Three functional variants of IFN regulatory factor 5 ( IRF5 ) define risk and protective haplotypes for human lupus
Open accessAbstract
Systematic genome-wide studies to map genomic regions associated with human diseases are becoming more practical. Increasingly, efforts will be focused on the identification of the specific functional variants responsible for the disease. The challenges of identifying causal variants include the need for complete ascertainment of genetic variants and the need to consider the possibility of multiple causal alleles. We recently reported that risk of systemic lupus erythematosus (SLE) is strongly associated with a common SNP in IFN regulatory factor 5 ( IRF5 ), and that this variant altered spicing in a way that might provide a functional explanation for the reproducible association to SLE risk. Here, by resequencing and genotyping in patients with SLE, we find evidence for three functional alleles of IRF5 : the previously described exon 1B splice site variant, a 30-bp in-frame insertion/deletion variant of exon 6 that alters a proline-, glutamic acid-, serine- and threonine-rich domain region, and a variant in a conserved polyA+ signal sequence that alters the length of the 3′ UTR and stability of IRF5 mRNAs. Haplotypes of these three variants define at least three distinct levels of risk to SLE. Understanding how combinations of variants influence IRF5 function may offer etiological and therapeutic insights in SLE; more generally, IRF5 and SLE illustrates how multiple common variants of the same gene can together influence risk of common disease.
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Cites
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
Self-citationThe 1982 revised criteria for the classification of systemic lupus erythematosus
Tan, E. M., Cohen, A. S., Fries, J. F., Masi, A. T., Mcshane, D. J., Rothfield, N. F., Schaller, J. G., Talal, N., & Winchester, R. J. (1982) · Arthritis & Rheumatism · doi:10.1002/art.1780251101 · Cited by 14,519 · see citing works
A haplotype map of the human genome
The International HapMap Consortium (2005) · Nature · doi:10.1038/nature04226 · Cited by 5,858 · see citing works
A Genome-Wide Association Study Identifies <i>IL23R</i> as an Inflammatory Bowel Disease Gene
Duerr, R. H., Taylor, K. D., Brant, S. R., Rioux, J. D., Silverberg, M. S., Daly, M. J., Steinhart, A. H., Abraham, C., Regueiro, M., Griffiths, A., et al. (2006) · Science · doi:10.1126/science.1135245 · Cited by 3,039 · see citing works
Self-citationHageman, G. S., Anderson, D. H., Johnson, L. V., Hancox, L. S., Taiber, A. J., Hardisty, L. I., Hageman, J. L., Stockman, H. A., Borchardt, J. D., Gehrs, K. M., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501536102 · Cited by 1,961 · see citing works
Lohmueller, K. E., Pearce, C. L., Pike, M., Lander, E. S., & Hirschhorn, J. N. (2003) · Nature Genetics · doi:10.1038/ng1071 · Cited by 1,900 · see citing works
Genetic analysis of genome-wide variation in human gene expression
Morley, M. P., Molony, C. M., Weber, T. M., Devlin, J. L., Ewens, K. G., Spielman, R. S., & Cheung, V. G. (2004) · Nature · doi:10.1038/nature02797 · Cited by 1,207 · see citing works
Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors
Takaoka, A., Yanai, H., Kondo, S., Duncan, G. S., Negishi, H., Mizutani, T., Kano, S., Honda, K., Ohba, Y., Mak, T. W., et al. (2005) · Nature · doi:10.1038/nature03308 · Cited by 1,042 · see citing works
Graham, R., Kozyrev, S. V., Baechler, E. C., Reddy, M., Plenge, R. M., Bauer, J. W., Ortmann, W. A., Koeuth, T., Escribano, M. F. G., Groups, T. A. A. S. C., et al. (2006) · Nature Genetics · doi:10.1038/ng1782 · Cited by 672 · see citing works
Self-citationSigurðsson, S., Nordmark, G., Göring, H. H. H., Lindroos, K. M., Wiman, A.-C., Sturfelt, G. K., Jönsen, A., Rantapää‐Dahlqvist, S., Möller, B., Kere, J., et al. (2005) · The American Journal of Human Genetics · doi:10.1086/428480 · Cited by 608 · see citing works
Self-citationMaller, J., George, S., Purcell, S., Fagerness, J., Altshuler, D., Daly, M. J., & Seddon, J. M. (2006) · Nature Genetics · doi:10.1038/ng1873 · Cited by 599 · see citing works
Self-citationMapping determinants of human gene expression by regional and genome-wide association
Cheung, V. G., Spielman, R. S., Ewens, K. G., Weber, T. M., Morley, M. P., & Burdick, J. T. (2005) · Nature · doi:10.1038/nature04244 · Cited by 588 · see citing works
The 3′ untranslated region of messenger RNA: A molecular ‘hotspot’ for pathology?
