A large candidate-gene association study suggests genetic variants at IRF5 and PRDM1 to be associated with aggressive periodontitis
Corresponding Author
Arne S. Schaefer
Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
Address:
Arne S. Schaefer
Institute of Clinical Molecular Biology
Christian-Albrechts-University
Arnold-Heller-Str. 3, 24105 Kiel, Germany
E-mail: [email protected]
Search for more papers by this authorArne Jochens
Institute of Medical Informatics and Statistics, Christian-Albrechts-University, Kiel, Germany
Search for more papers by this authorHenrik Dommisch
Department of Periodontology, Operative and Preventive Dentistry, University of Bonn, Bonn, Germany
Search for more papers by this authorChristian Graetz
Department of Operative Dentistry and Periodontology, University Medical Center Schleswig-Holstein, Kiel, Germany
Search for more papers by this authorYvonne Jockel-Schneider
Department of Periodontology, Clinic of Preventive Dentistry and Periodontology, University Medical Center of the Julius-Maximilians-University, Würzburg, Germany
Search for more papers by this authorInga Harks
Center of Periodontology, Operative and Preventive Dentistry, University Medical Center, Münster, Germany
Search for more papers by this authorIngmar Staufenbiel
Department of Conservative Dentistry, Periodontology and Preventive Dentistry, Hannover Medical School, Hannover, Germany
Search for more papers by this authorJoerg Meyle
Department of Periodontology, University Medical Center, Giessen, Marburg, Germany
Search for more papers by this authorPeter Eickholz
Department of Periodontology, Centre for Dental, Oral, and Maxillofacial Medicine (Carolinum), Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
Search for more papers by this authorMathias Folwaczny
Department of Preventive Dentistry and Periodontology, University of Munich, Munich, Germany
Search for more papers by this authorMarja Laine
Department of Periodontology and Oral Biochemistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands
Search for more papers by this authorBarbara Noack
Center of Periodontology, Operative and Preventive Dentistry, Clinic of Preventive Dentistry, University Medical Center Carl Gustav Carus der Technischen Universität Dresden, Dresden, Germany
Search for more papers by this authorCisca Wijmenga
Department of Genetics, University Medical Center, Groningen, The Netherlands
Search for more papers by this authorWolfgang Lieb
Biobank Popgen, University Medical Center Schleswig-Holstein, Kiel, Germany
Search for more papers by this authorCorinna Bruckmann
Department of Conservative Dentistry and Periodontology, Clinic of Dentistry, Bernhard Gottlieb University, Vienna, Austria
Search for more papers by this authorStefan Schreiber
Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
Search for more papers by this authorSøren Jepsen
Department of Periodontology, Operative and Preventive Dentistry, University of Bonn, Bonn, Germany
Search for more papers by this authorBruno G. Loos
Department of Periodontology and Oral Biochemistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands
Search for more papers by this authorCorresponding Author
Arne S. Schaefer
Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
Address:
Arne S. Schaefer
Institute of Clinical Molecular Biology
Christian-Albrechts-University
Arnold-Heller-Str. 3, 24105 Kiel, Germany
E-mail: [email protected]
Search for more papers by this authorArne Jochens
Institute of Medical Informatics and Statistics, Christian-Albrechts-University, Kiel, Germany
Search for more papers by this authorHenrik Dommisch
Department of Periodontology, Operative and Preventive Dentistry, University of Bonn, Bonn, Germany
Search for more papers by this authorChristian Graetz
Department of Operative Dentistry and Periodontology, University Medical Center Schleswig-Holstein, Kiel, Germany
Search for more papers by this authorYvonne Jockel-Schneider
Department of Periodontology, Clinic of Preventive Dentistry and Periodontology, University Medical Center of the Julius-Maximilians-University, Würzburg, Germany
Search for more papers by this authorInga Harks
Center of Periodontology, Operative and Preventive Dentistry, University Medical Center, Münster, Germany
Search for more papers by this authorIngmar Staufenbiel
Department of Conservative Dentistry, Periodontology and Preventive Dentistry, Hannover Medical School, Hannover, Germany
Search for more papers by this authorJoerg Meyle
Department of Periodontology, University Medical Center, Giessen, Marburg, Germany
Search for more papers by this authorPeter Eickholz
Department of Periodontology, Centre for Dental, Oral, and Maxillofacial Medicine (Carolinum), Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
Search for more papers by this authorMathias Folwaczny
Department of Preventive Dentistry and Periodontology, University of Munich, Munich, Germany
Search for more papers by this authorMarja Laine
Department of Periodontology and Oral Biochemistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands
Search for more papers by this authorBarbara Noack
Center of Periodontology, Operative and Preventive Dentistry, Clinic of Preventive Dentistry, University Medical Center Carl Gustav Carus der Technischen Universität Dresden, Dresden, Germany
Search for more papers by this authorCisca Wijmenga
Department of Genetics, University Medical Center, Groningen, The Netherlands
Search for more papers by this authorWolfgang Lieb
Biobank Popgen, University Medical Center Schleswig-Holstein, Kiel, Germany
Search for more papers by this authorCorinna Bruckmann
Department of Conservative Dentistry and Periodontology, Clinic of Dentistry, Bernhard Gottlieb University, Vienna, Austria
Search for more papers by this authorStefan Schreiber
Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
Search for more papers by this authorSøren Jepsen
Department of Periodontology, Operative and Preventive Dentistry, University of Bonn, Bonn, Germany
Search for more papers by this authorBruno G. Loos
Department of Periodontology and Oral Biochemistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands
Search for more papers by this authorConflict of interest and source of funding
The authors declare that they have no conflicts of interest. The Department of Periodontology at ACTA is funded in part by a grant from the University of Amsterdam for the focal point “Oral infection and inflammation.” Author AS is funded by a grant of the Deutsche Forschungsgemeinschaft (KFO208); author BL received a supportive contribution from the Dutch Society of Periodontology for research into the genetics of periodontitis. The popgen 2.0 network is supported by a grant from the German Ministry for Education and Research (01EY1103).
