Lack of replication of higher genetic risk load in men than in women with systemic lupus erythematosus

Elisa Alonso-Perez; Marian Suarez-Gestal; Manuel Calaza; Francisco J. Blanco; Ana Suarez; Maria J. Santos; Chryssa Papasteriades; Patricia Carreira; Rudolf Pullmann; Josep Ordi-Ros; Maurizio Marchini; Fotini N. Skopouli; Marc Bijl; Nadia Barrizone; Gian D. Sebastiani; Sergio Migliaresi; Torsten Witte; Bernard R. Lauwerys; Attila Kovacs; Sarka Ruzickova; Juan J. Gomez-Reino; Antonio Gonzalez; Myriam Liz; Iris Kappou-Rigatou; Lorenzo Beretta; Eva Balada; Cees G. Kallenberg; Filipe Vinagre; Maria Mavromati; Carmen Gutierrez; Ignacio Rego; Sandra D'Alfonso; Reinhold E. Schmidt; Emöke Endreffy; Ctibor Dostal

doi:10.1186/ar4585

Lack of replication of higher genetic risk load in men than in women with systemic lupus erythematosus

Elisa Alonso-Perez, Marian Suarez-Gestal, Manuel Calaza, Francisco J. Blanco, Ana Suarez, Maria J. Santos, Chryssa Papasteriades, Patricia Carreira, Rudolf Pullmann, Josep Ordi-Ros, Maurizio Marchini, Fotini N. Skopouli, Marc Bijl, Nadia Barrizone, Gian D. Sebastiani, Sergio Migliaresi, Torsten Witte, Bernard R. Lauwerys, Attila Kovacs, Sarka RuzickovaJuan J. Gomez-Reino, Antonio Gonzalez^*, Myriam Liz, Iris Kappou-Rigatou, Lorenzo Beretta, Eva Balada, Cees G. Kallenberg, Filipe Vinagre, Maria Mavromati, Carmen Gutierrez, Ignacio Rego, Sandra D'Alfonso, Reinhold E. Schmidt, Emöke Endreffy, Ctibor Dostal

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Introduction: We aimed to replicate a recent study which showed higher genetic risk load at 15 loci in men than in women with systemic lupus erythematosus (SLE). This difference was very significant, and it was interpreted as indicating that men require more genetic susceptibility than women to develop SLE.Methods: Nineteen SLE-associated loci (thirteen of which are shared with the previous study) were analyzed in 1,457 SLE patients and 1,728 healthy controls of European ancestry. Genetic risk load was calculated as sex-specific sum genetic risk scores (GRS_s).Results: Our results did not replicate those of the previous study at either the level of individual loci or the global level of GRS_s. GRS_s were larger in women than in men (4.20 ± 1.07 in women vs. 3.27 ± 0.98 in men). This very significant difference (P < 10^-16) was more dependent on the six new loci not included in the previous study (59% of the difference) than on the thirteen loci that are shared (the remaining 41%). However, the 13 shared loci also showed a higher genetic risk load in women than in men in our study (P = 6.6 × 10^-7), suggesting that heterogeneity of participants, in addition to different loci, contributed to the opposite results.Conclusion: Our results show the lack of a clear trend toward higher genetic risk in one of the sexes for the analyzed SLE loci. They also highlight several limitations of assessments of genetic risk load, including the possibility of ascertainment bias with loci discovered in studies that have included mainly women.

Original language	English
Article number	R128
Journal	Arthritis Research and Therapy
Volume	16
Issue number	3
DOIs	https://doi.org/10.1186/ar4585
State	Published - 19 Jun 2014
Externally published	Yes

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Alonso-Perez, E., Suarez-Gestal, M., Calaza, M., Blanco, F. J., Suarez, A., Santos, M. J., Papasteriades, C., Carreira, P., Pullmann, R., Ordi-Ros, J., Marchini, M., Skopouli, F. N., Bijl, M., Barrizone, N., Sebastiani, G. D., Migliaresi, S., Witte, T., Lauwerys, B. R., Kovacs, A., ... Dostal, C. (2014). Lack of replication of higher genetic risk load in men than in women with systemic lupus erythematosus. Arthritis Research and Therapy, 16(3), Article R128. https://doi.org/10.1186/ar4585

