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Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.

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Gorlova, Olga [] Martin, Jose-Ezequiel [] Rueda, Blanca [] Koeleman, Bobby P C [] Ying, Jun [] Vanthuyne, Marie [UCL] Houssiau, Frédéric [UCL]

The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32×10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 × 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39×10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79×10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57×10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84×10(-21), OR = 0.55) and ATA (P = 1.14×10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.

Document type Article de périodique (Journal article) – Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.
Access type Accès libre
Publication date 2011
Language Anglais
Journal information "PLoS Genetics" - Vol. 7, no. 7, p. e1002178 (2011)
Peer reviewed yes
Publisher Public Library of Science ((United States) [S.l.])
issn 1553-7390
e-issn 1553-7404
Publication status Publié
Affiliations UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales
UCL - (SLuc) Service de rhumatologie
UCL - (MGD) Service de rhumatologie
MESH Subject Scleroderma, Systemic - classification - genetics - immunology ; Polymorphism, Single Nucleotide - genetics ; Phenotype ; Middle Aged ; Male ; Humans ; HLA Antigens - genetics ; Genome-Wide Association Study - methods ; Genetic Predisposition to Disease ; Genetic Markers ; Genetic Loci - genetics ; Female ; Autoantibodies - immunology ; Alleles
Links
  1. Agarwal Sandeep K., Tan Filemon K., Arnett Frank C., Genetics and Genomic Studies in Scleroderma (Systemic Sclerosis), 10.1016/j.rdc.2007.10.001
  2. FC Arnett, Ann Rheum Dis, 69, 822 (2010)
  3. Zhou Xiaodong, Lee Jong Eun, Arnett Frank C., Xiong Momiao, Park Min Young, Yoo Yeon Kyeong, Shin Eun Soon, Reveille John D., Mayes Maureen D., Kim Jin Hyun, Song Ran, Choi Ji Yong, Park Ji Ah, Lee Yun Jong, Lee Eun Young, Song Yeong Wook, Lee Eun Bong, HLA–DPB1 and DPB2 are genetic loci for systemic sclerosis: A genome-wide association study in Koreans with replication in North Americans, 10.1002/art.24982
  4. Rueda B., Broen J., Simeon C., Hesselstrand R., Diaz B., Suarez H., Ortego-Centeno N., Riemekasten G., Fonollosa V., Vonk M.C., van den Hoogen F.H.J., Sanchez-Roman J., Aguirre-Zamorano M.A., Garcia-Portales R., Pros A., Camps M.T., Gonzalez-Gay M.A., Coenen M.J.H., Airo P., Beretta L., Scorza R., van Laar J., Gonzalez-Escribano M.F., Nelson J.L., Radstake T.R.D.J., Martin J., The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype, 10.1093/hmg/ddp119
  5. Dieudé P., Guedj M., Wipff J., Ruiz B., Hachulla E., Diot E., Granel B., Sibilia J., Tiev K., Mouthon L., Cracowski J.L., Carpentier P.H., Amoura Z., Fajardy I., Avouac J., Meyer O., Kahan A., Boileau C., Allanore Y., STAT4is a genetic risk factor for systemic sclerosis having additive effects withIRF5on disease susceptibility and related pulmonary fibrosis, 10.1002/art.24688
  6. Tsuchiya N, Kawasaki A, Hasegawa M, Fujimoto M, Takehara K, Kawaguchi Y, Kawamoto M, Hara M, Sato S, Association of STAT4 polymorphism with systemic sclerosis in a Japanese population, 10.1136/ard.2009.111310