Abstract
Aim
Epidemiological and clinical studies indicated a relationship of periodontitis with rheumatoid arthritis (RA). We aimed to identify shared genetic susceptibility loci of RA and periodontitis.
Materials and Methods
Forty-seven risk genes of genome-wide significance of RA and SLE were genotyped in a German case–control sample of aggressive periodontitis (AgP), using Immunochip genotyping arrays (Illumina, 600 cases, 1440 controls) and Affymetrix 500 K Genotyping Arrays (280 cases and 983 controls). Significant associations were replicated in 168 Dutch AgP cases and 679 controls and adjusted for the confounders smoking and sex.
Results
Variants at IRF5 and PRDM1 showed association with AgP. Upon covariate adjustment for smoking and sex, the most strongly associated variant at IRF5 was the rare variant rs62481981 (ppooled = 0.0012, odds ratio [OR] = 3.1, 95% confidence interval [95% CI] = 1.6–6.1; 801 cases, 1476 controls).Within PRDM1 it was rs6923419 (ppooled = 0.004, OR = 0.7, 95% CI = 0.6–0.9; 833 cases, 1440 controls). The associations lost significance after correction for multiple testing in the replication. Both genes are implicated in beta-interferon signalling and are also genome-wide associated with SLE and inflammatory bowel disease.
Conclusion
The study gives no definite evidence for a pathogenic genetic link of periodontitis and RA but suggests IRF5 and PRDM1 as shared susceptibility factors.
Supporting Information
| Filename | Description |
|---|---|
| jcpe12314-sup-0001-figS1.tifimage/tif, 3.4 MB | Figure S1. LD structure of SNPs at IL2RA, IRF5 and PRDM1, which showed significant associations in the German AgP case–control sample and were selected for replication. LD was calculated with 1000 healthy individuals from North-Germany (popgen biobank) by using the software Haploview. See text for details (Green diamonds – tagging SNPs that capture alleles at r2 > 0.8, yellow squares – GWAS lead SNPs, orange square – rare variant, numbers = r2). |
| jcpe12314-sup-0002-TableS1.pdfapplication/PDF, 1.4 MB | Table S1. SNPs, chromosomal positions and statistics of the loci that suggested significant associations. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- Abecasis, G. R., Altshuler, D., Auton, A., Brooks, L. D., Durbin, R. M., Gibbs, R. A., Hurles, M. E. & McVean, G. A. (2010) A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073.
- Allanore, Y., Saad, M., Dieude, P., Avouac, J., Distler, J. H., Amouyel, P., Matucci-Cerinic, M., Riemekasten, G., Airo, P., Melchers, I., Hachulla, E., Cusi, D., Wichmann, H. E., Wipff, J., Lambert, J. C., Hunzelmann, N., Tiev, K., Caramaschi, P., Diot, E., Kowal-Bielecka, O., Valentini, G., Mouthon, L., Czirjak, L., Damjanov, N., Salvi, E., Conti, C., Muller, M., Muller-Ladner, U., Riccieri, V., Ruiz, B., Cracowski, J. L., Letenneur, L., Dupuy, A. M., Meyer, O., Kahan, A., Munnich, A., Boileau, C. & Martinez, M. (2011) Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS Genetics 7, e1002091.
- Anderson, C. A., Boucher, G., Lees, C. W., Franke, A., D'Amato, M., Taylor, K. D., Lee, J. C., Goyette, P., Imielinski, M., Latiano, A., Lagace, C., Scott, R., Amininejad, L., Bumpstead, S., Baidoo, L., Baldassano, R. N., Barclay, M., Bayless, T. M., Brand, S., Buning, C., Colombel, J. F., Denson, L. A., De Vos, M., Dubinsky, M., Edwards, C., Ellinghaus, D., Fehrmann, R. S., Floyd, J. A., Florin, T., Franchimont, D., Franke, L., Georges, M., Glas, J., Glazer, N. L., Guthery, S. L., Haritunians, T., Hayward, N. K., Hugot, J. P., Jobin, G., Laukens, D., Lawrance, I., Lemann, M., Levine, A., Libioulle, C., Louis, E., McGovern, D. P., Milla, M., Montgomery, G. W., Morley, K. I., Mowat, C., Ng, A., Newman, W., Ophoff, R. A., Papi, L., Palmieri, O., Peyrin-Biroulet, L., Panes, J., Phillips, A., Prescott, N. J., Proctor, D. D., Roberts, R., Russell, R., Rutgeerts, P., Sanderson, J., Sans, M., Schumm, P., Seibold, F., Sharma, Y., Simms, L. A., Seielstad, M., Steinhart, A. H., Targan, S. R., van den Berg, L. H., Vatn, M., Verspaget, H., Walters, T., Wijmenga, C., Wilson, D. C., Westra, H. J., Xavier, R. J., Zhao, Z. Z., Ponsioen, C. Y., Andersen, V., Torkvist, L., Gazouli, M., Anagnou, N. P., Karlsen, T. H., Kupcinskas, L., Sventoraityte, J., Mansfield, J. C., Kugathasan, S., Silverberg, M. S., Halfvarson, J., Rotter, J. I., Mathew, C. G., Griffiths, A. M., Gearry, R., Ahmad, T., Brant, S. R., Chamaillard, M., Satsangi, J., Cho, J. H., Schreiber, S., Daly, M. J., Barrett, J. C., Parkes, M., Annese, V., Hakonarson, H., Radford-Smith, G., Duerr, R. H., Vermeire, S., Weersma, R. K. & Rioux, J. D. (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nature Genetics 43, 246–252.