@article{e6c9a382b5bf485bab2b1ab23039fa66,

title = "Lack of replication of higher genetic risk load in men than in women with systemic lupus erythematosus",

abstract = "Introduction: We aimed to replicate a recent study which showed higher genetic risk load at 15 loci in men than in women with systemic lupus erythematosus (SLE). This difference was very significant, and it was interpreted as indicating that men require more genetic susceptibility than women to develop SLE.Methods: Nineteen SLE-associated loci (thirteen of which are shared with the previous study) were analyzed in 1,457 SLE patients and 1,728 healthy controls of European ancestry. Genetic risk load was calculated as sex-specific sum genetic risk scores (GRSs).Results: Our results did not replicate those of the previous study at either the level of individual loci or the global level of GRSs. GRSs were larger in women than in men (4.20 ± 1.07 in women vs. 3.27 ± 0.98 in men). This very significant difference (P < 10-16) was more dependent on the six new loci not included in the previous study (59% of the difference) than on the thirteen loci that are shared (the remaining 41%). However, the 13 shared loci also showed a higher genetic risk load in women than in men in our study (P = 6.6 × 10-7), suggesting that heterogeneity of participants, in addition to different loci, contributed to the opposite results.Conclusion: Our results show the lack of a clear trend toward higher genetic risk in one of the sexes for the analyzed SLE loci. They also highlight several limitations of assessments of genetic risk load, including the possibility of ascertainment bias with loci discovered in studies that have included mainly women.",

author = "Elisa Alonso-Perez and Marian Suarez-Gestal and Manuel Calaza and Blanco, {Francisco J.} and Ana Suarez and Santos, {Maria J.} and Chryssa Papasteriades and Patricia Carreira and Rudolf Pullmann and Josep Ordi-Ros and Maurizio Marchini and Skopouli, {Fotini N.} and Marc Bijl and Nadia Barrizone and Sebastiani, {Gian D.} and Sergio Migliaresi and Torsten Witte and Lauwerys, {Bernard R.} and Attila Kovacs and Sarka Ruzickova and Gomez-Reino, {Juan J.} and Antonio Gonzalez and Myriam Liz and Iris Kappou-Rigatou and Lorenzo Beretta and Eva Balada and Kallenberg, {Cees G.} and Filipe Vinagre and Maria Mavromati and Carmen Gutierrez and Ignacio Rego and Sandra D'Alfonso and Schmidt, {Reinhold E.} and Em{\"o}ke Endreffy and Ctibor Dostal",

note = "Funding Information: The authors thank Carmen Pena for taking care of the samples and helping with the genotyping assays. This work was supported by the Health Research Fund of the Instituto de Salud Carlos III (Spain) (grants 08/0744 and 11/01048) and by the RETICS Program (RD08/0075 and RD12/0009/0008), which that are partially financed by the European Regional Development Fund of the European Union. The following are other contributors to the European Consortium of SLE DNA Collections who are participating in this study: Myriam Liz, Laboratorio de Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria–Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain; Iris Kappou-Rigatou, Department of Histocompatibility and Immunology, Evangelismos Hospital, Athens, Greece; Lorenzo Beretta, Clinical Immunology, University of Milan, and Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy; Eva Balada, Internal Medicine, Research Laboratory in Autoimmune Diseases Hospital Vall d{\textquoteright}Hebron, Barcelona, Spain; Cees G Kallenberg, Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, the Netherlands; Filipe Vinagre, Rheumatology Department, Hospital Garcia de Orta, Almada (Portugal), and Rheumatology Research Unit, Molecular Medicine Institute, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Rudolf Pullmann Jr, Gerontology Research Center, National Institute on Aging, Baltimore, MD, USA; Maria Mavromati, Pathophysiology Department, Athens University Medical School, Athens, Greece; Carmen Gutierrez, Department of Functional Biology, Hospital Universitario Central de Asturias, Universidad de Oviedo, Oviedo, Spain; Ignacio Rego, Servicio de Reumatolog{\'i}a, Complejo Hospitalario Universitario A Coru{\~n}a, A Coru{\~n}a, Spain; Sandra D{\textquoteright}Alfonso, Department of Medical Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont Amedeo Avogadro, Novara, Italy; Reinhold E Schmidt, Division of Clinical Immunology, Department of Internal Medicine, Hannover Medical School, Hannover, Germany; Em{\"o}ke Endreffy, Pediatrics Department, Albert Szent-Gy{\"o}rgyi Medical and Pharmaceutical Centre, University of Szeged, Szeged, Hungary; and Ctibor Dostal, Molecular Biology and Immunogenetics Department, Institute of Rheumatology, Prague, Czech Republic.",

