Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Ahluwalia, Tarunveer S.; Prins, Bram P.; Abdollahi, Mohammadreza; Armstrong, Nicola J.; Aslibekyan, Stella; Bain, Lisa; Jefferis, Barbara J.; Baumert, Jens; Beekman, Marian; Ben‐Shlomo, Yoav; Bis, Joshua C.; Mitchell, Braxton D.; Geus, Eco J. C. de; Delgado, Graciela; Marek, Diana; Eriksson, Joel; Kajantie, Eero; Kanoni, Stavroula; Kemp, John P.; Lu, Ciyong; Marioni, Riccardo E.; McLachlan, Stela; Milaneschi, Yuri; Nolte, Ilja M.; Petrelis, Alexandros M.; Porcu, Eleonora; Sabater‐Lleal, Maria; Naderi, Elnaz; Seppälä, Ilkka; Shah, Tina; Singhal, Gaurav; Standl, Marie; Teumer, Alexander; Thalamuthu, Anbupalam; Thiering, Elisabeth; Trompet, Stella; Ballantyne, Christie M.; Benjamin, Emelia J.; Casas, Juan P.; Toben, Catherine; Dedoussis, George; Deelen, Joris; Durda, Peter; Engmann, Jorgen; Feitosa, Mary F.; Grallert, Harald; Hammarstedt, Ann; Harris, Sarah E.; Homuth, Georg; Hottenga, Jouke‐Jan; Jalkanen, Sirpa; Jamshidi, Yalda; Jawahar, Magdalene C.; Jess, Tine; Kivimäki, Mika; Kleber, Marcus E.; Lahti, Jari; Liu, Yongmei; Marques‐Vidal, Pedro; Mellström, Dan; Mooijaart, Simon P.; Müller‐Nurasyid, Martina; Penninx, Brenda W. J. H.; Revez, Joana A.; Rossing, Peter; Räikkönen, Katri; Sattar, Naveed; Scharnagl, Hubert; Sennblad, Bengt; Silveira, Angela; Pourcain, Beaté St; Timpson, Nicholas J.; Trollor, Julian N.; Dongen, Jenny van; Heemst, Diana van; Visvikis‐Siest, Sophie; Vollenweider, Péter; Völker, Uwe; Waldenberger, Mélanie; Willemsen, Gonneke; Zabaneh, Delilah; Morris, Richard; Arnett, Donna K.; Baune, Bernhard T.; Boomsma, Dorret I.; Chang, Yen-Pei C.; Deary, Ian J.; Deloukas, Panos; Eriksson, Johan G.; Evans, David M.; Ferreira, Manuel; Gaunt, Tom R.; Gudnason, Vilmundur; Hamsten, Anders; Heinrich, Joachim; Hingorani, Aroon D.; Humphries, Steve E.; Jukema, J. Wouter; Köenig, Wolfgang; Kumari, Meena; Kutalik, Zoltán; Lawlor, Deborah A; Lehtimäki, Terho; März, Winfried; Mather, Karen A.; Naitza, Silvia; Nauck, Matthias; Ohlsson, Claes; Price, Jackie F.; Raitakari, Olli T.; Rice, Ken; Sachdev, Perminder S.; Slagboom, Eline; Sørensen, Thorkild I A; Spector, Tim D.; Stacey, David; Stathopoulou, Maria G.; Tanaka, Toshiko; Wannamethee, SG; Whincup, Peter H; Rotter, Jerome I.; Dehghan, Abbas; Boerwinkle, Eric; Psaty, Bruce M.; Snieder, Harold; Alizadeh, Behrooz Z.

doi:10.1093/hmg/ddab023

Cited by 41 publications

(24 citation statements)

References 90 publications

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“…We sought to validate our genetic instruments by testing for their associations with IL-6 levels and IL-6 receptor levels, available from a GWAS employing Olink protein assays. 27,28 We tested our genetic instruments for associations with the following clinical outcome parameters of interest for future cardiovascular outcome trials: coronary artery disease (CAD), 29 any stroke and ischaemic stroke, 30 heart failure (HF), 31 type 2 diabetes (T2D) 32 and atrial fibrillation (AF). 33 Because therapeutic agents targeting IL-6R are available for rheumatoid arthritis (RA), we also included RA in our analysis as a positive control.…”