- Barnes, B. J., Kellum, M. J., Field, A. E. & Pitha, P. M. (2002) Multiple regulatory domains of IRF-5 control activation, cellular localization, and induction of chemokines that mediate recruitment of T lymphocytes. Molecular and Cellular Biology 22, 5721–5740.
- Barnes, B. J., Moore, P. A. & Pitha, P. M. (2001) Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes. Journal of Biological Chemistry 276, 23382–23390.
- Barrett, J. C., Fry, B., Maller, J. & Daly, M. J. (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265.
- Barrett, J. C., Hansoul, S., Nicolae, D. L., Cho, J. H., Duerr, R. H., Rioux, J. D., Brant, S. R., Silverberg, M. S., Taylor, K. D., Barmada, M. M., Bitton, A., Dassopoulos, T., Datta, L. W., Green, T., Griffiths, A. M., Kistner, E. O., Murtha, M. T., Regueiro, M. D., Rotter, J. I., Schumm, L. P., Steinhart, A. H., Targan, S. R., Xavier, R. J., Libioulle, C., Sandor, C., Lathrop, M., Belaiche, J., Dewit, O., Gut, I., Heath, S., Laukens, D., Mni, M., Rutgeerts, P., Van Gossum, A., Zelenika, D., Franchimont, D., Hugot, J. P., de Vos, M., Vermeire, S., Louis, E., Cardon, L. R., Anderson, C. A., Drummond, H., Nimmo, E., Ahmad, T., Prescott, N. J., Onnie, C. M., Fisher, S. A., Marchini, J., Ghori, J., Bumpstead, S., Gwilliam, R., Tremelling, M., Deloukas, P., Mansfield, J., Jewell, D., Satsangi, J., Mathew, C. G., Parkes, M., Georges, M. & Daly, M. J. (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nature Genetics 40, 955–962.
- Bhagwat, M. (2010) Searching NCBI's dbSNP database. Current Protocols in Bioinformatics Chapter 1 (Unit 1), 19. doi: 10.1002/0471250953.bi0119s32.
- Chung, S. A., Taylor, K. E., Graham, R. R., Nititham, J., Lee, A. T., Ortmann, W. A., Jacob, C. O., Alarcon-Riquelme, M. E., Tsao, B. P., Harley, J. B., Gaffney, P. M., Moser, K. L., Petri, M., Demirci, F. Y., Kamboh, M. I., Manzi, S., Gregersen, P. K., Langefeld, C. D., Behrens, T. W. & Criswell, L. A. (2011) Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production. PLoS Genetics 7, e1001323.
- Cortes, A. & Brown, M. A. (2011) Promise and pitfalls of the Immunochip. Arthritis Research & Therapy 13, 101.
- Cotsapas, C., Voight, B. F., Rossin, E., Lage, K., Neale, B. M., Wallace, C., Abecasis, G. R., Barrett, J. C., Behrens, T., Cho, J., De Jager, P. L., Elder, J. T., Graham, R. R., Gregersen, P., Klareskog, L., Siminovitch, K. A., van Heel, D. A., Wijmenga, C., Worthington, J., Todd, J. A., Hafler, D. A., Rich, S. S. & Daly, M. J. (2011) Pervasive sharing of genetic effects in autoimmune disease. PLoS Genetics 7, e1002254.
- Crotty, S., Johnston, R. J. & Schoenberger, S. P. (2010) Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nature Immunology 11, 114–120.
- Detert, J., Pischon, N., Burmester, G. R. & Buttgereit, F. (2010) The association between rheumatoid arthritis and periodontal disease. Arthritis Research & Therapy 12, 218.
- Dupont, W. D. & Plummer, W. D. Jr (1998) Power and sample size calculations for studies involving linear regression. Controlled Clinical Trials 19, 589–601.
- Ellinghaus, D., Zhang, H., Zeissig, S., Lipinski, S., Till, A., Jiang, T., Stade, B., Bromberg, Y., Ellinghaus, E., Keller, A., Rivas, M. A., Skieceviciene, J., Doncheva, N. T., Liu, X., Liu, Q., Jiang, F., Forster, M., Mayr, G., Albrecht, M., Hasler, R., Boehm, B. O., Goodall, J., Berzuini, C. R., Lee, J., Andersen, V., Vogel, U., Kupcinskas, L., Kayser, M., Krawczak, M., Nikolaus, S., Weersma, R. K., Ponsioen, C. Y., Sans, M., Wijmenga, C., Strachan, D. P., McArdle, W. L., Vermeire, S., Rutgeerts, P., Sanderson, J. D., Mathew, C. G., Vatn, M. H., Wang, J., Nothen, M. M., Duerr, R. H., Buning, C., Brand, S., Glas, J., Winkelmann, J., Illig, T., Latiano, A., Annese, V., Halfvarson, J., D'Amato, M., Daly, M. J., Nothnagel, M., Karlsen, T. H., Subramani, S., Rosenstiel, P., Schreiber, S., Parkes, M. & Franke, A. (2013) Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies. Gastroenterology 145, 339–347.
