Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy

Olga Gorlova; Jose-Ezequiel Martin; Blanca Rueda; Bobby P. C. Koeleman; Jun Ying; Maria Teruel; Lina-Marcela Diaz-Gallo; Jasper C. Broen; Madelon C. Vonk; Carmen P. Simeon; Behrooz Z. Alizadeh; Marieke J. H. Coenen; Alexandre E. Voskuyl; Annemie J. Schuerwegh; Piet L. C. M. van Riel; Marie Vanthuyne; Ruben van't Slot; Annet Italiaander; Roel A. Ophoff; Nicolas Hunzelmann; Vicente Fonollosa; Norberto Ortego-Centeno; Miguel A. Gonzalez-Gay; Francisco J. Garcia-Hernandez; Maria F. Gonzalez-Escribano; Paolo Airo; Jacob van Laar; Jane Worthington; Roger Hesselstrand; Vanessa Smith; Filip de Keyser; Fredric Houssiau; Meng May Chee; Rajan Madhok; Paul G. Shiels; Rene Westhovens; Alexander Kreuter; Elfride de Baere; Torsten Witte; Leonid Padyukov; Annika Nordin; Raffaella Scorza; Claudio Lunardi; Benedicte A. Lie; Anna-Maria Hoffmann-Vold; Oyvind Palm; Paloma Garcia de la Pena; Patricia Carreira; John Varga; Monique Hinchcliff; Annette T. Lee; Pravitt Gourh; Christopher I. Amos; Frederick M. Wigley; Laura K. Hummers; J. Hummers; J. Lee Nelson; Gabriella Riemekasten; Ariane Herrick; Lorenzo Beretta; Carmen Fonseca; Christopher P. Denton; Peter K. Gregersen; Sandeep Agarwal; Shervin Assassi; Filemon K. Tan; Frank C. Arnett; Timothy R. D. J. Radstake; Maureen D. Mayes; Javier Martin

doi:10.1371/journal.pgen.1002178

Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy

Olga Gorlova, Jose-Ezequiel Martin, Blanca Rueda, Bobby P. C. Koeleman, Jun Ying, Maria Teruel, Lina-Marcela Diaz-Gallo, Jasper C. Broen, Madelon C. Vonk, Carmen P. Simeon, Behrooz Z. Alizadeh, Marieke J. H. Coenen, Alexandre E. Voskuyl, Annemie J. Schuerwegh, Piet L. C. M. van Riel, Marie Vanthuyne, Ruben van't Slot, Annet Italiaander, Roel A. Ophoff, Nicolas HunzelmannVicente Fonollosa, Norberto Ortego-Centeno, Miguel A. Gonzalez-Gay, Francisco J. Garcia-Hernandez, Maria F. Gonzalez-Escribano, Paolo Airo, Jacob van Laar, Jane Worthington, Roger Hesselstrand, Vanessa Smith, Filip de Keyser, Fredric Houssiau, Meng May Chee, Rajan Madhok, Paul G. Shiels, Rene Westhovens, Alexander Kreuter, Elfride de Baere, Torsten Witte, Leonid Padyukov, Annika Nordin, Raffaella Scorza, Claudio Lunardi, Benedicte A. Lie, Anna-Maria Hoffmann-Vold, Oyvind Palm, Paloma Garcia de la Pena, Patricia Carreira, John Varga, Monique Hinchcliff, Annette T. Lee, Pravitt Gourh, Christopher I. Amos, Frederick M. Wigley, Laura K. Hummers, J. Hummers, J. Lee Nelson, Gabriella Riemekasten, Ariane Herrick, Lorenzo Beretta, Carmen Fonseca, Christopher P. Denton, Peter K. Gregersen, Sandeep Agarwal, Shervin Assassi, Filemon K. Tan, Frank C. Arnett, Timothy R. D. J. Radstake, Maureen D. Mayes, Javier Martin

Rheumatology

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Abstract

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 (IcSSc) 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 = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-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 = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and autoantibody 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.