Section: Data and Contributing Studiesmentioning

confidence: 99%

Dissecting the IL‐6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R

Asselbergs

Natarajan

Ridker

et al. 2022

Brit J Clinical Pharma

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Aims Chronic inflammation is a risk factor for cardiovascular disease (CVD). IL‐6 signalling perturbation through IL‐6 or IL‐6R blockade may have potential benefit on cardiovascular risk. It is unknown whether targeting either IL‐6 or IL‐6 receptor may result in similar effects on CVD and adverse events. We compared the anticipated effects of targeting IL‐6 and IL‐6 receptor on cardiometabolic risk and potential side effects. Methods We constructed four instruments: two main instruments with genetic variants in the IL6 and IL6R loci weighted for their association with CRP, and two after firstly filtering variants for their association with IL‐6 or IL‐6R expression. Analyses were performed for coronary artery disease (CAD), ischemic stroke, atrial fibrillation (AF), heart failure, type 2 diabetes (T2D), rheumatoid arthritis (RA), infection endpoints, and quantitative haematological, metabolic and anthropometric parameters. Results A 1 mg/L lower CRP by the IL6 instrument was associated with lower CAD (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.77;0.96), AF and T2D risk. A 1 mg/L lower CRP by the IL6R instrument was associated with lower CAD (OR 0.90, 95% CI 0.86;0.95), any stroke and ischemic stroke, AF, RA risk and higher pneumonia risk. The eQTL‐filtered results were in concordance with the main results, but with wider confidence intervals. Conclusions IL‐6 signalling perturbation by either IL6 or IL6R genetic instruments is associated with a similar risk reduction for multiple cardiometabolic diseases, suggesting that both IL‐6 and IL‐6R are potential therapeutic targets to lower CVD. Moreover, IL‐6 rather than IL‐6R inhibition might have a more favourable pneumonia risk.

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Section: Data and Contributing Studiesmentioning

confidence: 99%

Dissecting the IL‐6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R

Asselbergs

Natarajan

Ridker

et al. 2022

Brit J Clinical Pharma

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“…found little evidence for a role of serum IL-6 levels in the risk of MS ( 49 ), again in line with our results. A potential explanation for the discrepancy between IL-6 signaling and IL-6 levels may be weak instrument bias, as the instruments selected for serum IL-6 levels explain solely ~1% of phenotypic variance ( 28 ) while the instruments selected for IL-6 signaling explain ~5% of phenotypic variation ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

“…SNPs reaching genome-wide significance for circulating serum IL-6 levels in the combined GWAS meta-analysis from the CHARGE Inflammation Working Group of 67,428 individuals of European ancestry were selected ( 28 ) ( Supplementary Table 6 ).…”

Section: Methodsmentioning

confidence: 99%

Body Mass Index, Interleukin-6 Signaling and Multiple Sclerosis: A Mendelian Randomization Study

Vandebergh¹,

Becelaere²,

Dubois³

2022

Front. Immunol.

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ObjectivesWe explored whether genetically predicted increased body mass index (BMI) modulates multiple sclerosis (MS) risk through interleukin-6 (IL-6) signaling.MethodsWe performed a two-sample Mendelian randomization (MR) study using multiple genome-wide association studies (GWAS) datasets for BMI, IL-6 signaling, IL-6 levels and c-reactive protein (CRP) levels as exposures and estimated their effects on risk of MS from GWAS data from the International Multiple Sclerosis Genetics Consortium (IMSGC) in 14,802 MS cases and 26,703 controls.ResultsIn univariable MR analyses, genetically predicted increased BMI and IL-6 signaling were associated with higher risk of MS (BMI: odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.15-1.47,p= 3.76 × 10-5; IL-6 signaling: OR = 1.51, 95% CI = 1.11-2.04,p= 0.01). Furthermore, higher BMI was associated with increased IL-6 signaling (β = 0.37, 95% CI = 0.32,0.41,p= 1.58 × 10-65). In multivariable MR analyses, the effect of IL-6 signaling on MS risk remained after adjusting for BMI (OR = 1.36, 95% CI = 1.11-1.68,p= 0.003) and higher BMI remained associated with an increased risk for MS after adjustment for IL-6 signaling (OR = 1.16, 95% CI =1.00-1.34,p= 0.046). The proportion of the effect of BMI on MS mediated by IL-6 signaling corresponded to 43% (95% CI = 25%-54%). In contrast to IL-6 signaling, there was little evidence for an effect of serum IL-6 levels or CRP levels on risk of MS.ConclusionIn this study, we identified IL-6 signaling as a major mediator of the association between BMI and risk of MS. Further explorations of pathways underlying the association between BMI and MS are required and will, together with our findings, improve the understanding of MS biology and potentially lead to improved opportunities for targeted prevention strategies.

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“…signaling (41)(42)(43)(44)(45)(46)(47). Importantly and supporting our findings, it is known that macrophages from T1D patients with high-risk HLA-DQB1 alleles are sensitized to secrete IL-6 in response to nonantigenic stimulation (43).…”

Section: Discussionmentioning

confidence: 99%

Correlates of circulating extracellular vesicle cargo with key clinical features of type 1 diabetes

Casu

Lopez

Clifford

et al. 2022

Preprint

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Type 1 diabetes (T1D) is a heterogeneous disease with a slower evolution in individuals diagnosed at older ages. There are no validated clinical or laboratory biomarkers to predict the rate of insulin secretion decline either before or after the clinical onset of the disease, or the rate of progression to chronic complications of the disease. This pilot study aimed to characterize the proteomic and phosphoproteomic landscape of circulating extracellular vesicles (EVs) across a range of obesity in carefully matched established T1D and control subjects. We used archived serum samples from 17 human subjects (N=10 with T1D and N=7 normal healthy volunteers) from the ACME study (NCT03379792). EVs were isolated using EVtrap technology. Mass spectrometry-based methods were used to detect the global circulating EV proteome and phosphoproteome. Differential expression, coexpression network (WGCNA), and pathway enrichment analyses were implemented. The detected proteins and phosphoproteins were highly enriched (75%) in exosomal proteins cataloged in the ExoCarta database. A total of 181 differentially expressed EV proteins and 15 differentially expressed EV phosphoproteins were identified, with 8 upregulated EV proteins (i.e., CD63, RAB14, VCP, BSG, FLNA, GNAI2, LAMP2, and EZR) and 1 downregulated EV phosphoprotein (i.e., TUBA1B) listed among the top 100 ExoCarta proteins. This suggests that T1D could indeed modulate EV biogenesis and secretion. Enrichment analyses of both differentially expressed EV proteins and EV phosphoproteins identified associations of upregulated features with neutrophil, platelet, and immune response functions, as well as prion disease and other neurodegenerative diseases, among others. On the other hand, downregulated EV proteins were involved in MHC class II signaling and the regulation of monocyte differentiation. Potential novel key roles in T1D for C1q, plasminogen, IL6ST, CD40, HLA-DQB1, and phosphorylated S100A9, are highlighted. Remarkably, WGCNA uncovered two protein modules significantly associated with pancreas size, which may be implicated in the pathogenesis of T1D. Similarly, these modules showed significant enrichment for membrane compartments, processes associated with inflammation and the immune response, and regulation of viral processes, among others. This study demonstrates the potential of EV proteomic and phosphoproteomic signatures to provide insight into the pathobiology of type 1 diabetes and its complications.

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Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Cited by 41 publications

References 90 publications

Dissecting the IL‐6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R

Dissecting the IL‐6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R

Body Mass Index, Interleukin-6 Signaling and Multiple Sclerosis: A Mendelian Randomization Study

Correlates of circulating extracellular vesicle cargo with key clinical features of type 1 diabetes

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