- Eyre, S., Bowes, J., Diogo, D., Lee, A., Barton, A., Martin, P., Zhernakova, A., Stahl, E., Viatte, S., McAllister, K., Amos, C. I., Padyukov, L., Toes, R. E., Huizinga, T. W., Wijmenga, C., Trynka, G., Franke, L., Westra, H. J., Alfredsson, L., Hu, X., Sandor, C., de Bakker, P. I., Davila, S., Khor, C. C., Heng, K. K., Andrews, R., Edkins, S., Hunt, S. E., Langford, C., Symmons, D., Concannon, P., Onengut-Gumuscu, S., Rich, S. S., Deloukas, P., Gonzalez-Gay, M. A., Rodriguez-Rodriguez, L., Arlsetig, L., Martin, J., Rantapaa-Dahlqvist, S., Plenge, R. M., Raychaudhuri, S., Klareskog, L., Gregersen, P. K. & Worthington, J. (2012) High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nature Genetics 44, 1336–1340.
- Franke, A., McGovern, D. P., Barrett, J. C., Wang, K., Radford-Smith, G. L., Ahmad, T., Lees, C. W., Balschun, T., Lee, J., Roberts, R., Anderson, C. A., Bis, J. C., Bumpstead, S., Ellinghaus, D., Festen, E. M., Georges, M., Green, T., Haritunians, T., Jostins, L., Latiano, A., Mathew, C. G., Montgomery, G. W., Prescott, N. J., Raychaudhuri, S., Rotter, J. I., Schumm, P., Sharma, Y., Simms, L. A., Taylor, K. D., Whiteman, D., Wijmenga, C., Baldassano, R. N., Barclay, M., Bayless, T. M., Brand, S., Buning, C., Cohen, A., Colombel, J. F., Cottone, M., Stronati, L., Denson, T., De Vos, M., D'Inca, R., Dubinsky, M., Edwards, C., Florin, T., Franchimont, D., Gearry, R., Glas, J., Van Gossum, A., Guthery, S. L., Halfvarson, J., Verspaget, H. W., Hugot, J. P., Karban, A., Laukens, D., Lawrance, I., Lemann, M., Levine, A., Libioulle, C., Louis, E., Mowat, C., Newman, W., Panes, J., Phillips, A., Proctor, D. D., Regueiro, M., Russell, R., Rutgeerts, P., Sanderson, J., Sans, M., Seibold, F., Steinhart, A. H., Stokkers, P. C., Torkvist, L., Kullak-Ublick, G., Wilson, D., Walters, T., Targan, S. R., Brant, S. R., Rioux, J. D., D'Amato, M., Weersma, R. K., Kugathasan, S., Griffiths, A. M., Mansfield, J. C., Vermeire, S., Duerr, R. H., Silverberg, M. S., Satsangi, J., Schreiber, S., Cho, J. H., Annese, V., Hakonarson, H., Daly, M. J. & Parkes, M. (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature Genetics 42, 1118–1125.
- Gorlova, O., Martin, J. E., Rueda, B., Koeleman, B. P., Ying, J., Teruel, M., Diaz-Gallo, L. M., Broen, J. C., Vonk, M. C., Simeon, C. P., Alizadeh, B. Z., Coenen, M. J., Voskuyl, A. E., Schuerwegh, A. J., van Riel, P. L., Vanthuyne, M., van ‘t Slot, R., Italiaander, A., Ophoff, R. A., Hunzelmann, N., Fonollosa, V., Ortego-Centeno, N., Gonzalez-Gay, M. A., Garcia-Hernandez, F. J., Gonzalez-Escribano, M. F., Airo, P., van Laar, J., Worthington, J., Hesselstrand, R., Smith, V., de Keyser, F., Houssiau, F., Chee, M. M., Madhok, R., Shiels, P. G., Westhovens, R., Kreuter, A., de Baere, E., Witte, T., Padyukov, L., Nordin, A., Scorza, R., Lunardi, C., Lie, B. A., Hoffmann-Vold, A. M., Palm, O., Garcia de la Pena, P., Carreira, P., Varga, J., Hinchcliff, M., Lee, A. T., Gourh, P., Amos, C. I., Wigley, F. M., Hummers, L. K., Nelson, J. L., Riemekasten, G., Herrick, A., Beretta, L., Fonseca, C., Denton, C. P., Gregersen, P. K., Agarwal, S., Assassi, S., Tan, F. K., Arnett, F. C., Radstake, T. R., Mayes, M. D. & Martin, J. (2011) Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy. PLoS Genetics 7, e1002178.
- Guerra, S. G., Vyse, T. J. & Cunninghame Graham, D. S. (2012) The genetics of lupus: a functional perspective. Arthritis Research & Therapy 14, 211.
- Hafler, D. A., Compston, A., Sawcer, S., Lander, E. S., Daly, M. J., De Jager, P. L., de Bakker, P. I., Gabriel, S. B., Mirel, D. B., Ivinson, A. J., Pericak-Vance, M. A., Gregory, S. G., Rioux, J. D., McCauley, J. L., Haines, J. L., Barcellos, L. F., Cree, B., Oksenberg, J. R. & Hauser, S. L. (2007) Risk alleles for multiple sclerosis identified by a genomewide study. New England Journal of Medicine 357, 851–862.
- Hampe, J., Franke, A., Rosenstiel, P., Till, A., Teuber, M., Huse, K., Albrecht, M., Mayr, G., De La Vega, F. M., Briggs, J., Gunther, S., Prescott, N. J., Onnie, C. M., Hasler, R., Sipos, B., Folsch, U. R., Lengauer, T., Platzer, M., Mathew, C. G., Krawczak, M. & Schreiber, S. (2007) A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nature Genetics 39, 207–211.
