Abstract
Cytokines are major immune system regulators. Previously, innate cytokine profiles determined by lipopolysaccharide stimulation were shown to be highly heritable. To identify regulating genes in innate immunity, we analyzed data from a genome-wide linkage scan using microsatellites in osteoarthritis (OA) patients (The GARP study) and their innate cytokine data on interleukin (IL)-1β, IL-1Ra, IL-10 and tumor necrosis factor (TNF)α. A confirmation cohort consisted of the Leiden 85-Plus study. In this study, a linkage analysis was followed by manual selection of candidate genes in linkage regions showing LOD scores over 2.5. An single-nucleotide polymorphism (SNP) gene tagging method was applied to select SNPs on the basis of the highest level of gene tagging and possible functional effects. QTDT was used to identify the SNPs associated with innate cytokine production. Initial association signals were modeled by a linear mixed model. Through these analyses, we identified 10 putative genes involved in the regulation of TNFα. SNP rs6679497 in gene CD53 showed significant association with TNFα levels (P=0.001). No association of this SNP was observed with OA. A novel gene involved in the innate immune response of TNFα is identified. Genetic variation in this gene may have a role in diseases and disorders in which TNFα is closely involved.
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Ohlsson K, Linder C, Lundberg E, Axelsson L : Release of cytokines, proteases from human peripheral blood mononuclear, polymorphonuclear cells following phagocytosis, LPS stimulation. Scand J Clin Lab Invest 1996; 56: 461–470.
van der Linden MW, Huizinga TW, Stoeken DJ, Sturk A, Westendorp RG : Determination of tumour necrosis factor-alpha, interleukin-10 production in a whole blood stimulation system: assessment of laboratory error, individual variation. J Immunol Methods 1998; 218: 63–71.
de Craen AJ, Posthuma D, Remarque EJ, van den Biggelaar AH, Westendorp RG, Boomsma DI : Heritability estimates of innate immunity: an extended twin study. Genes Immun 2005; 6: 167–170.
de Jong BA, Schrijver HM, Huizinga TW et al: Innate production of interleukin-10, tumor necrosis factor affects the risk of multiple sclerosis. Ann Neurol 2000; 48: 641–646.
McGeer PL, McGeer EG : Innate immunity, local inflammation, degenerative disease. Sci Aging Knowledge Environ 2002; 2002: re3.
Goldring MB : Update on the biology of the chondrocyte, new approaches to treating cartilage diseases. Best Pract Res Clin Rheumatol 2006; 20: 1003–1025.
Goldring MB, Otero M, Tsuchimochi K, Ijiri K, Li Y : Defining the roles of inflammatory, anabolic cytokines in cartilage metabolism. Ann Rheum Dis 2008; 67 (Suppl 3): iii75–iii82.
Riyazi N, Slagboom E, de Craen AJ et al: Association of the risk of osteoarthritis with high innate production of interleukin-1beta, low innate production of interleukin-10 ex vivo, upon lipopolysaccharide stimulation. Arthritis Rheum 2005; 52: 1443–1450.
Chapman K, Loughlin J : Association of the interleukin-1 gene cluster with osteoarthritis of the hip: comment on the article by Meulenbelt et al, the letter by Smith et al. Arthritis Rheum 2006; 54: 3722–3723.
Bos SD, Suchiman HE, Kloppenburg M et al: Allelic variation at the C-reactive protein gene associates to both hand osteoarthritis severity, serum high sensitive CRP levels in the GARP study. Ann Rheum Dis 2007; 67: 877–879.
Curran JE, Jowett JB, Elliott KS et al: Genetic variation in selenoprotein S influences inflammatory response. Nat Genet 2005; 37: 1234–1241.
Rafiq S, Frayling TM, Murray A et al: A common variant of the interleukin 6 receptor (IL-6r) gene increases IL-6r and IL-6 levels, without other inflammatory effects. Genes Immun 2007; 8: 552–559.
Haukim N, Bidwell JL, Smith AJ et al: Cytokine gene polymorphism in human disease: on-line databases, supplement 2. Genes Immun 2002; 3: 313–330.
Danis VA, Millington M, Hyland VJ, Grennan D : Cytokine production by normal human monocytes: inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism. Clin Exp Immunol 1995; 99: 303–310.
Wen AQ, Wang J, Feng K, Zhu PF, Wang ZG, Jiang JX : Effects of haplotypes in the interleukin 1beta promoter on lipopolysaccharide-induced interleukin 1beta expression. Shock 2006; 26: 25–30.
Temple SE, Lim E, Cheong KY et al: Alleles carried at positions -819 and -592 of the IL10 promoter affect transcription following stimulation of peripheral blood cells with Streptococcus pneumoniae. Immunogenetics 2003; 55: 629–632.
Meulenbelt I, Min JL, Bos S et al: Identification of DIO2 as new susceptibility locus for symptomatic Osteoarthritis. Hum Mol Genet 2008; 17: 1867–1875.
van Exel E, Gussekloo J, Houx P et al: Atherosclerosis and cognitive impairment are linked in the elderly. The Leiden 85-plus Study. Atherosclerosis 2002; 165: 353–359.
