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This work was supported by grants 08/0744 and 11/01048 and by RETICS Program, RD08/0075 (RIER) of the Instituto de Salud Carlos III (Spain) that are partially financed by the European Regional Development Fund of the European Union, and by grants from the Xunta de Galicia and by DFG KFO 250, TP 03 to TW., Alonso-Perez, E., Suarez-Gestal, M., Calaza, M., Ordi-Ros, J., Balada, E., Bijl, M., Papasteriades, C., Carreira, P., Skopouli, F.N., Witte, T., Endreffy, E., Marchini, M., Migliaresi, S., Sebastiani, G.D., Santos, M.J., Suarez, A., Blanco, F.J., Barizzone, N., Pullmann, R., Ruzickova, S., Lauwerys, B.R., Gomez-Reino, J.J., Gonzalez, A., Liz, M., Schmidt, R.E., Kappou-Rigatou, I., Scorza, R., Kovacs, A., Balada, E., Kallenberg, C.G., Vinagre, F., Dostal, C., Pullmann Jr., R., Mavromati, M., D'Alfonso, S., Gutierrez, C., Rego, I.

This work was supported by Fondo de Investigacion Sanitaria of the Instituto de Salud Carlos III(Spain) grant 08/0744 and by RETICS Program RD08/0075 that are partially financed by the European Regional Development Fund of the European Union, and by grants from the Xunta de Galicia and BMBF KN Rheuma (C2.12 to TW)., Alonso-Perez, E., Suarez-Gestal, M., Calaza, M., Sebastiani, G.D., Pullmann, R., Papasteriades, C., Kovacs, A., Skopouli, F.N., Bijl, M., Suarez, A., Marchini, M., Migliaresi, S., Carreira, P., Ordi-Ros, J., Witte, T., Ruzickova, S., Santos, M.J., Barizzone, N., Blanco, F.J., Lauwerys, B.R., Gomez-Reino, J.J., Gonzalez, A.

Introduction: 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. Conclusion: 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.

Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a very varied spectrum of clinical manifestations that could be partly determined by genetic factors. We aimed to determine the relationship between prevalence of 11 clinical features and age of disease onset with European population genetic substructure. Data from 1413 patients of European ancestry recruited in nine countries was tested for association with genotypes of top ancestry informative markers. This analysis was done with logistic regression between phenotypes and genotypes or principal components extracted from them. We used a genetic additive model and adjusted for gender and disease duration. Three clinical features showed association with ancestry informative markers: autoantibody production defined as immunologic disorder (P = 6.8x10(-4)), oral ulcers (P = 6.9x10(-4)) and photosensitivity (P = 0.002). Immunologic disorder was associated with genotypes more common in Southern European ancestries, whereas the opposite trend was observed for photosensitivity. Oral ulcers were specifically more common in patients of Spanish and Portuguese self-reported ancestry. These results should be taken into account in future research and suggest new hypotheses and possible underlying mechanisms to be investigated. A first hypothesis linking photosensitivity with variation in skin pigmentation is suggested.

The authors thank Carmen Pena-Pena for providing outstanding technical assistance. MS-G is the recipient of a FPU predoctoral bursary of the Spanish Ministry of Education. The present work was supported by Fondo de Investigación Sanitaria of the Instituto de Salud Carlos III (Spain), grants 04/1651 and 06/0620 that are partially financed by the Fondo Europeo de Desarrollo Regional program of the European Union, by grants from the Xunta de Galicia, and by BMBF KN Rheuma grant C2.12 (to TW)., Suarez-Gestal, M., Calaza, M., Endreffy, E., Pullmann Jr., R., Ordi-Ros, J., Domenico Sebastiani, G., Ruzickova, S., Jose Santos, M., Papasteriades, C., Marchini, M., Skopouli, F.N., Suarez, A., Blanco, F.J., D'Alfonso, S., Bijl, M., Carreira, P., Witte, T., Migliaresi, S., Gomez-Reino, J.J., Gonzalez, A., Kovacs, A., Balada, E., Dostal, C., Vinagre, F., Kappou-Rigatou, I., Scorza, R., Mavromati, M., Gutierrez, C., Rego, I., Barizzone, N., Kallenberg, C.G., Schmidt, R.E.

Introduction We aimed to replicate association of newly identified systemic lupus erythematosus (SLE) loci. Methods We selected the most associated SNP in 10 SLE loci. These 10 SNPs were analysed in 1,579 patients with SLE and 1,726 controls of European origin by single-base extension. Comparison of allele frequencies between cases and controls was done with the Mantel-Haenszel approach to account for heterogeneity between sample collections. Results A previously controversial association with a SNP in the TYK2 gene was replicated (odds ratio (OR) = 0.79, P = 2.5 x 10(-5)), as well as association with the X chromosome MECP2 gene (OR = 1.26, P = 0.00085 in women), which had only been reported in a single study, and association with four other loci, 1q25.1 (OR = 0.81, P = 0.0001), PXK (OR = 1.19, P = 0.0038), BANK1 (OR = 0.83, P = 0.006) and KIAA1542 (OR = 0.84, P = 0.001), which have been identified in a genome-wide association study, but not found in any other study. All these replications showed the same disease-associated allele as originally reported. No association was found with the LY9 SNP, which had been reported in a single study. Conclusions Our results confirm nine SLE loci. For six of them, TYK2, MECP2, 1q25.1, PXK, BANK1 and KIAA1542, this replication is important. The other three loci, ITGAM, STAT4 and C8orf13-BLK, were already clearly confirmed. Our results also suggest that MECP2 association has no influence in the sex bias of SLE, contrary to what has been proposed. In addition, none of the other associations seems important in this respect.

Abnormal death signaling in lymphocytes of systemic lupus erythematosus (SLE) patients has been associated with elevation of the mitochondrial transmembrane potential (Delta psi(m)) and increased production of reactive oxygen intermediates (ROI). The resultant ATP depletion sensitizes T cells for necrosis that may significantly contribute to inflammation in patients with SLE. In the present study, the role of mitochondrial signal processing in T cell activation was investigated. CD3/CD28 costimulation of PBL elicited transient mitochondrial hyperpolarization and intracellular pH (pH(i)) elevation, followed by increased ROI production. Baseline Delta psi(m), ROI production, and pH(i) were elevated, while T cell activation-induced changes were blunted in 15 patients with SLE in comparison with 10 healthy donors and 10 rheumatoid arthritis patients. Similar to CD3/CD28 costimulation, treatment of control PBL with IL-3, IL-10, TGF-beta(1), and IFN-gamma led to transient Delta psi(m) elevation. IL-10 had diametrically opposing effects on mitochondrial signaling in lupus and control donors. Unlike healthy or rheumatoid arthritis PBL, cells of lupus patients were resistant to IL-10-induced mitochondrial hyperpolarization. By contrast, IL-10 enhanced ROI production and cell death in lupus PBL without affecting ROI levels and survival of control PBL. Ab-mediated IL-10 blockade or stimulation with antagonistic lymphokine IL-12 normalized baseline and CD3/CD28-induced changes in ROI production and pH(i) with no impact on Delta psi(m) of lupus PBL. The results suggest that mitochondrial hyperpolarization, increased ROI production, and cytoplasmic alkalinization play crucial roles in altered IL-10 responsiveness in SLE.