- Han, J. W., Zheng, H. F., Cui, Y., Sun, L. D., Ye, D. Q., Hu, Z., Xu, J. H., Cai, Z. M., Huang, W., Zhao, G. P., Xie, H. F., Fang, H., Lu, Q. J., Li, X. P., Pan, Y. F., Deng, D. Q., Zeng, F. Q., Ye, Z. Z., Zhang, X. Y., Wang, Q. W., Hao, F., Ma, L., Zuo, X. B., Zhou, F. S., Du, W. H., Cheng, Y. L., Yang, J. Q., Shen, S. K., Li, J., Sheng, Y. J., Zuo, X. X., Zhu, W. F., Gao, F., Zhang, P. L., Guo, Q., Li, B., Gao, M., Xiao, F. L., Quan, C., Zhang, C., Zhang, Z., Zhu, K. J., Li, Y., Hu, D. Y., Lu, W. S., Huang, J. L., Liu, S. X., Li, H., Ren, Y. Q., Wang, Z. X., Yang, C. J., Wang, P. G., Zhou, W. M., Lv, Y. M., Zhang, A. P., Zhang, S. Q., Lin, D., Low, H. Q., Shen, M., Zhai, Z. F., Wang, Y., Zhang, F. Y., Yang, S., Liu, J. J. & Zhang, X. J. (2009) Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nature Genetics 41, 1234–1237.
- Hirschfield, G. M., Liu, X., Xu, C., Lu, Y., Xie, G., Gu, X., Walker, E. J., Jing, K., Juran, B. D., Mason, A. L., Myers, R. P., Peltekian, K. M., Ghent, C. N., Coltescu, C., Atkinson, E. J., Heathcote, E. J., Lazaridis, K. N., Amos, C. I. & Siminovitch, K. A. (2009) Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. New England Journal of Medicine 360, 2544–2555.
- Hom, G., Graham, R. R., Modrek, B., Taylor, K. E., Ortmann, W., Garnier, S., Lee, A. T., Chung, S. A., Ferreira, R. C., Pant, P. V., Ballinger, D. G., Kosoy, R., Demirci, F. Y., Kamboh, M. I., Kao, A. H., Tian, C., Gunnarsson, I., Bengtsson, A. A., Rantapaa-Dahlqvist, S., Petri, M., Manzi, S., Seldin, M. F., Ronnblom, L., Syvanen, A. C., Criswell, L. A., Gregersen, P. K. & Behrens, T. W. (2008) Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. New England Journal of Medicine 358, 900–909.
- Jin, Y., Birlea, S. A., Fain, P. R., Gowan, K., Riccardi, S. L., Holland, P. J., Mailloux, C. M., Sufit, A. J., Hutton, S. M., Amadi-Myers, A., Bennett, D. C., Wallace, M. R., McCormack, W. T., Kemp, E. H., Gawkrodger, D. J., Weetman, A. P., Picardo, M., Leone, G., Taieb, A., Jouary, T., Ezzedine, K., van Geel, N., Lambert, J., Overbeck, A. & Spritz, R. A. (2010) Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. New England Journal of Medicine 362, 1686–1697.
- Jostins, L., Ripke, S., Weersma, R. K., Duerr, R. H., McGovern, D. P., Hui, K. Y., Lee, J. C., Schumm, L. P., Sharma, Y., Anderson, C. A., Essers, J., Mitrovic, M., Ning, K., Cleynen, I., Theatre, E., Spain, S. L., Raychaudhuri, S., Goyette, P., Wei, Z., Abraham, C., Achkar, J. P., Ahmad, T., Amininejad, L., Ananthakrishnan, A. N., Andersen, V., Andrews, J. M., Baidoo, L., Balschun, T., Bampton, P. A., Bitton, A., Boucher, G., Brand, S., Buning, C., Cohain, A., Cichon, S., D'Amato, M., De Jong, D., Devaney, K. L., Dubinsky, M., Edwards, C., Ellinghaus, D., Ferguson, L. R., Franchimont, D., Fransen, K., Gearry, R., Georges, M., Gieger, C., Glas, J., Haritunians, T., Hart, A., Hawkey, C., Hedl, M., Hu, X., Karlsen, T. H., Kupcinskas, L., Kugathasan, S., Latiano, A., Laukens, D., Lawrance, I. C., Lees, C. W., Louis, E., Mahy, G., Mansfield, J., Morgan, A. R., Mowat, C., Newman, W., Palmieri, O., Ponsioen, C. Y., Potocnik, U., Prescott, N. J., Regueiro, M., Rotter, J. I., Russell, R. K., Sanderson, J. D., Sans, M., Satsangi, J., Schreiber, S., Simms, L. A., Sventoraityte, J., Targan, S. R., Taylor, K. D., Tremelling, M., Verspaget, H. W., De Vos, M., Wijmenga, C., Wilson, D. C., Winkelmann, J., Xavier, R. J., Zeissig, S., Zhang, B., Zhang, C. K., Zhao, H., Silverberg, M. S., Annese, V., Hakonarson, H., Brant, S. R., Radford-Smith, G., Mathew, C. G., Rioux, J. D., Schadt, E. E., Daly, M. J., Franke, A., Parkes, M., Vermeire, S., Barrett, J. C. & Cho, J. H. (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124.
- Keller, A. D. & Maniatis, T. (1991) Identification and characterization of a novel repressor of beta-interferon gene expression. Genes & Development 5, 868–879.
- Kobayashi, T., Ito, S., Yamamoto, K., Hasegawa, H., Sugita, N., Kuroda, T., Kaneko, S., Narita, I., Yasuda, K., Nakano, M., Gejyo, F. & Yoshie, H. (2003) Risk of periodontitis in systemic lupus erythematosus is associated with Fcgamma receptor polymorphisms. Journal of Periodontology 74, 378–384.