year = "2014",

month = jun,

day = "19",

doi = "10.1186/ar4585",

language = "אנגלית",

volume = "16",

journal = "Arthritis Research and Therapy",

issn = "1478-6354",

publisher = "BioMed Central Ltd.",

number = "3",

}

Alonso-Perez, E, Suarez-Gestal, M, Calaza, M, Blanco, FJ, Suarez, A, Santos, MJ, Papasteriades, C, Carreira, P, Pullmann, R, Ordi-Ros, J, Marchini, M, Skopouli, FN, Bijl, M, Barrizone, N, Sebastiani, GD, Migliaresi, S, Witte, T, Lauwerys, BR, Kovacs, A, Ruzickova, S, Gomez-Reino, JJ, Gonzalez, A, Liz, M, Kappou-Rigatou, I, Beretta, L, Balada, E, Kallenberg, CG, Vinagre, F, Mavromati, M, Gutierrez, C, Rego, I, D'Alfonso, S, Schmidt, RE, Endreffy, E & Dostal, C 2014, 'Lack of replication of higher genetic risk load in men than in women with systemic lupus erythematosus', Arthritis Research and Therapy, vol. 16, no. 3, R128. https://doi.org/10.1186/ar4585

TY - JOUR

T1 - Lack of replication of higher genetic risk load in men than in women with systemic lupus erythematosus

AU - Alonso-Perez, Elisa

AU - Suarez-Gestal, Marian

AU - Calaza, Manuel

AU - Blanco, Francisco J.

AU - Suarez, Ana

AU - Santos, Maria J.

AU - Papasteriades, Chryssa

AU - Carreira, Patricia

AU - Pullmann, Rudolf

AU - Ordi-Ros, Josep

AU - Marchini, Maurizio

AU - Skopouli, Fotini N.

AU - Bijl, Marc

AU - Barrizone, Nadia

AU - Sebastiani, Gian D.

AU - Migliaresi, Sergio

AU - Witte, Torsten

AU - Lauwerys, Bernard R.

AU - Kovacs, Attila

AU - Ruzickova, Sarka

AU - Gomez-Reino, Juan J.

AU - Gonzalez, Antonio

AU - Liz, Myriam

AU - Kappou-Rigatou, Iris

AU - Beretta, Lorenzo

AU - Balada, Eva

AU - Kallenberg, Cees G.

AU - Vinagre, Filipe

AU - Mavromati, Maria

AU - Gutierrez, Carmen

AU - Rego, Ignacio

AU - D'Alfonso, Sandra

AU - Schmidt, Reinhold E.

