Open Access Open Badges Research article

Bias in effect size of systemic lupus erythematosus susceptibility loci across Europe: a case-control study

Elisa Alonso-Perez1, Marian Suarez-Gestal1, Manuel Calaza1, Gian Domenico Sebastiani2, Rudolf Pullmann3, Chryssa Papasteriades4, Attila Kovacs5, Fotini N Skopouli6, Marc Bijl7, Ana Suarez8, Maurizio Marchini9, Sergio Migliaresi10, Patricia Carreira11, Josep Ordi-Ros12, Torsten Witte13, Sarka Ruzickova14, Maria Jose Santos15, Nadia Barizzone16, Francisco J Blanco17, Bernard R Lauwerys18, Juan J Gomez-Reino119, Antonio Gonzalez1* and the European Consortium of SLE DNA Collections

Author Affiliations

1 Laboratorio de Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria - Hospital Clinico Universitario de Santiago, Choupana s/n, Santiago de Compostela 15706, Spain

2 U.O. Complessa di Reumatologia, Azienda Ospedaliera San Camillo - Forlanini, Piazza Carlo Forlanini 1, Rome 00151, Italy

3 Institute of Clinical Biochemistry, Martin Faculty Hospital and Jessenius Medical Faculty, Kollárova 2, Martin 036 59, Slovakia

4 Department of Histocompatibility and Immunology, Evangelismos Hospital, Ipsilantou Str. 45-47, Athens 10675, Greece

5 Department of Rheumatology, Hospital of Hungarian Railways, Lukács György utca 4, Szolnok 5000, Hungary

6 Pathophysiology Department, Athens University Medical School, Korai 5, Athens 115 27, Greece

7 Department of Internal Medicine and Rheumatology, Martini Hospital, Van Swietenplein 1, Groningen 9728, the Netherlands

8 Department of Functional Biology, University of Oviedo, Calle Catedrático Valentín Andrés Álvarez s/n, Oviedo 33006, Spain

9 Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Via Francesco Sforza 35, Milan 20122, Italy

10 Rheumatology Unit, Second University of Naples, Via Sergio Pansini 5, Naples 80131, Italy

11 Rheumatology Department, Hospital 12 de Octubre, Av. Andalucía s/n, Madrid 28041, Spain

12 Internal Medicine and Research Laboratory in Autoimmune Diseases, Hospital Vall d'Hebron, Passeig Vall d'Hebron 119-129, Barcelona 08035, Spain

13 Department of Internal Medicine and Division of Clinical Immunology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany

14 Institute of Biotechnology, Academy of Sciences of the Czech Republic, Národní 1009/3, Prague 110 00, Czech Republic

15 Rheumatology Department, Hospital Garcia de Orta and Rheumatology Reseach Unit, Instituto de Medicina Molecular, Av. Torrado da Silva s/n, Lisboa 2801-951, Portugal

16 Department of Medical Sciences and IRCAD, Eastern Piedmont University, Via dei Tornielli 12, Novara 28100, Italy

17 Laboratorio de Investigación Osteoarticular y del Envejecimiento, Servicio de Reumatología, INIBIC-CH Universitario, Jubias de Arriba 84A, A Coruña 15006, Spain

18 Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Avenue Emmanuel Mounier 81, Brussels 1200, Belgium

19 Department of Medicine, University of Santiago de Compostela, Calle Choupana s/n, Santiago de Compostela 15706, Spain

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Arthritis Research & Therapy 2012, 14:R94  doi:10.1186/ar3818

Published: 27 April 2012



We aimed to investigate whether the effect size of the systemic lupus erythematosus (SLE) risk alleles varies across European subpopulations.


European SLE patients (n = 1,742) and ethnically matched healthy controls (n = 2,101) were recruited at 17 centres from 10 different countries. Only individuals with self-reported ancestry from the country of origin were included. In addition, participants were genotyped for top ancestry informative markers and for 25 SLE associated SNPs. The results were used to compare effect sizes between the Central Eureopan and Southern European subgroups.


Twenty of the 25 SNPs showed independent association with SLE, These SNPs showed a significant bias to larger effect sizes in the Southern subgroup, with 15/20 showing this trend (P = 0.019) and a larger mean odds ratio of the 20 SNPs (1.46 vs. 1.34, P = 0.02) as well as a larger difference in the number of risk alleles (2.06 vs. 1.63, P = 0.027) between SLE patients and controls than for Central Europeans. This bias was reflected in a very significant difference in the cumulative genetic risk score (4.31 vs. 3.48, P = 1.8 × 10-32). Effect size bias was accompanied by a lower number of SLE risk alleles in the Southern subjects, both patients and controls, the difference being more marked between the controls (P = 1.1 × 10-8) than between the Southern and Central European patients (P = 0.016). Seven of these SNPs showed significant allele frequency clines.


Our findings showed a bias to larger effect sizes of SLE loci in the Southern Europeans relative to the Central Europeans together with clines of SLE risk allele frequencies. These results indicate the need to study risk allele clines and the implications of the polygenic model of inheritance in SLE.