- Lee, Y. H., Bae, S. C., Choi, S. J., Ji, J. D. & Song, G. G. (2012) Genome-wide pathway analysis of genome-wide association studies on systemic lupus erythematosus and rheumatoid arthritis. Molecular Biology Reports 39, 10627–10635.
- Linden, G. J., Lyons, A. & Scannapieco, F. A. (2013) Periodontal systemic associations: review of the evidence. Journal of Periodontology 84, S8–S19.
- Liu, X., Invernizzi, P., Lu, Y., Kosoy, R., Bianchi, I., Podda, M., Xu, C., Xie, G., Macciardi, F., Selmi, C., Lupoli, S., Shigeta, R., Ransom, M., Lleo, A., Lee, A. T., Mason, A. L., Myers, R. P., Peltekian, K. M., Ghent, C. N., Bernuzzi, F., Zuin, M., Rosina, F., Borghesio, E., Floreani, A., Lazzari, R., Niro, G., Andriulli, A., Muratori, L., Muratori, P., Almasio, P. L., Andreone, P., Margotti, M., Brunetto, M., Coco, B., Alvaro, D., Bragazzi, M. C., Marra, F., Pisano, A., Rigamonti, C., Colombo, M., Marzioni, M., Benedetti, A., Fabris, L., Strazzabosco, M., Portincasa, P., Palmieri, V. O., Tiribelli, C., Croce, L., Bruno, S., Rossi, S., Vinci, M., Prisco, C., Mattalia, A., Toniutto, P., Picciotto, A., Galli, A., Ferrari, C., Colombo, S., Casella, G., Morini, L., Caporaso, N., Colli, A., Spinzi, G., Montanari, R., Gregersen, P. K., Heathcote, E. J., Hirschfield, G. M., Siminovitch, K. A., Amos, C. I., Gershwin, M. E. & Seldin, M. F. (2010) Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nature Genetics 42, 658–660.
- Mercado, F. B., Marshall, R. I. & Bartold, P. M. (2003) Inter-relationships between rheumatoid arthritis and periodontal disease. A review. Journal of Clinical Periodontology 30, 761–772.
- Mikuls, T. R., Payne, J. B., Yu, F., Thiele, G. M., Reynolds, R. J., Cannon, G. W., Markt, J., McGowan, D., Kerr, G. S., Redman, R. S., Reimold, A., Griffiths, G., Beatty, M., Gonzalez, S. M., Bergman, D. A., Hamilton, B. C. 3rd, Erickson, A. R., Sokolove, J., Robinson, W. H., Walker, C., Chandad, F. & O'Dell, J. R. (2014) Periodontitis and Porphyromonas gingivalis in patients with rheumatoid arthritis. Arthritis & Rheumatology 66, 1090–1100.
- Mutlu, S., Richards, A., Maddison, P. & Scully, C. (1993) Gingival and periodontal health in systemic lupus erythematosus. Community Dentistry and Oral Epidemiology 21, 158–161.
- Novo, E., Garcia-MacGregor, E., Viera, N., Chaparro, N. & Crozzoli, Y. (1999) Periodontitis and anti-neutrophil cytoplasmic antibodies in systemic lupus erythematosus and rheumatoid arthritis: a comparative study. Journal of Periodontology 70, 185–188.
- Plagnol, V., Howson, J. M., Smyth, D. J., Walker, N., Hafler, J. P., Wallace, C., Stevens, H., Jackson, L., Simmonds, M. J., Bingley, P. J., Gough, S. C. & Todd, J. A. (2011) Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases. PLoS Genetics 7, e1002216.
- Potikuri, D., Dannana, K. C., Kanchinadam, S., Agrawal, S., Kancharla, A., Rajasekhar, L., Pothuraju, S. & Gumdal, N. (2012) Periodontal disease is significantly higher in non-smoking treatment-naive rheumatoid arthritis patients: results from a case-control study. Annals of the Rheumatic Diseases 71, 1541–1544.
- Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A., Bender, D., Maller, J., Sklar, P., de Bakker, P. I., Daly, M. J. & Sham, P. C. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics 81, 559–575.
- Radstake, T. R., Gorlova, O., Rueda, B., Martin, J. E., Alizadeh, B. Z., Palomino-Morales, R., Coenen, M. J., Vonk, M. C., Voskuyl, A. E., Schuerwegh, A. J., Broen, J. C., van Riel, P. L., van ‘t Slot, R., Italiaander, A., Ophoff, R. A., Riemekasten, G., Hunzelmann, N., Simeon, C. P., Ortego-Centeno, N., Gonzalez-Gay, M. A., Gonzalez-Escribano, M. F., Airo, P., van Laar, J., Herrick, A., Worthington, J., Hesselstrand, R., Smith, V., de Keyser, F., Houssiau, F., Chee, M. M., Madhok, R., Shiels, P., Westhovens, R., Kreuter, A., Kiener, H., de Baere, E., Witte, T., Padykov, L., Klareskog, L., Beretta, L., Scorza, R., Lie, B. A., Hoffmann-Vold, A. M., Carreira, P., Varga, J., Hinchcliff, M., Gregersen, P. K., Lee, A. T., Ying, J., Han, Y., Weng, S. F., Amos, C. I., Wigley, F. M., Hummers, L., Nelson, J. L., Agarwal, S. K., Assassi, S., Gourh, P., Tan, F. K., Koeleman, B. P., Arnett, F. C., Martin, J. & Mayes, M. D. (2010) Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nature Genetics 42, 426–429.
