Further evidence of subphenotype association with systemic lupus erythematosus susceptibility loci: a European cases only study.
BACKGROUND
Systemic Lupus Erythematosus (SLE) shows a spectrum of clinical manifestations that complicate its diagnosis, treatment and research. This variability is likely related with environmental exposures and genetic factors among which known SLE susceptibility loci are prime candidates. The first published analyses seem to indicate that this is the case for some of them, but results are still inconclusive and we aimed to further explore this question.


METHODS
European SLE patients, 1444, recruited at 17 centres from 10 countries were analyzed. Genotypes for 26 SLE associated SNPs were compared between patients with and without each of 11 clinical features: ten of the American College of Rheumatology (ACR) classification criteria (except ANAs) and age of disease onset. These analyses were adjusted for centre of recruitment, top ancestry informative markers, gender and time of follow-up. Overlap of samples with previous studies was excluded for assessing replication.


RESULTS
THERE WERE THREE NEW ASSOCIATIONS: the SNPs in XKR6 and in FAM167A-BLK were associated with lupus nephritis (OR=0.76 and 1.30, P(corr) =0.007 and 0.03, respectively) and the SNP of MECP2, which is in chromosome X, with earlier age of disease onset in men. The previously reported association of STAT4 with early age of disease onset was replicated. Some other results were suggestive of the presence of additional associations. Together, the association signals provided support to some previous findings and to the characterization of lupus nephritis, autoantibodies and age of disease onset as the clinical features more associated with SLE loci.


CONCLUSIONS
Some of the SLE loci shape the disease phenotype in addition to increase susceptibility to SLE. This influence is more prominent for some clinical features than for others. However, results are only partially consistent between studies and subphenotype specific GWAS are needed to unravel their genetic component.
Laboratorio de Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria - Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.
Elisa
E
Alonso-Perez
Marian
M
Suarez-Gestal
Manuel
M
Calaza
Josep
J
Ordi-Ros
Eva
E
Balada
Marc
M
Bijl
Chryssa
C
Papasteriades
Patricia
P
Carreira
Fotini N
FN
Skopouli
Torsten
T
Witte
Emöke
E
Endreffy
Maurizio
M
Marchini
Sergio
S
Migliaresi
Gian Domenico
GD
Sebastiani
Maria Jose
MJ
Santos
Ana
A
Suarez
Francisco J
FJ
Blanco
Nadia
N
Barizzone
Rudolf
R
Pullmann
Sarka
S
Ruzickova
Bernard R
BR
Lauwerys
Juan J
JJ
Gomez-Reino
Antonio
A
Gonzalez
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001323:Autoantibodies / Q000276:immunology; D005060:Europe / Q000453:epidemiology; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000276:immunology; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000276:immunology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000276:immunology; D044465:White People
D001323:Autoantibodies; C497392:MECP2 protein, human; D026901:Membrane Transport Proteins; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human