CoChat
Sign Up
Cited by 104Rheumatoid Arthritis Research and TherapiesGenetic Associations and EpidemiologySystemic Lupus Erythematosus Research

Genome‐wide association study of rheumatoid arthritis in the Spanish population: KLF12 as a risk locus for rheumatoid arthritis susceptibility

Open access
Julià, Antonio, Ballina, Javier, Cañete, Juan D., Balsa, Alejandro, Tornero‐Molina, Jesus, Naranjo, Antonio, Alperi‐López, Mercedes, Erra, Alba +4 more·2008·Arthritis & Rheumatism
DOI 10.1002/art.23623
Open this paper in CoChat — free accountOpen PDF

Abstract

Objective: To identify new genes associated with susceptibility to rheumatoid arthritis (RA), using a 2‐stage genome‐wide association study. Methods: Following a liability‐based study design, we analyzed 317,503 single‐nucleotide polymorphisms (SNPs) in 400 patients with RA and 400 control subjects. We selected a group of candidate SNPs for replication in an independent group of 410 patients with RA and 394 control subjects. Using data from the 3 previous genome‐wide association studies in RA, we also looked for genomic regions showing evidence of common association signals. Finally, we analyzed the presence of genome‐wide epistasis using the binary test implemented in the PLINK program. Results: We identified several genomic regions showing evidence of genome‐wide association ( P < 1 × 10 −5 ). In the replication analysis, we identified KLF12 SNP rs1324913 as the most strongly associated SNP ( P = 0.01). In our study, we observed that this SNP showed higher significance than PTPN22 SNP rs2476601, in both the genome‐wide association studies and the replication analyses. Furthermore, the integration of our data with those from previous genome‐wide association studies showed that KLF12 and PTPRT are the unique loci that are commonly associated in 3 different studies ( P = 0.004 and P = 0.002 for KLF12 in the Wellcome Trust Case Control Consortium study and the Brigham and Women's Rheumatoid Arthritis Sequential Study genome‐wide association study, respectively). The genome‐wide epistasis analysis identified several SNP pairs close to significance after multiple test correction. Conclusion: The present genome‐wide association study identified KLF12 as a new susceptibility gene for RA. The joint analysis of our results and those from previous genome‐wide association studies showed genomic regions with a higher probability of being genuine susceptibility loci for RA.

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1002/art.23623

Cites

1 of 1 references verified0 citation errors · 0 not checkable

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.

A few free checks a day · papers already verified open instantly · results are public

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?

  • This is the first study to suggest the involvement of TBX3 in B cell proliferation and development of CIA, and adds mechanistic links to three independent GWAS that linked TBX3 to RA.

    “To our knowledge, this is the first study to suggest the involvement of TBX3 in B cell proliferation and development of CIA, and adds mechanistic links to three independent genome-wide association studies (GWAS) that linked TBX3 to RA [65–67].”

    From The oncoprotein TBX3 is controlling severity in experimental arthritis (2019) · cites this paper as [67]

    The introduction says that three earlier RA genome-wide association studies had been performed, but it does not say they linked TBX3 to RA. The section on genomic regions shared with earlier studies discusses other loci; searches for TBX3 and T-box 3 found no passage addressing a TBX3–RA association. The sentence’s claim about a first mechanistic study is the citing authors’ own framing, not a finding attributed to this source. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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