- Ramos, P. S., Criswell, L. A., Moser, K. L., Comeau, M. E., Williams, A. H., Pajewski, N. M., Chung, S. A., Graham, R. R., Zidovetzki, R., Kelly, J. A., Kaufman, K. M., Jacob, C. O., Vyse, T. J., Tsao, B. P., Kimberly, R. P., Gaffney, P. M., Alarcon-Riquelme, M. E., Harley, J. B. & Langefeld, C. D. (2011) A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap. PLoS Genetics 7, e1002406.
- Rhodus, N. L. & Johnson, D. K. (1990) The prevalence of oral manifestations of systemic lupus erythematosus. Quintessence International 21, 461–465.
- Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C. C., Patsopoulos, N. A., Moutsianas, L., Dilthey, A., Su, Z., Freeman, C., Hunt, S. E., Edkins, S., Gray, E., Booth, D. R., Potter, S. C., Goris, A., Band, G., Oturai, A. B., Strange, A., Saarela, J., Bellenguez, C., Fontaine, B., Gillman, M., Hemmer, B., Gwilliam, R., Zipp, F., Jayakumar, A., Martin, R., Leslie, S., Hawkins, S., Giannoulatou, E., D'Alfonso, S., Blackburn, H., Martinelli Boneschi, F., Liddle, J., Harbo, H. F., Perez, M. L., Spurkland, A., Waller, M. J., Mycko, M. P., Ricketts, M., Comabella, M., Hammond, N., Kockum, I., McCann, O. T., Ban, M., Whittaker, P., Kemppinen, A., Weston, P., Hawkins, C., Widaa, S., Zajicek, J., Dronov, S., Robertson, N., Bumpstead, S. J., Barcellos, L. F., Ravindrarajah, R., Abraham, R., Alfredsson, L., Ardlie, K., Aubin, C., Baker, A., Baker, K., Baranzini, S. E., Bergamaschi, L., Bergamaschi, R., Bernstein, A., Berthele, A., Boggild, M., Bradfield, J. P., Brassat, D., Broadley, S. A., Buck, D., Butzkueven, H., Capra, R., Carroll, W. M., Cavalla, P., Celius, E. G., Cepok, S., Chiavacci, R., Clerget-Darpoux, F., Clysters, K., Comi, G., Cossburn, M., Cournu-Rebeix, I., Cox, M. B., Cozen, W., Cree, B. A., Cross, A. H., Cusi, D., Daly, M. J., Davis, E., de Bakker, P. I., Debouverie, M., D'Hooghe, M. B., Dixon, K., Dobosi, R., Dubois, B., Ellinghaus, D., Elovaara, I., Esposito, F., Fontenille, C., Foote, S., Franke, A., Galimberti, D., Ghezzi, A., Glessner, J., Gomez, R., Gout, O., Graham, C., Grant, S. F., Guerini, F. R., Hakonarson, H., Hall, P., Hamsten, A., Hartung, H. P., Heard, R. N., Heath, S., Hobart, J., Hoshi, M., Infante-Duarte, C., Ingram, G., Ingram, W., Islam, T., Jagodic, M., Kabesch, M., Kermode, A. G., Kilpatrick, T. J., Kim, C., Klopp, N., Koivisto, K., Larsson, M., Lathrop, M., Lechner-Scott, J. S., Leone, M. A., Leppa, V., Liljedahl, U., Bomfim, I. L., Lincoln, R. R., Link, J., Liu, J., Lorentzen, A. R., Lupoli, S., Macciardi, F., Mack, T., Marriott, M., Martinelli, V., Mason, D., McCauley, J. L., Mentch, F., Mero, I. L., Mihalova, T., Montalban, X., Mottershead, J., Myhr, K. M., Naldi, P., Ollier, W., Page, A., Palotie, A., Pelletier, J., Piccio, L., Pickersgill, T., Piehl, F., Pobywajlo, S., Quach, H. L., Ramsay, P. P., Reunanen, M., Reynolds, R., Rioux, J. D., Rodegher, M., Roesner, S., Rubio, J. P., Ruckert, I. M., Salvetti, M., Salvi, E., Santaniello, A., Schaefer, C. A., Schreiber, S., Schulze, C., Scott, R. J., Sellebjerg, F., Selmaj, K. W., Sexton, D., Shen, L., Simms-Acuna, B., Skidmore, S., Sleiman, P. M., Smestad, C., Sorensen, P. S., Sondergaard, H. B., Stankovich, J., Strange, R. C., Sulonen, A. M., Sundqvist, E., Syvanen, A. C., Taddeo, F., Taylor, B., Blackwell, J. M., Tienari, P., Bramon, E., Tourbah, A., Brown, M. A., Tronczynska, E., Casas, J. P., Tubridy, N., Corvin, A., Vickery, J., Jankowski, J., Villoslada, P., Markus, H. S., Wang, K., Mathew, C. G., Wason, J., Palmer, C. N., Wichmann, H. E., Plomin, R., Willoughby, E., Rautanen, A., Winkelmann, J., Wittig, M., Trembath, R. C., Yaouanq, J., Viswanathan, A. C., Zhang, H., Wood, N. W., Zuvich, R., Deloukas, P., Langford, C., Duncanson, A., Oksenberg, J. R., Pericak-Vance, M. A., Haines, J. L., Olsson, T., Hillert, J., Ivinson, A. J., De Jager, P. L., Peltonen, L., Stewart, G. J., Hafler, D. A., Hauser, S. L., McVean, G., Donnelly, P. & Compston, A. (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219.