Original language	English
Journal	PLoS Genetics
Volume	7
Issue number	7
DOIs	https://doi.org/10.1371/journal.pgen.1002178
Publication status	Published - 2011

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Rheumatology and Autoimmunity

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Gorlova, O., Martin, J.-E., Rueda, B., Koeleman, B. P. C., Ying, J., Teruel, M., Diaz-Gallo, L.-M., Broen, J. C., Vonk, M. C., Simeon, C. P., Alizadeh, B. Z., Coenen, M. J. H., Voskuyl, A. E., Schuerwegh, A. J., van Riel, P. L. C. M., Vanthuyne, M., van't Slot, R., Italiaander, A., Ophoff, R. A., ... Martin, J. (2011). Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy. PLoS Genetics, 7(7). https://doi.org/10.1371/journal.pgen.1002178

@article{7ca5bdbe021143b3b8d5a84cb21539c0,

title = "Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy",

abstract = "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 (IcSSc) 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 = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-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 = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and autoantibody 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.",

author = "Olga Gorlova and Jose-Ezequiel Martin and Blanca Rueda and Koeleman, {Bobby P. C.} and Jun Ying and Maria Teruel and Lina-Marcela Diaz-Gallo and Broen, {Jasper C.} and Vonk, {Madelon C.} and Simeon, {Carmen P.} and Alizadeh, {Behrooz Z.} and Coenen, {Marieke J. H.} and Voskuyl, {Alexandre E.} and Schuerwegh, {Annemie J.} and {van Riel}, {Piet L. C. M.} and Marie Vanthuyne and {van't Slot}, Ruben and Annet Italiaander and Ophoff, {Roel A.} and Nicolas Hunzelmann and Vicente Fonollosa and Norberto Ortego-Centeno and Gonzalez-Gay, {Miguel A.} and Garcia-Hernandez, {Francisco J.} and Gonzalez-Escribano, {Maria F.} and Paolo Airo and {van Laar}, Jacob and Jane Worthington and Roger Hesselstrand and Vanessa Smith and {de Keyser}, Filip and Fredric Houssiau and Chee, {Meng May} and Rajan Madhok and Shiels, {Paul G.} and Rene Westhovens and Alexander Kreuter and {de Baere}, Elfride and Torsten Witte and Leonid Padyukov and Annika Nordin and Raffaella Scorza and Claudio Lunardi and Lie, {Benedicte A.} and Anna-Maria Hoffmann-Vold and Oyvind Palm and {Garcia de la Pena}, Paloma and Patricia Carreira and John Varga and Monique Hinchcliff and Lee, {Annette T.} and Pravitt Gourh and Amos, {Christopher I.} and Wigley, {Frederick M.} and Hummers, {Laura K.} and J. Hummers and Nelson, {J. Lee} and Gabriella Riemekasten and Ariane Herrick and Lorenzo Beretta and Carmen Fonseca and Denton, {Christopher P.} and Gregersen, {Peter K.} and Sandeep Agarwal and Shervin Assassi and Tan, {Filemon K.} and Arnett, {Frank C.} and Radstake, {Timothy R. D. J.} and Mayes, {Maureen D.} and Javier Martin",