Conne, B., Stutz, A., & Vassalli, J. (2000) · Nature Medicine · doi:10.1038/76211 · Cited by 530 · see citing works
Hughes, A. E., Orr, N., Esfandiary, H., Diaz-Torres, M., Goodship, T., & Chakravarthy, U. (2006) · Nature Genetics · doi:10.1038/ng1890 · Cited by 467 · see citing works
Barnes, B. J., Moore, P. A., & Pitha, P. M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101216200 · Cited by 388 · see citing works
Gaffney, P. M., Kearns, G. M., Shark, K. B., Ortmann, W. A., Selby, S. A., Malmgren, M. L., Rohlf, K. E., Ockenden, T. C., Messner, R. P., King, R. A., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.14875 · Cited by 355 · see citing works
Self-citationRegulation of the type I IFN induction: a current view
Honda, K., Yanai, H., Takaoka, A., & Taniguchi, T. (2005) · International Immunology · doi:10.1093/intimm/dxh318 · Cited by 347 · see citing works
Barnes, B. J., Kellum, M. J., Field, A. E., & Pitha, P. M. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.16.5721-5740.2002 · Cited by 251 · see citing works
Gaffney, P. M., Ortmann, W. A., Selby, S. A., Shark, K. B., Ockenden, T. C., Rohlf, K. E., Walgrave, N. L., Boyum, W. P., Malmgren, M. L., Miller, M. E., et al. (2000) · The American Journal of Human Genetics · doi:10.1086/302767 · Cited by 230 · see citing works
Self-citationGlobal and Distinct Targets of IRF-5 and IRF-7 during Innate Response to Viral Infection
Barnes, B. J., Richards, J. O., Mancl, M. E., Hanash, S., Beretta, L., & Pitha, P. M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400726200 · Cited by 223 · see citing works
A history of poly A sequences: from formation to factors to function
Edmonds, M. (2002) · Progress in nucleic acid research and molecular biology · doi:10.1016/s0079-6603(02)71046-5 · Cited by 194 · see citing works
Svenungsson, E., Gunnarsson, I., Fei, G., Lundberg, I. E., Klareskog, L., & Frostegård, J. (2003) · Arthritis & Rheumatism · doi:10.1002/art.11264 · Cited by 164 · see citing works
Self-citationMancl, M. E., Hu, G., Sangster‐Guity, N., Olshalsky, S. L., Hoops, K. E. M., Fitzgerald-Bocarsly, P. A., Pitha, P. M., Pinder, K. E., & Barnes, B. J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m500543200 · Cited by 157 · see citing works
Farrer, L. A. (1997) · JAMA · doi:10.1001/jama.1997.03550160069041 · Cited by 124 · see citing works
The New York Cancer Project: Rationale, Organization, Design, and Baseline Characteristics
Mitchell, M. K. (2004) · Journal of Heredity · doi:10.1093/jurban/jth116 · Cited by 91 · see citing works
Review: ICSBP/IRF-8 Transactivation: A Tale of Protein-Protein Interaction
Levi, B.-Z., Hashmueli, S., Gleit-Kielmanowicz, M., Azriel, A., & Meraro, D. (2002) · Journal of Interferon & Cytokine Research · doi:10.1089/107999002753452764 · Cited by 70 · see citing works
Genetics and molecular genetics of the MHC.
