probing the causal relevance of IL-6 signaling in a range of cardiometabolic diseases.
authors.affiliation: Genetic Epidemiology Group, Research Department of Epidemiology and Public Health, UCL Institute of Epidemiology & Health Care, London WC1E 6BT, United Kingdom. t.shah@ucl.ac.uk
authors.forename: Tina
authors.initials: T
authors.lastname: Shah
authors.forename: Delilah
authors.initials: D
authors.lastname: Zabaneh
authors.forename: Tom
authors.initials: T
authors.lastname: Gaunt
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Swerdlow
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.forename: Ian N
authors.initials: IN
authors.lastname: Day
authors.forename: John
authors.initials: J
authors.lastname: Whittaker
authors.forename: Michael V
authors.initials: MV
authors.lastname: Holmes
authors.forename: Reecha
authors.initials: R
authors.lastname: Sofat
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimaki
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: Juan P
authors.initials: JP
authors.lastname: Casas
mesh_terms: D000368:Aged; D000483:Alleles; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis; D003324:Coronary Artery Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019947:Receptors, Interleukin-6 / Q000235:genetics; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D002097:C-Reactive Protein