IL-1 receptor antagonist gene as a predictive biomarker of progression of knee osteoarthritis in a population cohort
Open accessAbstract
Objective Within the interleukin-1 (IL-1) cytokine family, IL-1 receptor antagonist (IL1RN) gene variants have been associated with radiological severity of knee osteoarthritis (OA) in cross-sectional studies. The present study tested the relation between IL1RN gene variants and progression of knee OA assessed radiographically by change in Kellgren-Lawrence (KL) score over time.Design 1153 Caucasian adults (age range: 44-89) from the Johnson County Osteoarthritis Project were evaluated for unequivocal radiographic evidence of knee OA at baseline, defined as KL score ≥2, and were re-examined after 4-11 years for radiographic changes typical of OA progression. IL1RN gene variants were tested for association with OA progression and for potential interaction with body mass index (BMI). Other IL-1 gene variations were tested for association with OA progression as a secondary objective.Results Of 154 subjects with OA at baseline, 88 showed progression at follow-up. Seven IL1RN single nucleotide polymorphisms (SNPs) and one IL-1 receptor SNP were associated with progression. Four IL1RN haplotypes, each occurring in >5% of this population, showed different relationships with progression, including one (rs315931/rs4251961/rs2637988/rs3181052/rs1794066/rs419598/rs380092/rs579543/rs315952/rs9005/rs315943/rs1374281; ACAGATACTGCC) associated with increased progression [odds ratio (OR) 1.91 (95%CI 1.16-3.15); P = 0.012]. Haplotypes associated with progression by KL score were also associated with categorical change in joint space narrowing. BMI was associated with OA progression in subjects carrying a specific IL1RN haplotype, but not in subjects without that haplotype.Conclusion A significantly greater likelihood of radiological progression of knee OA was associated with a commonly occurring IL1RN haplotype that could be tagged by three IL1RN SNPs (rs419598, rs9005, rs315943). Interactions were also observed between IL1RN gene variants and BMI relative to OA progression. This suggests that IL1RN gene markers may be useful in stratifying patients for medical management and drug development.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
IL1RN variants affect the pathophysiology of human infections and the risk of insulin resistance and knee osteoarthritis.
“These findings have been confirmed in three independent cohorts26, and further research has demonstrated that these factors affect the pathophysiology of human infections27 and the risk of developing insulin resistance28 and knee osteoarthritis29.”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [29]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing
Benjamini, Y., & Hochberg, Y. (1995) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1995.tb02031.x · Cited by 109,482 · see citing works
PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089 · see citing works
Individual Comparisons by Ranking Methods
Wilcoxon, F. (1945) · Biometrics Bulletin · doi:10.2307/3001968 · Cited by 15,354 · see citing works
Haploview: analysis and visualization of LD and haplotype maps
Barrett, J., Fry, B., Maller, J., & Daly, M. (2005) · Bioinform. · doi:10.1093/bioinformatics/bth457 · Cited by 15,086 · see citing works
On a Test of Whether one of Two Random Variables is Stochastically Larger than the Other
Mann, H. B., & Whitney, D. R. (1947) · The Annals of Mathematical Statistics · doi:10.1214/aoms/1177730491 · Cited by 14,320 · see citing works
The International HapMap Project
†The International HapMap Consortium, Genotyping centres: Baylor College of Medicine and ParAllele BioScience, Gibbs, R. A., Belmont, J. W., Hardenbol, P., Willis, T. D., Yu, F., Chinese HapMap Consortium, Yang, H., Ch'ang, L.-Y., et al. (2003) · Nature · doi:10.1038/nature02168 · Cited by 6,057 · see citing works