Rhodes, D. A., & Trowsdale, J. (1999) · PubMed · Cited by 68 · see citing works
Evidence for unique association signals in SLE at the CD28–CTLA4–ICOS locus in a family-based study
Graham, D. S. C., Wong, A., McHugh, N. J., Whittaker, J. C., & Vyse, T. J. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl395 · Cited by 63 · see citing works
Self-citationParsa, A., Peden, E. A., Lum, R. F., Seligman, V. A., Olson, J. L., Li, H., Seldin, M. F., & Criswell, L. A. (2002) · Genes and Immunity · doi:10.1038/sj.gene.6363907 · Cited by 50 · see citing works
Self-citationKlos, K. L. E., Sing, C. F., Boerwinkle, E., Hamon, S., Rea, T. J., Clark, A. G., Fornage, M., & Hixson, J. E. (2006) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000231523.19199.45 · Cited by 50 · see citing works
Graham, R., Langefeld, C. D., Gaffney, P. M., Ortmann, W. A., Selby, S. A., Baechler, E. C., Shark, K. B., Ockenden, T. C., Rohlf, K. E., Moser, K. L., et al. (2001) · Arthritis Research & Therapy · doi:10.1186/ar319 · Cited by 43 · see citing works
Self-citationMantel‐haenszel statistics and direct standardization
Woolson, R. F., & Bean, J. A. (1982) · Statistics in Medicine · doi:10.1002/sim.4780010106 · Cited by 24 · see citing works
Tong, A. (2000) · PubMed · Cited by 1 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- [11]Rhodes DA, Trowsdale J. Rev Immunogenet. 1999;1:21–31. [PubMed] [Google Scholar]
- [12]Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. J Am Med Assoc. 1997;278:1349–1356. [PubMed] [Google Scholar]
Cited by
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Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
Saxena, R., Voight, B. F., Lyssenko, V., Burtt, N. P., de Bakker, P. I. W., Chen, H., Roix, J. J., Kathiresan, S., Hirschhorn, J. N., Daly, M. J., et al. (2007) · Science · doi:10.1126/science.1142358 · Cited by 2,843 · see citing works
Self-citationRisk Alleles for Multiple Sclerosis Identified by a Genomewide Study
(2007) · New England Journal of Medicine · doi:10.1056/nejmoa073493 · Cited by 1,746 · see citing works
Genetic Mapping in Human Disease
Altshuler, D., Daly, M. J., & Lander, E. S. (2008) · Science · doi:10.1126/science.1156409 · Cited by 1,452 · see citing works
Self-citationSankaran, V. G., Menne, T. F., Xu, J., Akie, T. E., Lettre, G., Van Handel, B., Mikkola, H. K. A., Hirschhorn, J. N., Cantor, A. B., & Orkin, S. H. (2008) · Science · doi:10.1126/science.1165409 · Cited by 919 · see citing works
Genetic susceptibility to systemic lupus erythematosus in the genomic era
Deng, Y., & Tsao, B. P. (2010) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2010.176 · Cited by 379 · see citing works
Network biology concepts in complex disease comorbidities
Hu, J. X., Thomas, C. E., & Brunak, S. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.87 · Cited by 328 · see citing works
The study of eQTL variations by RNA-seq: from SNPs to phenotypes
Majewski, J., & Pastinen, T. (2011) · Trends in Genetics · doi:10.1016/j.tig.2010.10.006 · Cited by 232 · see citing works
Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis
Hirschfield, G. M., Liu, X., Han, Y., Gorlov, I. P., Lu, Y., Xu, C., Lu, Y., Chen, W., Juran, B. D., Coltescu, C., et al. (2010) · Nature Genetics · doi:10.1038/ng.631 · Cited by 215 · see citing works