Flagged first, then by citations

Research works printed but not linked: 42

  1. MacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, Aho K, et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 2000;43:30-7.
  2. Cornelis F, Faure S, Martinez M, Prud'homme JF, Fritz P, Dib C, et al, for the European Consortium on Rheumatoid Arthritis Families. New susceptibility locus for rheumatoid arthritis sug- gested by a genome-wide linkage study. Proc Natl Acad Sci U S A 1998;95:10746-50.
  3. Jawaheer D, Li W, Graham RR, Chen W, Damle A, Xiao X, et al. Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis. Am J Hum Genet 2002;71:585-94.
  4. Chapman J, Clayton D. Detecting association using epistatic information. Genet Epidemiol 2007;31:894-909.
  5. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkal- ingam AP, Alexander HC, et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 2004;75:330-7.
  6. Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheuma- toid arthritis. Nat Genet 2003;34:395-402.
  7. Rodriguez MR, Nunez-Roldan A, Aguilar F, Valenzuela A, Garcia A, Gonzalez-Escribano MF. Association of the CTLA4 3Ј untranslated region polymorphism with the susceptibility to rheu- matoid arthritis. Hum Immunol 2002;63:76-81.
  8. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K. A com- prehensive review of genetic association studies [review]. Genet Med 2002;4:45-61.
  9. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science 1996;273:1516-7.
  10. Reich DE, Lander ES. On the allelic spectrum of human disease. Trends Genet 2001;17:502-10.
  11. Hirschhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits [review]. Nat Rev Genet 2005;6:95-108.
  12. Wellcome Trust Case Control Consortium. Genome-wide associ- ation study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447:661-78.
  13. Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, Ding B, et al. TRAF1-C5 as a risk locus for rheumatoid arthritis: a genomewide study. N Engl J Med 2007;357:1199-209.
  14. Plenge RM, Cotsapas C, Davies L, Price AL, de Bakker PI, Maller J, et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet 2007;39:1477-82.
  15. Morton NE, Collins A. Tests and estimates of allelic association in complex inheritance. Proc Natl Acad Sci U S A 1998;95:11389-93.
  16. Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, et al. NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med 2007;356:1216-25.
  17. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007;357:977-86.
  18. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-24.
  19. Doran MF, Pond GR, Crowson CS, O'Fallon WM, Gabriel SE. Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period. Arthritis Rheum 2002;46:625-31.
  20. Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, et al, for the International HapMap Consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature 2007;449:851-61.
  21. Buetow KH, Edmonson M, MacDonald R, Clifford R, Yip P, Kelley J, et al. High-throughput development and characterization of a genomewide collection of gene-based single nucleotide poly- morphism markers by chip-based matrix-assisted laser desorption/ ionization time-of-flight mass spectrometry. Proc Natl Acad Sci U S A 2001;98:581-4.
  22. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratifica- tion in genome-wide association studies. Nat Genet 2006;38: 904-9.
  23. Devlin B, Roeder K, Wasserman L. Genomic control, a new approach to genetic-based association studies [review]. Theor Popul Biol 2001;60:155-66.
  24. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81:559-75.
  25. Winkelmann J, Schormair B, Lichtner P, Ripke S, Xiong L, Jalilzadeh S, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet 2007;39:1000-6.
  26. Kochi Y, Yamada R, Suzuki A, Harley JB, Shirasawa S, Sawada T, et al. A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet 2005;37:478-85.
  27. Balding DJ. Handbook of statistical genetics. West Sussex (UK): John Wiley & Sons; 2001.
  28. Bieker JJ. Kruppel-like factors: three fingers in many pies. J Biol Chem 2001;276:34355-8.
  29. Schuierer M, Hilger-Eversheim K, Dobner T, Bosserhoff AK, Moser M, Turner J, et al. Induction of AP-2␣ expression by adenoviral infection involves inactivation of the AP-2rep transcrip- tional corepressor CtBP1. J Biol Chem 2001;276:27944-9.
  30. Kannan P, Buettner R, Chiao PJ, Yim SO, Sarkiss M, Tainsky MA. N-ras oncogene causes AP-2 transcriptional self-interference, which leads to transformation. Genes Dev 1994;8:1258-69.
  31. Wajapeyee N, Somasundaram K. Cell cycle arrest and apoptosis induction by activator protein 2␣ (AP-2␣) and the role of p53 and p21WAF1/CIP1 in AP-2␣-mediated growth inhibition. J Biol Chem 2003;278:52093-101.
  32. Zhou M, McPherson L, Feng D, Song A, Dong C, Lyu SC, et al. Kruppel-like transcription factor 13 regulates T lymphocyte sur- vival in vivo. J Immunol 2007;178:5496-504.
  33. Simpson RW, McGinty L, Simon L, Smith CA, Godzeski CW, Boyd RJ. Association of parvoviruses with rheumatoid arthritis of humans. Science 1984;223:1425-8.
  34. Takahashi Y, Murai C, Shibata S, Munakata Y, Ishii T, Ishii K, et al. Human parvovirus B19 as a causative agent for rheumatoid arthritis. Proc Natl Acad Sci U S A 1998;95:8227-32.
  35. Zhang X, Guo A, Yu J, Possemato A, Chen Y, Zheng W, et al. Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T. Proc Natl Acad Sci U S A 2007;104:4060-4.
  36. Lau WL, Scholnick SB. Identification of two new members of the CSMD gene family small star, filled. Genomics 2003;82: 412-5.
  37. Kraus DM, Elliott GS, Chute H, Horan T, Pfenninger KH, Sanford SD, et al. CSMD1 is a novel multiple domain comple- ment-regulatory protein highly expressed in the central nervous system and epithelial tissues. J Immunol 2006;176:4419-30.
  38. Yang CS, Yu C, Chuang HC, Chang CW, Chang GD, Yao TP, et al. FBW2 targets GCMa to the ubiquitin-proteasome degradation system. J Biol Chem 2005;280:10083-90.
  39. Julia A, Moore J, Miquel L, Alegre C, Barcelo P, Ritchie M, et al. Identification of a two-loci epistatic interaction associated with susceptibility to rheumatoid arthritis through reverse engineering and multifactor dimensionality reduction. Genomics 2007;90:6-13.
  40. Evans DM, Marchini J, Morris AP, Cardon LR. Two-stage two-locus models in genome-wide association. PLoS Genet 2006;2:e157.
  41. Kodaira Y, Nair SK, Wrenshall LE, Gilboa E, Platt JL. Phenotypic and functional maturation of dendritic cells mediated by heparan sulfate. J Immunol 2000;165:1599-604.
  42. Furusawa M, Taira T, Iguchi-Ariga SM, Ariga H. AMY-1 interacts with S-AKAP84 and AKAP95 in the cytoplasm and the nucleus, respectively, and inhibits cAMP-dependent protein kinase activity by preventing binding of its catalytic subunit to A-kinase-anchor- ing protein (AKAP) complex. J Biol Chem 2002;277:50885-92. DOI 10.1002/art.23652 · DOI

