1. ¹Laboratorio de Investigacion 2, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain
2. ²Department of Medical Sciences and IRCAD, Eastern Piedmont University, Novara, Italy
3. ³Department of Histocompatibility and Immunology, Evangelismos Hospital, Athens, Greece
4. ⁴Department of Pathophysiology, Athens University Medical School, Athens, Greece
5. ⁵Department of Clinical Immunology, University of Milan and Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy
6. ⁶Rheumatology Unit, Second University of Naples, Naples, Italy
7. ⁷Ospedale S Camillo – Forlanini – UO Complessa di Reumatologia, Roma, Italy
8. ⁸Department of Paediatrics, Albert Szent-Györgyi Medical and Pharmaceutical Centre, University of Szeged, Szeged, Hungary
9. ⁹Department of Molecular Biology and Immunogenetics, Institute of Rheumatology, Prague, Czech Republic
10. ¹⁰Division of Clinical Immunology, Department of Internal Medicine of the Hannover Medical School, Hannover, Germany
11. ¹¹Reumatology Unit, Hospital Clinico Universitario de Santiago, Santiago, Spain
12. ¹²Department of Medicine, University of Santiago de Compostela, Santiago, Spain

Correspondence: Dr A Gonzalez, Laboratorio de Investigacion 2, Hospital Clinico Universitario de Santiago, 15706-Santiago de Compostela, Spain. E-mail: Antonio.Gonzalez.Martinez.Pedrayo@sergas.es

Received 18 October 2006; Revised 28 November 2006; Accepted 29 November 2006; Published online 18 January 2007.

Abstract

We obtained eight collections of DNA samples from ethnically matched systemic lupus erythematosus (SLE) patients and controls from five European countries totaling 783 patients and 1210 controls. A highly significant cline in the frequency of the PD1.3 A allele was found among controls but not among SLE patients. The frequency of the PD1.3 A allele increased from the Northeast to the Southwest of Europe. The cline was clearly apparent (P=1.2 10^-6) when data from controls of other five SLE susceptibility studies were included in the analysis. This variation has severely biased SLE association studies owing to the lack of parallel changes in SLE patients. As a consequence, the PD1.3 A allele was more common in SLE patients than in controls in the Northeast and Center of Europe, similar to controls in Southeast Europe, and less frequent than in the controls in the Southwest of the Continent. This dissociation in allele frequencies between SLE patients and controls in different subpopulations indicated that programmed cell death 1 variation and disease susceptibility are not independent but the type of relationship is currently unclear. As allele frequency clines are common in other polymorphisms their impact in genetic epidemiology studies should be carefully considered.