  7. Dieudé P., Guedj M., Wipff J., Avouac J., Fajardy I., Diot E., Granel B., Sibilia J., Cabane J., Mouthon L., Cracowski J. L., Carpentier P. H., Hachulla E., Meyer O., Kahan A., Boileau C., Allanore Y., Association between theIRF5rs2004640 functional polymorphism and systemic sclerosis: A new perspective for pulmonary fibrosis, 10.1002/art.24183
  8. Ito Ikue, Kawaguchi Yasushi, Kawasaki Aya, Hasegawa Minoru, Ohashi Jun, Hikami Koki, Kawamoto Manabu, Fujimoto Manabu, Takehara Kazuhiko, Sato Shinichi, Hara Masako, Tsuchiya Naoyuki, Association of a functional polymorphism in theIRF5region with systemic sclerosis in a Japanese population, 10.1002/art.24600
  9. Gourh Pravitt, Agarwal Sandeep K., Martin Ezequiel, Divecha Dipal, Rueda Blanca, Bunting Haley, Assassi Shervin, Paz Gene, Shete Sanjay, McNearney Terry, Draeger Hilda, Reveille John D., Radstake T.R.D.J., Simeon Carmen P., Rodriguez Luis, Vicente Esther, Gonzalez-Gay Miguel A., Mayes Maureen D., Tan Filemon K., Martin Javier, Arnett Frank C., Association of the C8orf13-BLK region with systemic sclerosis in North-American and European populations, 10.1016/j.jaut.2009.08.014
  10. Ito Ikue, Kawaguchi Yasushi, Kawasaki Aya, Hasegawa Minoru, Ohashi Jun, Kawamoto Manabu, Fujimoto Manabu, Takehara Kazuhiko, Sato Shinichi, Hara Masako, Tsuchiya Naoyuki, Association of the FAM167A-BLK region with systemic sclerosis, 10.1002/art.27303
  11. Dieudé P., Wipff J., Guedj M., Ruiz B., Melchers I., Hachulla E., Riemekasten G., Diot E., Hunzelmann N., Sibilia J., Tiev K., Mouthon L., Cracowski J. L., Carpentier P. H., Distler J., Amoura Z., Tarner I., Avouac J., Meyer O., Kahan A., Boileau C., Allanore Y., BANK1is a genetic risk factor for diffuse cutaneous systemic sclerosis and has additive effects withIRF5andSTAT4 : Association ofBANK1with SSc, 10.1002/art.24885
  12. Rueda B., Gourh P., Broen J., Agarwal S. K., Simeon C., Ortego-Centeno N., Vonk M. C., Coenen M., Riemekasten G., Hunzelmann N., Hesselstrand R., Tan F. K., Reveille J. D., Assassi S., Garcia-Hernandez F. J., Carreira P., Camps M., Fernandez-Nebro A., de la Pena P. G., Nearney T., Hilda D., Gonzalez-Gay M. A., Airo P., Beretta L., Scorza R., Radstake T. R. D. J., Mayes M. D., Arnett F. C., Martin J., BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians, 10.1136/ard.2009.118174
  13. Gourh P., Arnett F. C., Tan F. K., Assassi S., Divecha D., Paz G., McNearney T., Draeger H., Reveille J. D., Mayes M. D., Agarwal S. K., Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis, 10.1136/ard.2009.116434
  14. Bossini-Castillo L., Broen J. C. A., Simeon C. P., Beretta L., Vonk M. C., Ortego-Centeno N., Espinosa G., Carreira P., Camps M. T., Navarrete N., Gonzalez-Escribano M. F., Vicente-Rabaneda E., Rodriguez L., Tolosa C., Roman-Ivorra J. A., Gomez-Gracia I., Garcia-Hernandez F. J., Castellvi I., Gallego M., Fernandez-Nebro A., Garcia-Portales R., Egurbide M. V., Fonollosa V., de la Pena P. G., Pros A., Gonzalez-Gay M. A., Hesselstrand R., Riemekasten G., Witte T., Coenen M. J. H., Koeleman B. P., Houssiau F., Smith V., de Keyser F., Westhovens R., De Langhe E., Voskuyl A. E., Schuerwegh A. J., Chee M. M., Madhok R., Shiels P., Fonseca C., Denton C., Claes K., Padykov L., Nordin A., Palm O., Lie B. A., Airo P., Scorza R., van Laar J. M., Hunzelmann N., Kreuter A., Herrick A., Worthington J., Radstake T. R. D. J., Martin J., Rueda B., A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort, 10.1136/ard.2010.141838