Self-citationLawrence, R. C., Felson, D. T., Helmick, C. G., Arnold, L. M., Choi, H. K., Deyo, R. A., Gabriel, S. E., Hirsch, R., Hochberg, M. C., Hunder, G. G., et al. (2007) · Arthritis & Rheumatism · doi:10.1002/art.23176 · Cited by 5,500 · see citing works
Self-citationApplied Logistic Regression Analysis
Ziegel, E. R., & Menard, S. (1996) · Technometrics · doi:10.1080/00401706.1996.10484485 · Cited by 3,923 · see citing works
Applied Logistic Regression Analysis
Menard, S. (2002) · Sage eBooks · doi:10.4135/9781412983433 · Cited by 3,011 · see citing works
Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part I
Helmick, C. G., Felson, D. T., Lawrence, R. C., Gabriel, S. E., Hirsch, R., Kwoh, C. K., Liang, M. H., Kremers, H. M., Mayes, M. D., Merkel, P. A., et al. (2007) · Arthritis & Rheumatism · doi:10.1002/art.23177 · Cited by 2,054 · see citing works
Score Tests for Association between Traits and Haplotypes when Linkage Phase Is Ambiguous
Schaid, D. J., Rowland, C. M., Tines, D. E., Jacobson, R. M., & Poland, G. A. (2002) · The American Journal of Human Genetics · doi:10.1086/338688 · Cited by 1,772 · see citing works
Healthcare Cost and Utilization Project (HCUP)
Schmidt, A. S. (2016) · The SAGE Encyclopedia of Pharmacology and Society · doi:10.4135/9781483349985.n182 · Cited by 1,057 · see citing works
Jordan, J. M., Helmick, C. G., Renner, J. B., LUTA, G., DRAGOMIR, A. D., Woodard, J., FANG, F., Schwartz, T. A., Nelson, A. E., ABBATE, L. M., et al. (2009) · The Journal of Rheumatology · doi:10.3899/jrheum.080677 · Cited by 739 · see citing works
Self-citationOsteoarthritis — an untreatable disease?
Wieland, H. A., Michaelis, M., Kirschbaum, B. J., & Rudolphi, K. A. (2005) · Nature Reviews Drug Discovery · doi:10.1038/nrd1693 · Cited by 585 · see citing works
Chen, H., Wilkins, L. M., Aziz, N., Cannings, C., Wyllie, D. H., Bingle, C. D., Rogus, J. J., Beck, J. D., Offenbacher, S., Cork, M. J., et al. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddi469 · Cited by 309 · see citing works
Self-citationGenetic epidemiology of hip and knee osteoarthritis
Valdes, A. M., & Spector, T. D. (2011) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2010.191 · Cited by 256 · see citing works
Definition of osteoarthritis of the knee for epidemiological studies.
Spector, T. D., Hart, D. J., Byrne, J. C., et al. (1993) · Annals of the Rheumatic Diseases · doi:10.1136/ard.52.11.790 · Cited by 235 · see citing works
A genome‐wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22
Kerkhof, H. J. M., Lories, R. J. U., Meulenbelt, I., Jónsdóttir, I., Valdes, A. M., Arp, P., Ingvarsson, Þ., Jhamai, M. M., Jónsson, H., Stolk, L., et al. (2010) · Arthritis & Rheumatism · doi:10.1002/art.27184 · Cited by 221 · see citing works
Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis
Meulenbelt, I., Min, J. L., Bos, S. D., Riyazi, N., Houwing‐Duistermaat, J. J., van der Wijk, H.-J., Kroon, H. M. J. A., Nakajima, M., Ikegawa, S., Uitterlinden, A. G., et al. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn082 · Cited by 202 · see citing works
Rheumatism in Miners. Part II: X-ray Study
Kellgren, J., & Lawrence, J. S. (1952) · Occupational and Environmental Medicine · doi:10.1136/oem.9.3.197 · Cited by 194 · see citing works
(1989) · PubMed · Cited by 191 · see citing works
Belo, J. N., Berger, M. Y., Reijman, M., et al. (2007) · Arthritis Care & Research · doi:10.1002/art.22475 · Cited by 184 · see citing works
Association study of candidate genes for the prevalence and progression of knee osteoarthritis
Valdes, A. M., Hart, D. J., Jones, K. A., Surdulescu, G. L., Swarbrick, P. A., Doyle, D., Schafer, A. J., & Spector, T. D. (2004) · Arthritis & Rheumatism · doi:10.1002/art.20443 · Cited by 176 · see citing works
WHAP: haplotype-based association analysis