year = "2011",

doi = "10.1371/journal.pgen.1002178",

language = "English",

volume = "7",

journal = "PLoS Genetics",

issn = "1553-7404",

publisher = "Public Library of Science (PLoS)",

number = "7",

}

Gorlova, O, Martin, J-E, Rueda, B, Koeleman, BPC, Ying, J, Teruel, M, Diaz-Gallo, L-M, Broen, JC, Vonk, MC, Simeon, CP, Alizadeh, BZ, Coenen, MJH, Voskuyl, AE, Schuerwegh, AJ, van Riel, PLCM, Vanthuyne, M, van't Slot, R, Italiaander, A, Ophoff, RA, Hunzelmann, N, Fonollosa, V, Ortego-Centeno, N, Gonzalez-Gay, MA, Garcia-Hernandez, FJ, Gonzalez-Escribano, MF, Airo, P, van Laar, J, Worthington, J, Hesselstrand, R, Smith, V, de Keyser, F, Houssiau, F, Chee, MM, Madhok, R, Shiels, PG, Westhovens, R, Kreuter, A, de Baere, E, Witte, T, Padyukov, L, Nordin, A, Scorza, R, Lunardi, C, Lie, BA, Hoffmann-Vold, A-M, Palm, O, Garcia de la Pena, P, Carreira, P, Varga, J, Hinchcliff, M, Lee, AT, Gourh, P, Amos, CI, Wigley, FM, Hummers, LK, Hummers, J, Nelson, JL, Riemekasten, G, Herrick, A, Beretta, L, Fonseca, C, Denton, CP, Gregersen, PK, Agarwal, S, Assassi, S, Tan, FK, Arnett, FC, Radstake, TRDJ, Mayes, MD & Martin, J 2011, 'Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy', PLoS Genetics, vol. 7, no. 7. https://doi.org/10.1371/journal.pgen.1002178

TY - JOUR

T1 - Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy

AU - Gorlova, Olga

AU - Martin, Jose-Ezequiel

AU - Rueda, Blanca

AU - Koeleman, Bobby P. C.

AU - Ying, Jun

AU - Teruel, Maria

AU - Diaz-Gallo, Lina-Marcela

AU - Broen, Jasper C.

AU - Vonk, Madelon C.

AU - Simeon, Carmen P.

AU - Alizadeh, Behrooz Z.

AU - Coenen, Marieke J. H.

AU - Voskuyl, Alexandre E.

AU - Schuerwegh, Annemie J.

AU - van Riel, Piet L. C. M.

AU - Vanthuyne, Marie

AU - van't Slot, Ruben

AU - Italiaander, Annet

AU - Ophoff, Roel A.

AU - Hunzelmann, Nicolas

AU - Fonollosa, Vicente

AU - Ortego-Centeno, Norberto

AU - Gonzalez-Gay, Miguel A.

AU - Garcia-Hernandez, Francisco J.

AU - Gonzalez-Escribano, Maria F.

AU - Airo, Paolo

AU - van Laar, Jacob

AU - Worthington, Jane

AU - Hesselstrand, Roger

AU - Smith, Vanessa

AU - de Keyser, Filip

AU - Houssiau, Fredric

AU - Chee, Meng May

AU - Madhok, Rajan

AU - Shiels, Paul G.

AU - Westhovens, Rene

AU - Kreuter, Alexander

AU - de Baere, Elfride

AU - Witte, Torsten

AU - Padyukov, Leonid

AU - Nordin, Annika

AU - Scorza, Raffaella

AU - Lunardi, Claudio

AU - Lie, Benedicte A.

AU - Hoffmann-Vold, Anna-Maria

AU - Palm, Oyvind

AU - Garcia de la Pena, Paloma

AU - Carreira, Patricia

AU - Varga, John

AU - Hinchcliff, Monique

AU - Lee, Annette T.

AU - Gourh, Pravitt

AU - Amos, Christopher I.

AU - Wigley, Frederick M.

AU - Hummers, Laura K.

AU - Hummers, J.

AU - Nelson, J. Lee

AU - Riemekasten, Gabriella

AU - Herrick, Ariane

AU - Beretta, Lorenzo

AU - Fonseca, Carmen

AU - Denton, Christopher P.

AU - Gregersen, Peter K.

AU - Agarwal, Sandeep

AU - Assassi, Shervin

AU - Tan, Filemon K.

AU - Arnett, Frank C.

AU - Radstake, Timothy R. D. J.

AU - Mayes, Maureen D.

AU - Martin, Javier

PY - 2011

Y1 - 2011

N2 - 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 (IcSSc) 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 = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-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 = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and autoantibody 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.

AB - 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 (IcSSc) 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 = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-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 = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and autoantibody 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.

U2 - 10.1371/journal.pgen.1002178

DO - 10.1371/journal.pgen.1002178

M3 - Article

C2 - 21779181

SN - 1553-7404

VL - 7

JO - PLoS Genetics

JF - PLoS Genetics

IS - 7

ER -

Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy

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