  15. Radstake Timothy R D J, Gorlova Olga, Rueda Blanca, Martin Jose-Ezequiel, Alizadeh Behrooz Z, Palomino-Morales Rogelio, Coenen Marieke J, Vonk Madelon C, Voskuyl Alexandre E, Schuerwegh Annemie J, Broen Jasper C, van Riel Piet L C M, van 't Slot Ruben, Italiaander Annet, Ophoff Roel A, Riemekasten Gabriela, Hunzelmann Nico, Simeon Carmen P, Ortego-Centeno Norberto, González-Gay Miguel A, González-Escribano María F, Airo Paolo, van Laar Jaap, Herrick Ariane, Worthington Jane, Hesselstrand Roger, Smith Vanessa, de Keyser Filip, Houssiau Fredric, Chee Meng May, Madhok Rajan, Shiels Paul, Westhovens Rene, Kreuter Alexander, Kiener Hans, de Baere Elfride, Witte Torsten, Padykov Leonid, Klareskog Lars, Beretta Lorenzo, Scorza Rafaella, Lie Benedicte A, Hoffmann-Vold Anna-Maria, Carreira Patricia, Varga John, Hinchcliff Monique, Gregersen Peter K, Lee Annette T, Ying Jun, Han Younghun, Weng Shih-Feng, Amos Christopher I, Wigley Fredrick M, Hummers Laura, Nelson J Lee, Agarwal Sandeep K, Assassi Shervin, Gourh Pravitt, Tan Filemon K, Koeleman Bobby P C, Arnett Frank C, Martin Javier, Mayes Maureen D, Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus, 10.1038/ng.565
  16. Jimenez Sergio A., Following the Molecular Pathways toward an Understanding of the Pathogenesis of Systemic Sclerosis, 10.7326/0003-4819-140-2-200401200-00013
  17. EC LeRoy, J Rheumatol, 28, 1573 (2001)
  18. Gabrielli Armando, Avvedimento Enrico V., Krieg Thomas, Scleroderma, 10.1056/nejmra0806188
  19. Steen Virginia D., The Many Faces of Scleroderma, 10.1016/j.rdc.2007.12.001
  20. PJ Nietert, J Rheumatol, 33, 263 (2006)
  21. Assassi Shervin, Arnett Frank C., Reveille John D., Gourh Pravitt, Mayes Maureen D., Clinical, immunologic, and genetic features of familial systemic sclerosis, 10.1002/art.22647
  22. Arnett F. C., Gourh P., Shete S., Ahn C. W., Honey R. E., Agarwal S. K., Tan F. K., McNearney T., Fischbach M., Fritzler M. J., Mayes M. D., Reveille J. D., Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls, 10.1136/ard.2009.111906
  23. Gourh Pravitt, Tan Filemon K., Assassi Shervin, Ahn Chul W., McNearney Terry A., Fischbach Michael, Arnett Frank C., Mayes Maureen D., Association of thePTPN22 R620W polymorphism with anti–topoisomerase I– and anticentromere antibody–positive systemic sclerosis, 10.1002/art.22196
  24. Hardie William D., Korfhagen Thomas R., Sartor Maureen A., Prestridge Adrienne, Medvedovic Mario, Le Cras Timothy D., Ikegami Machiko, Wesselkamper Scott C., Davidson Cynthia, Dietsch Maggie, Nichols William, Whitsett Jeffrey A., Leikauf George D., Genomic Profile of Matrix and Vasculature Remodeling in TGF-α–Induced Pulmonary Fibrosis, 10.1165/rcmb.2006-0455oc
  25. Silver Richard M., Miller K.Scott, Kinsella Margaret B., Smith Edwin A., Schabel Stephen I., Evaluation and management of scleroderma lung disease using bronchoalveolar lavage, 10.1016/0002-9343(90)90425-d
  26. Rubin Lewis J., Primary Pulmonary Hypertension, 10.1056/nejm199701093360207
  27. Zhernakova Alexandra, Stahl Eli A., Trynka Gosia, Raychaudhuri Soumya, Festen Eleanora A., Franke Lude, Westra Harm-Jan, Fehrmann Rudolf S. N., Kurreeman Fina A. S., Thomson Brian, Gupta Namrata, Romanos Jihane, McManus Ross, Ryan Anthony W., Turner Graham, Brouwer Elisabeth, Posthumus Marcel D., Remmers Elaine F., Tucci Francesca, Toes Rene, Grandone Elvira, Mazzilli Maria Cristina, Rybak Anna, Cukrowska Bozena, Coenen Marieke J. H., Radstake Timothy R. D. J., van Riel Piet L. C. M., Li Yonghong, de Bakker Paul I. W., Gregersen Peter K., Worthington Jane, Siminovitch Katherine A., Klareskog Lars, Huizinga Tom W. J., Wijmenga Cisca, Plenge Robert M., Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci, 10.1371/journal.pgen.1002004