Purcell, S., Daly, M. J., & Sham, P. C. (2006) · Bioinformatics · doi:10.1093/bioinformatics/btl580 · Cited by 154 · see citing works
Chapple, C., Nicholson, H. D., Baxter, D. G., & Abbott, J. H. (2011) · Arthritis Care & Research · doi:10.1002/acr.20492 · Cited by 143 · see citing works
Smith, A. J. P., Keen, L. J., Billingham, M., Perry, M. J., Elson, C. J., Kirwan, J., Sims, J. E., Doherty, M., Spector, T. D., & Bidwell, J. L. (2004) · Genes and Immunity · doi:10.1038/sj.gene.6364107 · Cited by 135 · see citing works
Genetic epidemiology of primary osteoarthritis
Loughlin, J. A. (2001) · Current Opinion in Rheumatology · doi:10.1097/00002281-200103000-00004 · Cited by 128 · see citing works
Association of the interleukin‐1 gene cluster on chromosome 2q13 with knee osteoarthritis
Loughlin, J. A., Dowling, B., Mustafa, Z., et al. (2002) · Arthritis & Rheumatism · doi:10.1002/art.10260 · Cited by 99 · see citing works
Rafiq, S., Stevens, K., Hurst, A. J., Murray, A., Henley, W., Weedon, M. N., Bandinelli, S., Corsi, A. M., Guralnik, J. M., Ferruci, L., et al. (2007) · Genes & Immunity · doi:10.1038/sj.gene.6364393 · Cited by 92 · see citing works
Kerkhof, H. J. M., Doherty, M., Arden, N., et al. (2010) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2010.12.003 · Cited by 91 · see citing works
Kerkhof, H. J. M., Meulenbelt, I., Akune, T., Arden, N., Aromaa, A. J., Bierma‐Zeinstra, S., Carr, A. J., Cooper, C. C., Dai, J. M., Doherty, M., et al. (2010) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2010.10.027 · Cited by 89 · see citing works
IL1B gene promoter haplotype pairs predict clinical levels of interleukin-1β and C-reactive protein
Rogus, J. J., Beck, J. D., Offenbacher, S., Huttner, K. M., Iacoviello, L., Latella, M. C., de Gaetano, M., Wang, H., Kornman, K. S., & Duff, G. W. (2008) · Human Genetics · doi:10.1007/s00439-008-0488-6 · Cited by 86 · see citing works
Self-citationReiner, A. P., Wurfel, M. M., Lange, L. A., Carlson, C. S., Nord, A. S., Carty, C. L., Rieder, M. J., Desmarais, C., Jenny, N. S., Iribarren, C., et al. (2008) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.108.167437 · Cited by 85 · see citing works
Genetic influence on the progression of radiographic knee osteoarthritis: a longitudinal twin study
Zhai, G., Hart, D. J., Kato, B. S., MacGregor, A. J., & Spector, T. D. (2006) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2006.09.004 · Cited by 82 · see citing works
Attur, M. G., Wang, H.-Y., Kraus, V. B., Bukowski, J. F., Aziz, N., Krasnokutsky, S., Samuels, J., Greenberg, J., McDaniel, G. E., Abramson, S. B., et al. (2009) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2009.113043 · Cited by 75 · see citing works
Self-citationFrancis, P. J., Schultz, D. W., Hamon, S., Ott, J., Weleber, R. G., & Klein, M. L. (2007) · PLoS ONE · doi:10.1371/journal.pone.0001197 · Cited by 74 · see citing works
Kerkhof, H. J. M., Bierma‐Zeinstra, S., Castano-Betancourt, M. C., de Maat, M. P. M., Albert Hofman, D., Pols, H. A. P., Rivadeneira, F., Witteman, J. C. M., Uitterlinden, A. G., & van Meurs, J. B. J. (2010) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2009.125260 · Cited by 67 · see citing works
Gordon, A. C., Kiss‐Toth, E., Stockley, I., Eastell, R., & Wilkinson, J. M. (2008) · Arthritis & Rheumatism · doi:10.1002/art.23863 · Cited by 65 · see citing works
Allelic variants of IL1R1gene associate with severe hand osteoarthritis
Näkki, A., Kouhia, S. T., Saarela, J., et al. (2010) · BMC Medical Genetics · doi:10.1186/1471-2350-11-50 · Cited by 53 · see citing works
BAADER, E. W. (1951) · PubMed · Cited by 49 · see citing works
Interleukin-1 region meta-analysis with osteoarthritis phenotypes
Moxley, G. F., Meulenbelt, I., Chapman, K., et al. (2009) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2009.08.006 · Cited by 40 · see citing works