Cited by

Sorted by citations

Authors
Julià, A., Ballina, J., Cañete, J. D., Balsa, A., Tornero‐Molina, J., Naranjo, A., Alperi‐López, M., Erra, A., Pascual‐Salcedo, D., Barceló, P., Camps, J., & Marsal, S.
Affiliations
  • Universitat Autònoma de Barcelona (ES)
  • Hospital Universitario Central de Asturias (ES)
  • Hospital Clínic de Barcelona (ES)
  • Hospital Universitario La Paz (ES)
  • Hospital Universitario de Gran Canaria Doctor Negrín (ES)
  • Vall d'Hebron Hospital Universitari (ES)
  • Barcelona Supercomputing Center (ES)
ORCID
Venue
Arthritis & Rheumatism
Publisher
Wiley
Published
2008-07-30
Volume
58
Issue
8
Pages
2275-2286
ISSN
  • 0004-3591 (ISSN-L)
  • 1529-0131
DOI
10.1002/art.23623
OpenAlex
W2064628575
Cited by
104
References
1
Citations by year
2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 6 · 2021: 1 · 2020: 1 · 2019: 6 · 2018: 4 · 2017: 3 · 2016: 3 · 2015: 4 · 2014: 8 · 2013: 9 · 2012: 9
FWCI
9.89
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Arthritis & Rheumatism (publishedVersion)
  • PubMed (publishedVersion)
  • Acceda (Universidad de Las Palmas de Gran Canaria) (submittedVersion)
  • Consultation of the Doctoral Thesis Database (TESEO) (Ministerio de Educación, Cultura y Deporte) (submittedVersion, cc-by-nc-nd)
Topics
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
Keywords
rheumatoid arthritis, KLF12, PTPN22, PTPRT, genetic susceptibility, single nucleotide polymorphisms, Spanish population
MeSH terms
Adult, Aged, Aged, 80 and over, Arthritis, Rheumatoid, Chromosome Mapping, Female, Humans, Male, Middle Aged, Spain, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Kruppel-Like Transcription Factors

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