  28. Valdes A. M., Thomson G., , Several loci in the HLA class III region are associated with T1D risk after adjusting for DRB1-DQB1, 10.1111/j.1463-1326.2008.01002.x
  29. Kochi Yuta, Yamada Ryo, Kobayashi Kyoko, Takahashi Atsushi, Suzuki Akari, Sekine Akihiro, Mabuchi Akihiko, Akiyama Fumihiro, Tsunoda Tatsuhiko, Nakamura Yusuke, Yamamoto Kazuhiko, Analysis of single-nucleotide polymorphisms in Japanese rheumatoid arthritis patients shows additional susceptibility markers besides the classic shared epitope susceptibility sequences, 10.1002/art.11366
  30. R Tazi-Ahnini, Hum Genet, 112, 400 (2003)
  31. Petukhova Lynn, Duvic Madeleine, Hordinsky Maria, Norris David, Price Vera, Shimomura Yutaka, Kim Hyunmi, Singh Pallavi, Lee Annette, Chen Wei V., Meyer Katja C., Paus Ralf, Jahoda Colin A. B., Amos Christopher I., Gregersen Peter K., Christiano Angela M., Genome-wide association study in alopecia areata implicates both innate and adaptive immunity, 10.1038/nature09114
  32. Assassi Shervin, Mayes Maureen D., Arnett Frank C., Gourh Pravitt, Agarwal Sandeep K., McNearney Terry A., Chaussabel Damien, Oommen Nancy, Fischbach Michael, Shah Kairav R., Charles Julio, Pascual Virginia, Reveille John D., Tan Filemon K., Systemic sclerosis and lupus: Points in an interferon-mediated continuum, 10.1002/art.27224
  33. Trinchieri Giorgio, Type I interferon: friend or foe?, 10.1084/jem.20101664
  34. Eloranta M.-L., Franck-Larsson K., Lovgren T., Kalamajski S., Ronnblom A., Rubin K., Alm G. V., Ronnblom L., Type I interferon system activation and association with disease manifestations in systemic sclerosis, 10.1136/ard.2009.121400
  35. Zhao Jie, Kong Hee Jeong, Li Hongxing, Huang Bo, Yang Min, Zhu Chen, Bogunovic Milena, Zheng Feng, Mayer Lloyd, Ozato Keiko, Unkeless Jay, Xiong Huabao, IRF-8/Interferon (IFN) Consensus Sequence-binding Protein Is Involved in Toll-like Receptor (TLR) Signaling and Contributes to the Cross-talk between TLR and IFN-γ Signaling Pathways, 10.1074/jbc.m507788200
  36. Wang H., Lee C. H., Qi C., Tailor P., Feng J., Abbasi S., Atsumi T., Morse H. C., IRF8 regulates B-cell lineage specification, commitment, and differentiation, 10.1182/blood-2008-01-129049
  37. De Jager Philip L, Jia Xiaoming, Wang Joanne, de Bakker Paul I W, Ottoboni Linda, Aggarwal Neelum T, Piccio Laura, Raychaudhuri Soumya, Tran Dong, Aubin Cristin, Briskin Rebeccah, Romano Susan, Baranzini Sergio E, McCauley Jacob L, Pericak-Vance Margaret A, Haines Jonathan L, Gibson Rachel A, Naeglin Yvonne, Uitdehaag Bernard, Matthews Paul M, Kappos Ludwig, Polman Chris, McArdle Wendy L, Strachan David P, Evans Denis, Cross Anne H, Daly Mark J, Compston Alastair, Sawcer Stephen J, Weiner Howard L, Hauser Stephen L, Hafler David A, Oksenberg Jorge R, Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci, 10.1038/ng.401
  38. Lefebvre V., Behringer R.R., de Crombrugghe B., L-Sox5, Sox6 and Sox9 control essential steps of the chondrocyte differentiation pathway, 10.1053/joca.2001.0447
  39. BE Bobick, J Cell Physiol, 224, 178 (2010)