- Schaefer, A. S., Bochenek, G., Manke, T., Nothnagel, M., Graetz, C., Thien, A., Jockel-Schneider, Y., Harks, I., Staufenbiel, I., Wijmenga, C., Eberhardt, J., Guzeldemir, E., Cine, N., Folwaczny, M., Noack, B., Meyle, J., Eickholz, P., Trombelli, L., Scapoli, C., Nohutcu, R., Bruckmann, C., Doerfer, C., Jepsen, S., Loos, B. G. & Schreiber, S. (2013) Validation of reported genetic risk factors for periodontitis in a large-scale replication study. Journal of Clinical Periodontology 40(6), 563–72. doi:10.1111/jcpe.12092.
- Schaefer, A. S., Richter, G. M., Groessner-Schreiber, B., Noack, B., Nothnagel, M., El Mokhtari, N. E., Loos, B. G., Jepsen, S. & Schreiber, S. (2009) Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis. PLoS Genetics 5, e1000378.
- Schaefer, A. S., Richter, G. M., Nothnagel, M., Manke, T., Dommisch, H., Jacobs, G., Arlt, A., Rosenstiel, P., Noack, B., Groessner-Schreiber, B., Jepsen, S., Loos, B. G. & Schreiber, S. (2010) A genome-wide association study identifies GLT6D1 as a susceptibility locus for periodontitis. Human Molecular Genetics 19, 553–562.
- Scher, J. U., Ubeda, C., Equinda, M., Khanin, R., Buischi, Y., Viale, A., Lipuma, L., Attur, M., Pillinger, M. H., Weissmann, G., Littman, D. R., Pamer, E. G., Bretz, W. A. & Abramson, S. B. (2012) Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis. Arthritis and Rheumatism 64, 3083–3094.
- Sivakumaran, S., Agakov, F., Theodoratou, E., Prendergast, J. G., Zgaga, L., Manolio, T., Rudan, I., McKeigue, P., Wilson, J. F. & Campbell, H. (2011) Abundant pleiotropy in human complex diseases and traits. American Journal of Human Genetics 89, 607–618.
- Stahl, E. A., Raychaudhuri, S., Remmers, E. F., Xie, G., Eyre, S., Thomson, B. P., Li, Y., Kurreeman, F. A., Zhernakova, A., Hinks, A., Guiducci, C., Chen, R., Alfredsson, L., Amos, C. I., Ardlie, K. G., Barton, A., Bowes, J., Brouwer, E., Burtt, N. P., Catanese, J. J., Coblyn, J., Coenen, M. J., Costenbader, K. H., Criswell, L. A., Crusius, J. B., Cui, J., de Bakker, P. I., De Jager, P. L., Ding, B., Emery, P., Flynn, E., Harrison, P., Hocking, L. J., Huizinga, T. W., Kastner, D. L., Ke, X., Lee, A. T., Liu, X., Martin, P., Morgan, A. W., Padyukov, L., Posthumus, M. D., Radstake, T. R., Reid, D. M., Seielstad, M., Seldin, M. F., Shadick, N. A., Steer, S., Tak, P. P., Thomson, W., van der Helm-van Mil, A. H., van der Horst-Bruinsma, I. E., van der Schoot, C. E., van Riel, P. L., Weinblatt, M. E., Wilson, A. G., Wolbink, G. J., Wordsworth, B. P., Wijmenga, C., Karlson, E. W., Toes, R. E., de Vries, N., Begovich, A. B., Worthington, J., Siminovitch, K. A., Gregersen, P. K., Klareskog, L. & Plenge, R. M. (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nature Genetics 42, 508–514.
- Steinhagen, F., McFarland, A. P., Rodriguez, L. G., Tewary, P., Jarret, A., Savan, R. & Klinman, D. M. (2013) IRF-5 and NF-kappaB p50 co-regulate IFN-beta and IL-6 expression in TLR9-stimulated human plasmacytoid dendritic cells. European Journal of Immunology 43, 1896–1906.
- Yang, W., Tang, H., Zhang, Y., Tang, X., Zhang, J., Sun, L., Yang, J., Cui, Y., Zhang, L., Hirankarn, N., Cheng, H., Pan, H. F., Gao, J., Lee, T. L., Sheng, Y., Lau, C. S., Li, Y., Chan, T. M., Yin, X., Ying, D., Lu, Q., Leung, A. M., Zuo, X., Chen, X., Tong, K. L., Zhou, F., Diao, Q., Tse, N. K., Xie, H., Mok, C. C., Hao, F., Wong, S. N., Shi, B., Lee, K. W., Hui, Y., Ho, M. H., Liang, B., Lee, P. P., Cui, H., Guo, Q., Chung, B. H., Pu, X., Liu, Q., Zhang, X., Zhang, C., Chong, C. Y., Fang, H., Wong, R. W., Sun, Y., Mok, M. Y., Li, X. P., Avihingsanon, Y., Zhai, Z., Rianthavorn, P., Deekajorndej, T., Suphapeetiporn, K., Gao, F., Shotelersuk, V., Kang, X., Ying, S. K., Wong, W. H., Zhu, D., Fung, S. K., Zeng, F., Lai, W. M., Wong, C. M., Ng, I. O., Garcia-Barcelo, M. M., Cherny, S. S., Shen, N., Tam, P. K., Sham, P. C., Ye, D. Q., Yang, S. & Lau, Y. L. (2013) Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians. American Journal of Human Genetics 92, 41–51.
- Zhou, X. J., Lu, X. L., Lv, J. C., Yang, H. Z., Qin, L. X., Zhao, M. H., Su, Y., Li, Z. G. & Zhang, H. (2011) Genetic association of PRDM1-ATG5 intergenic region and autophagy with systemic lupus erythematosus in a Chinese population. Annals of the Rheumatic Diseases 70, 1330–1337.
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