Carrol, E. D., Payton, A., Payne, D., Miyajima, F., Chaponda, M., Mankhambo, L. A., Banda, D. L., Molyneux, E. M., Cox, H., Jacobson, G., et al. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002402 · Cited by 38 · see citing works
Bergholdt, R., Larsen, Z., Andersen, N. A., Johannesen, J., Kristiansen, O., Mandrup-Poulsen, T. R., Nerup, J., Pociot, F., DSGD, & DIEGG (2000) · Genes and Immunity · doi:10.1038/sj.gene.6363719 · Cited by 34 · see citing works
Kerna, I., Kisand, K., Tamm, A. E., Lintrop, M., Veske, K., & Tamm, A. O. (2009) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2009.02.006 · Cited by 33 · see citing works
Genetic predisposition to the presence and 5-year clinical progression of hip osteoarthritis
Pollard, T. C. B., Batra, R. N., Judge, A., et al. (2012) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2012.02.003 · Cited by 22 · see citing works
Defining osteoarthritis: a moving target
Nelson, A. E., & Jordan, J. M. (2011) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2011.10.008 · Cited by 18 · see citing works
Self-citationMeulenbelt, I., Bos, S. D., Kloppenburg, M., et al. (2010) · Arthritis & Rheumatism · doi:10.1002/art.27325 · Cited by 12 · see citing works
A POSSIBLE ROLE OF IL-1RA 3′-UNTRANSLATED REGION IN MODULATION OF PROTEIN PRODUCTION
Yamshchikov, V. F., Mishina, M., & Cominelli, F. (2002) · Cytokine · doi:10.1006/cyto.2001.0973 · Cited by 7 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- [20]Kellgren JH Lawrence JS The epidemiology of chronic rheumatism, atlas of standard radiographs 1963 Blackwell Scientific Oxford
- [21]Burnett SJ Hart DJ Spector TD A radiographic atlas of osteoarthritis 1994 Springer-Verlag London
- [49]NCBI GRCh37.p5: http://www.ncbi.nlm.nih.gov/assembly/GCF_000001405.17/
Cited by
Sorted by citations
Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty
Ferrucci, L., & Fabbri, E. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0064-2 · Cited by 3,690 · see citing works
Attur, M., Krasnokutsky, S., Statnikov, A., Samuels, J., Li, Z., Friese, O., Hellio Le Graverand‐Gastineau, M., Rybak, L., Kraus, V. B., Jordan, J. M., et al. (2015) · Arthritis & Rheumatology · doi:10.1002/art.39279 · Cited by 120 · see citing works
Self-citation
- Authors
- Wu, X., Kondragunta, V., Kornman, K. S., Wang, H. Y., Duff, G. W., Renner, J. B., & Jordan, J. M.
- Affiliations
- University of Sheffield (GB)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Wu, X.
- Kondragunta, V.
- Kornman, K.S.
- Wang, H.Y.
- Duff, G.W.
- Renner, J.B.
- Jordan, J.M.
- Venue
- Osteoarthritis and Cartilage
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 21
- Issue
- 7
- Pages
- 930-938
- ISSN
- 1063-4584 (ISSN-L)
- PMC
- PMC3725144
- OpenAlex
- W2024043682
- Cited by
- 60
- References
- 48
- Citations by year
- 2025: 2 · 2023: 4 · 2022: 6 · 2021: 3 · 2020: 10 · 2019: 4 · 2018: 1 · 2017: 4 · 2016: 4 · 2015: 9 · 2014: 11 · 2013: 2
- FWCI
- 7.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Osteoarthritis and Cartilage (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Johnston County Osteoarthritis Project (5-P60-AR30701)
- NIAMS Multipurpose Arthritis and Musculoskeletal Disease Center (5 P60 AR49465-03)
- NIAMS Multidisciplinary Clinical Research Center
- Topics
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- knee osteoarthritis, disease progression, interleukin-1 receptor antagonist, Kellgren-Lawrence grade, radiographic progression, single nucleotide polymorphisms, haplotypes, body mass index, joint space narrowing, genetic susceptibility, predictive biomarkers, cartilage degeneration
- MeSH terms
- Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Haplotypes, Humans, Male, Middle Aged, Radiography, Risk Factors, Body Mass Index, Osteoarthritis, Knee, Polymorphism, Single Nucleotide, Interleukin 1 Receptor Antagonist Protein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