AU - Endreffy, Emöke

AU - Dostal, Ctibor

N1 - Funding Information: The authors thank Carmen Pena for taking care of the samples and helping with the genotyping assays. This work was supported by the Health Research Fund of the Instituto de Salud Carlos III (Spain) (grants 08/0744 and 11/01048) and by the RETICS Program (RD08/0075 and RD12/0009/0008), which that are partially financed by the European Regional Development Fund of the European Union. The following are other contributors to the European Consortium of SLE DNA Collections who are participating in this study: Myriam Liz, Laboratorio de Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria–Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain; Iris Kappou-Rigatou, Department of Histocompatibility and Immunology, Evangelismos Hospital, Athens, Greece; Lorenzo Beretta, Clinical Immunology, University of Milan, and Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy; Eva Balada, Internal Medicine, Research Laboratory in Autoimmune Diseases Hospital Vall d’Hebron, Barcelona, Spain; Cees G Kallenberg, Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, the Netherlands; Filipe Vinagre, Rheumatology Department, Hospital Garcia de Orta, Almada (Portugal), and Rheumatology Research Unit, Molecular Medicine Institute, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Rudolf Pullmann Jr, Gerontology Research Center, National Institute on Aging, Baltimore, MD, USA; Maria Mavromati, Pathophysiology Department, Athens University Medical School, Athens, Greece; Carmen Gutierrez, Department of Functional Biology, Hospital Universitario Central de Asturias, Universidad de Oviedo, Oviedo, Spain; Ignacio Rego, Servicio de Reumatología, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain; Sandra D’Alfonso, Department of Medical Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont Amedeo Avogadro, Novara, Italy; Reinhold E Schmidt, Division of Clinical Immunology, Department of Internal Medicine, Hannover Medical School, Hannover, Germany; Emöke Endreffy, Pediatrics Department, Albert Szent-Györgyi Medical and Pharmaceutical Centre, University of Szeged, Szeged, Hungary; and Ctibor Dostal, Molecular Biology and Immunogenetics Department, Institute of Rheumatology, Prague, Czech Republic.

PY - 2014/6/19

Y1 - 2014/6/19

N2 - Introduction: We aimed to replicate a recent study which showed higher genetic risk load at 15 loci in men than in women with systemic lupus erythematosus (SLE). This difference was very significant, and it was interpreted as indicating that men require more genetic susceptibility than women to develop SLE.Methods: Nineteen SLE-associated loci (thirteen of which are shared with the previous study) were analyzed in 1,457 SLE patients and 1,728 healthy controls of European ancestry. Genetic risk load was calculated as sex-specific sum genetic risk scores (GRSs).Results: Our results did not replicate those of the previous study at either the level of individual loci or the global level of GRSs. GRSs were larger in women than in men (4.20 ± 1.07 in women vs. 3.27 ± 0.98 in men). This very significant difference (P < 10-16) was more dependent on the six new loci not included in the previous study (59% of the difference) than on the thirteen loci that are shared (the remaining 41%). However, the 13 shared loci also showed a higher genetic risk load in women than in men in our study (P = 6.6 × 10-7), suggesting that heterogeneity of participants, in addition to different loci, contributed to the opposite results.Conclusion: Our results show the lack of a clear trend toward higher genetic risk in one of the sexes for the analyzed SLE loci. They also highlight several limitations of assessments of genetic risk load, including the possibility of ascertainment bias with loci discovered in studies that have included mainly women.

AB - Introduction: We aimed to replicate a recent study which showed higher genetic risk load at 15 loci in men than in women with systemic lupus erythematosus (SLE). This difference was very significant, and it was interpreted as indicating that men require more genetic susceptibility than women to develop SLE.Methods: Nineteen SLE-associated loci (thirteen of which are shared with the previous study) were analyzed in 1,457 SLE patients and 1,728 healthy controls of European ancestry. Genetic risk load was calculated as sex-specific sum genetic risk scores (GRSs).Results: Our results did not replicate those of the previous study at either the level of individual loci or the global level of GRSs. GRSs were larger in women than in men (4.20 ± 1.07 in women vs. 3.27 ± 0.98 in men). This very significant difference (P < 10-16) was more dependent on the six new loci not included in the previous study (59% of the difference) than on the thirteen loci that are shared (the remaining 41%). However, the 13 shared loci also showed a higher genetic risk load in women than in men in our study (P = 6.6 × 10-7), suggesting that heterogeneity of participants, in addition to different loci, contributed to the opposite results.Conclusion: Our results show the lack of a clear trend toward higher genetic risk in one of the sexes for the analyzed SLE loci. They also highlight several limitations of assessments of genetic risk load, including the possibility of ascertainment bias with loci discovered in studies that have included mainly women.

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DO - 10.1186/ar4585

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C2 - 24946689

AN - SCOPUS:84902740947

SN - 1478-6354

VL - 16

JO - Arthritis Research and Therapy

JF - Arthritis Research and Therapy

IS - 3

M1 - R128

ER -

Lack of replication of higher genetic risk load in men than in women with systemic lupus erythematosus

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