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Bias in association studies of systemic lupus erythematosus susceptibility due to geographical variation in the frequency of a programmed cell death 1 polymorphism across Europe

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.

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Abbreviations

HWE:

Hardy–Weinberg equilibrium

LD:

linkage disequilibrium

PDCD1:

programmed cell death 1

RFLP:

restriction fragment length polymorphism

SLE:

systemic lupus erythematosus

SNP:

single-nucleotide polymorphism

MH:

Mantel–Haenszel

OR:

odds ratio

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Acknowledgements

We acknowledge Harry M Moutsopoulos for his collaboration and comments, Snaevar Sigurdsson and Ann-Christine Syvänen for sharing data and Manuel Calaza, Marta Alarcon and Javier Costas for their comments. Cristina Fernandez-Lopez and Marta Picado have provided outstanding technical support. This work has been supported by Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III (Spain), Grants 01/3138, 02/0713, 04/1651 that are partially financed by the FEDER program of the EU and by grants from the Xunta de Galicia. IF-V is supported by a BEFI fellowship of the Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III (Spain). SR and CD were supported by Grant 00023728 of the Ministry of Health of the Czech Republic. RES and TW were supported by BMBF, KN Rheuma C2.12. Work by SD'A was supported by Telethon (Grant E1221) and the CARIPLO Foundation.

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Correspondence to A Gonzalez.

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Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

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Ferreiros-Vidal, I., D'Alfonso, S., Papasteriades, C. et al. Bias in association studies of systemic lupus erythematosus susceptibility due to geographical variation in the frequency of a programmed cell death 1 polymorphism across Europe. Genes Immun 8, 138–146 (2007). https://doi.org/10.1038/sj.gene.6364370

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