Self-citationRNA sequencing reveals the role of splicing polymorphisms in regulating human gene expression
Lalonde, E., Ha, K. C. H., Wang, Z., Bemmo, A., Kleinman, C. L., Kwan, T., Pastinen, T., & Majewski, J. (2011) · Genome Research · doi:10.1101/gr.111211.110 · Cited by 111 · see citing works
Hikami, K., Kawasaki, A., Ito, I., Koga, M., Ito, S., Hayashi, T., Matsumoto, I., Tsutsumi, A., Kusaoi, M., Takasaki, Y., et al. (2011) · Arthritis & Rheumatism · doi:10.1002/art.30188 · Cited by 58 · see citing works
- Authors
- Graham, R. R., Kyogoku, C., Sigurdsson, S., Vlasova, I. A., Davies, L. R. L., Baechler, E. C., Plenge, R. M., Koeuth, T., Ortmann, W. A., Hom, G., Bauer, J. W., Gillett, C., Burtt, N., Cunninghame Graham, D. S., Onofrio, R., Petri, M., Gunnarsson, I., Svenungsson, E., Rönnblom, L., Nordmark, G., Gregersen, P. K., Moser, K., Gaffney, P. M., Criswell, L. A., Vyse, T. J., Syvänen, A.-C., Bohjanen, P. R., Daly, M. J., Behrens, T. W., & Altshuler, D.
- Affiliations
- Broad Institute (US)
- University of Minnesota (US)
- Molecular Medicine, Department of Medical Sciences, Uppsala University, SE-751 Uppsala, Sweden;
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455;
- Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142;
- Rheumatology Section, Imperial College, Hammersmith Hospital, London W12 0NN, United Kingdom;
- Johns Hopkins University (US)
- Karolinska University Hospital (SE)
- Uppsala University (SE)
- Northwell Health (US)
- University of California, San Francisco (US)
- Hammersmith Hospital (GB)
- ORCID
- Graham, Robert R.
- Davies, Leela R. L.
- Plenge, Robert M.
- Koeuth, Thearith
- Ortmann, Ward A.
- Petri, Michelle
- Gunnarsson, Iva
- Svenungsson, Elisabet
- Rönnblom, Lars
- Nordmark, Gunnel
- Gregersen, Peter K.
- Gaffney, Patrick M.
- Criswell, Lindsey A.
- Vyse, Timothy J.
- Bohjanen, Paul R.
- Daly, Mark J.
- Behrens, Timothy W.
- Altshuler, David
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-04-17
- Volume
- 104
- Issue
- 16
- Pages
- 6758-6763
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1847749
- OpenAlex
- W2026255377
- Cited by
- 450
- References
- 33
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 13 · 2023: 13 · 2022: 11 · 2021: 20 · 2020: 10 · 2019: 19 · 2018: 19 · 2017: 11 · 2016: 17 · 2015: 16 · 2014: 16 · 2013: 30 · 2012: 33
- FWCI
- 38.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- National Institutes of Health (5m01rr000079-42)
- National Institute of Allergy and Infectious Diseases (R56AI057484, R01AI049494, K02AI052170)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR43727, R01AR043727)
- National Center for Research Resources (M01 RR-00052, 5M01-RR00079, M01-RR000079, M01RR000052)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- IRF5, systemic lupus erythematosus, single nucleotide polymorphisms, haplotypes, 3' untranslated region, mRNA stability, genetic risk variants
- MeSH terms
- Cell Line, Transformed, Gene Expression Regulation, Haplotypes, Humans, Lupus Erythematosus, Systemic, Risk Factors, Genetic Variation, Case-Control Studies, Genetic Predisposition to Disease, Protein Isoforms, Interferon Regulatory Factors
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