  40. OSAKI Makoto, TAN Lujian, CHOY Bob K., YOSHIDA Yasuhiro, CHEAH Kathryn S.E., AURON Philip E., GOLDRING Mary B., The TATA-containing core promoter of the type II collagen gene (COL2A1) is the target of interferon-gamma-mediated inhibition in human chondrocytes: requirement for Stat1alpha, Jak1 and Jak2, 10.1042/bj20020928
  41. Kanno Yuka, Levi Ben-Zion, Tamura Tomohiko, Ozato Keiko, Immune Cell-Specific Amplification of Interferon Signaling by the IRF-4/8-PU.1 Complex, 10.1089/jir.2005.25.770
  42. Nantel André, Mohammad-Ali Khosro, Sherk Jennifer, Posner Barry I., Thomas David Y., Interaction of the Grb10 Adapter Protein with the Raf1 and MEK1 Kinases, 10.1074/jbc.273.17.10475
  43. SIMEON C. P., FONOLLOSA V., TOLOSA C., PALOU E., SELVA A., SOLANS R., ARMADANS L., MORENO E., MARSAL S., VILARDELL M., Association of HLA Class II Genes with Systemic Sclerosis in Spanish Patients, 10.3899/jrheum.090377
  44. Hunter David J, Kraft Peter, Jacobs Kevin B, Cox David G, Yeager Meredith, Hankinson Susan E, Wacholder Sholom, Wang Zhaoming, Welch Robert, Hutchinson Amy, Wang Junwen, Yu Kai, Chatterjee Nilanjan, Orr Nick, Willett Walter C, Colditz Graham A, Ziegler Regina G, Berg Christine D, Buys Saundra S, McCarty Catherine A, Feigelson Heather Spencer, Calle Eugenia E, Thun Michael J, Hayes Richard B, Tucker Margaret, Gerhard Daniela S, Fraumeni Joseph F, Hoover Robert N, Thomas Gilles, Chanock Stephen J, A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer, 10.1038/ng2075
  45. Yeager Meredith, Orr Nick, Hayes Richard B, Jacobs Kevin B, Kraft Peter, Wacholder Sholom, Minichiello Mark J, Fearnhead Paul, Yu Kai, Chatterjee Nilanjan, Wang Zhaoming, Welch Robert, Staats Brian J, Calle Eugenia E, Feigelson Heather Spencer, Thun Michael J, Rodriguez Carmen, Albanes Demetrius, Virtamo Jarmo, Weinstein Stephanie, Schumacher Fredrick R, Giovannucci Edward, Willett Walter C, Cancel-Tassin Geraldine, Cussenot Olivier, Valeri Antoine, Andriole Gerald L, Gelmann Edward P, Tucker Margaret, Gerhard Daniela S, Fraumeni Joseph F, Hoover Robert, Hunter David J, Chanock Stephen J, Thomas Gilles, Genome-wide association study of prostate cancer identifies a second risk locus at 8q24, 10.1038/ng2022
  46. Masi Alfonse T., , Preliminary criteria for the classification of systemic sclerosis (scleroderma), 10.1002/art.1780230510
  47. EC LeRoy, J Rheumatol, 15, 202 (1988)
  48. Marchini Jonathan, Howie Bryan, Myers Simon, McVean Gil, Donnelly Peter, A new multipoint method for genome-wide association studies by imputation of genotypes, 10.1038/ng2088
  49. Skol Andrew D, Scott Laura J, Abecasis Gonçalo R, Boehnke Michael, Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies, 10.1038/ng1706
  50. Barrett J. C., Fry B., Maller J., Daly M. J., Haploview: analysis and visualization of LD and haplotype maps, 10.1093/bioinformatics/bth457
  51. Purcell Shaun, Neale Benjamin, Todd-Brown Kathe, Thomas Lori, Ferreira Manuel A.R., Bender David, Maller Julian, Sklar Pamela, de Bakker Paul I.W., Daly Mark J., Sham Pak C., PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses, 10.1086/519795
Bibliographic reference Gorlova, Olga ; Martin, Jose-Ezequiel ; Rueda, Blanca ; Koeleman, Bobby P C ; Ying, Jun ; et. al. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.. In: PLoS Genetics, Vol. 7, no. 7, p. e1002178 (2011)
Permanent URL http://hdl.handle.net/2078.1/105300