Riyazi N, Meulenbelt I, Kroon HM et al: Evidence for familial aggregation of hand, hip, and spine but not knee osteoarthritis in siblings with multiple joint involvement: the GARP study. Ann Rheum Dis 2005; 64: 438–443.
van Exel E, Gussekloo J, de Craen AJ, Bootsma-van der WA, Frolich M, Westendorp RG : Inflammation and stroke: the Leiden 85-Plus Study. Stroke 2002; 33: 1135–1138.
Abecasis GR, Cherny SS, Cookson WO, Cardon LR : Merlin--rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.
Kuhn RM, Karolchik D, Zweig AS et al: The UCSC Genome Browser Database: update 2009. Nucleic Acids Res 2009; 37: D755–D761.
Frazer KA, Ballinger DG, Cox DR et al: A second generation human haplotype map of over 3.1 million SNPs. Nature 2007; 449: 851–861.
Goode EL, Fridley BL, Sun Z et al: Comparison of tagging single-nucleotide polymorphism methods in association analyses. BMC Proc 2007; 1 (Suppl 1): S6.
Abecasis GR, Cardon LR, Cookson WO : A general test of association for quantitative traits in nuclear families. Am J Hum Genet 2000; 66: 279–292.
Diggle PJ, Liang KY, Zeger SL : General linear models for longitudinal data. In: Atkinson AC, Copas JB, Pierce DA, Schervish MJ, Titterington DM (ed). Analysis of Longitudinal Data. Oxford University Press: Oxford, 1994; pp 68–77.
Mollinedo F, Fontan G, Barasoain I, Lazo PA : Recurrent infectious diseases in human CD53 deficiency. Clin Diagn Lab Immunol 1997; 4: 229–231.
Kim TR, Yoon JH, Kim YC et al: LPS-induced CD53 expression: a protection mechanism against oxidative and radiation stress. Mol Cells 2004; 17: 125–131.
Mollinedo F, Martin-Martin B, Gajate C, Lazo PA : Physiological activation of human neutrophils down-regulates CD53 cell surface antigen. J Leukoc Biol 1998; 63: 699–706.
Yunta M, Lazo PA : Apoptosis protection and survival signal by the CD53 tetraspanin antigen. Oncogene 2003; 22: 1219–1224.
Hernandez-Torres J, Yunta M, Lazo PA : Differential cooperation between regulatory sequences required for human CD53 gene expression. J Biol Chem 2001; 276: 35405–35413.
Pedersen-Lane JH, Zurier RB, Lawrence DA : Analysis of the thiol status of peripheral blood leukocytes in rheumatoid arthritis patients. J Leukoc Biol 2007; 81: 934–941.
Smith AJ, Keen LJ, Billingham MJ et al: Extended haplotypes and linkage disequilibrium in the IL1R1-IL1A-IL1B-IL1RN gene cluster: association with knee osteoarthritis. Genes Immun 2004.
Moxley G, Han J, Stern AG, Riley BP : Potential influence of IL1B haplotype and IL1A-IL1B-IL1RN extended haplotype on hand osteoarthritis risk. Osteoarthritis Cartilage 2007; 15: 1106–1112.
Scanzello CR, Plaas A, Crow MK : Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound? Curr Opin Rheumatol 2008; 20: 565–572.
Acknowledgements
We acknowledge the support of the following cooperating hospitals and referring rheumatologists, as well as the orthopedic surgeons and general practitioners in our region, for identifying eligible GARP patients, in random order: Dr LNJEM Coene, Department of orthopedic surgery and Dr HK Ronday, Department of rheumatology, Leyenburg Hospital, the Hague; I Speyer and Dr ML Westedt, Department of rheumatology, Bronovo Hospital, the Hague; Dr D van Schaardenburg, Department of Rheumatology, Jan van Breemen, Institute in Amsterdam; Dr AJ Peeters and Dr D van Zeben, Department of rheumatology, Reinier de Graaf Hospital, Delft; Dr EJ Langelaan, Department of orthopedic surgery, Rijnland Hospital in Leiderdorp; and Dr Y Groeneveld, general practitioner, associated with the Leiden University Medical Center. In addition to the grant support from The Dutch League against Rheumatism (NR 04-1-403), Pfizer Inc., Groton, CT, USA and the Center of Medical Systems Biology (CMSB) provided generous financial support for this work. The Leiden 85-plus Study is a collaborative project of the Department of Gerontology and Geriatrics (Rudi Westendorp, principal investigator) and the Department of Public Health and Primary Care (Jacobijn Gussekloo, principal investigator) of the Leiden University Medical Center, Leiden, the Netherlands.
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Bos, S., Lakenberg, N., van der Breggen, R. et al. A genome-wide linkage scan reveals CD53 as an important regulator of innate TNF-α levels. Eur J Hum Genet 18, 953–959 (2010). https://doi.org/10.1038/ejhg.2010.52
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DOI: https://doi.org/10.1038/ejhg.2010.52
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