Dataset Information

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

ABSTRACT: Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

SUBMITTER: Ahluwalia TS

PROVIDER: S-EPMC8098112 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

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

Human molecular genetics 20210401 5

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inv ...[more]

PMID: 33517400

Similar Datasets

Project description:Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N?=?4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value?=?9.88×10(-204)) and 10 loci for sphingolipids (smallest P-value?=?3.10×10(-57)). After a correction for multiple comparisons (P-value<2.2×10(-9)), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits.

Project description:Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.

Project description:BACKGROUND:Plasma neurofilament light (NFL) is a promising biomarker for Alzheimer disease (AD), which increases in the early stage of AD and is associated with the progression of AD. We performed a genome-wide association study (GWAS) of plasma NFL in Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) cohort to identify novel variants associated with AD. METHODS:This study included 179 cognitively healthy controls (HC), 176 patients with mild cognitive impairment (MCI), and 172 patients with AD. All subjects were restricted to non-Hispanic Caucasian derived from the ADNI cohort and met all quality control (QC) criteria. Association of plasma NFL with the genetic variants was assessed using PLINK with an additive genetic model, i.e.dose-dependent effect of the minor alleles. The influence of a genetic variant associated with plasma NFL (rs7943454) on brain structure was further assessed using PLINK with a linear regression model. RESULTS:The minor allele (T) of rs7943454 in leucine zipper protein 2 gene (LUZP2) was associated with higher plasma NFL at suggestive levels (P = 1.39 × 10- 6) in a dose-dependent fashion. In contrast, the minor allele (G) of rs640476 near GABRB2 was associated with lower plasma NFL at suggestive levels (P = 6.71 × 10- 6) in a dose-dependent effect in all diagnostic groups except the MCI group. Furthermore, the minor allele (T) of rs7943454 within LUZP2 increased the onset risk of AD (odds ratio = 1.547, confidence interval 95% = 1.018-2.351) and was associated with atrophy of right middle temporal gyrus in the whole cohort in the longitudinal study (P = 0.0234). CONCLUSION:GWAS found the associations of two single nucleotide polymorphisms (rs7943454 and rs640476) with plasma NFL at suggestive levels. Rs7943454 in LUZP2 was associated with the onset risk of AD and atrophy of right middle temporal gyrusin the whole cohort. Using an endophenotype-based approach, we identified rs7943454 as a new AD risk locus.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets