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Extended report
PXK locus in systemic lupus erythematosus: fine mapping and functional analysis reveals novel susceptibility gene ABHD6
  1. Nina Y Oparina1,
  2. Angelica M Delgado-Vega2,
  3. Manuel Martinez-Bueno3,
  4. César Magro-Checa4,
  5. Concepción Fernández5,
  6. Rafaela Ortega Castro6,
  7. Bernardo A Pons-Estel7,
  8. Sandra D'Alfonso8,
  9. Gian Domenico Sebastiani9,
  10. Torsten Witte10,
  11. Bernard R Lauwerys11,
  12. Emoke Endreffy12,
  13. László Kovács13,
  14. Alejandro Escudero6,
  15. Chary López-Pedrera6,
  16. Carlos Vasconcelos14,
  17. Berta Martins da Silva14,
  18. Johan Frostegård15,
  19. Lennart Truedsson16,
  20. Javier Martin17,
  21. Enrique Raya4,
  22. Norberto Ortego-Centeno5,
  23. Maria de los Angeles Aguirre6,
  24. Enrique de Ramón Garrido18,
  25. María-Jesús Castillo Palma19,
  26. Marta E Alarcon-Riquelme3,20,
  27. Sergey V Kozyrev1
  1. 1Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
  2. 2Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
  3. 3Centro de Genómica e Investigación Oncológica (GENYO). Pfizer-Universidad de Granada-Junta de Andalucía, PTS, Granada, Spain
  4. 4Department of Rheumatology, Hospital Universitario San Cecilio, Granada, Spain
  5. 5Unidad de Enfermedades Autoimmunes Sistémicas, UGC Medicina Interna, Hospital Universitario San Cecilio, Granada, Spain
  6. 6Servicio de Reumatologia, Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica IMIBIC, Córdoba, Spain
  7. 7Department of Rheumatology, Sanatorio Parque, Rosario, Argentina
  8. 8Department of Health Sciences and IRCAD, University of Eastern Piedmont, Novara, Italy
  9. 9Unità Operativa Complessa Reumatología, Azienda Ospedaliera San Camillo- Forlanini, Roma, Italy
  10. 10Hannover Medical School, Hannover, Germany
  11. 11Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Bruxells, Belgium
  12. 12Department of Pediatrics and Health Center, University of Szeged, Szeged, Hungary
  13. 13Department of Rheumatology, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary
  14. 14Centro Hospitalar do Porto/Hospital Santo Antonio and UMIB/ICBAS, Porto, Portugal
  15. 15IMM, Unit of Immunology and Chronic disease, Karolinska Institutet, Stockholm, Sweden
  16. 16Department of Laboratory Medicine, Section of M.I.G., Lund University, Lund, Sweden
  17. 17Instituto de Biomedicina y Parasitología López Neyra, CSIC, Armilla, Spain
  18. 18Department of Medicine, Hospital Carlos Haya, Málaga, Spain
  19. 19Department of Internal Medicine, Hospital Universitario Virgen del Rocío, Seville, Spain
  20. 20Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  1. Correspondence to Dr Sergey V Kozyrev, Department of Medical Biochemistry and Microbiology, Uppsala University, Box 597, Uppsala SE-751 24, Sweden; sergey.kozyrev{at}


Objectives To perform fine mapping of the PXK locus associated with systemic lupus erythematosus (SLE) and study functional effects that lead to susceptibility to the disease.

Methods Linkage disequilibrium (LD) mapping was conducted by using 1251 SNPs (single nucleotide polymorphism) covering a 862 kb genomic region on 3p14.3 comprising the PXK locus in 1467 SLE patients and 2377 controls of European origin. Tag SNPs and genotypes imputed with IMPUTE2 were tested for association by using SNPTEST and PLINK. The expression QTLs data included three independent datasets for lymphoblastoid cells of European donors: HapMap3, MuTHER and the cross-platform eQTL catalogue. Correlation analysis of eQTLs was performed using Vassarstats. Alternative splicing for the PXK gene was analysed on mRNA from PBMCs.

Results Fine mapping revealed long-range LD (>200 kb) extended over the ABHD6, RPP14, PXK, and PDHB genes on 3p14.3. The highly correlated variants tagged an SLE-associated haplotype that was less frequent in the patients compared with the controls (OR=0.89, p=0.00684). A robust correlation between the association with SLE and enhanced expression of ABHD6 gene was revealed, while neither expression, nor splicing alterations associated with SLE susceptibility were detected for PXK. The SNP allele frequencies as well as eQTL pattern analysed in the CEU and CHB HapMap3 populations indicate that the SLE association and the effect on ABHD6 expression are specific to Europeans.

Conclusions These results confirm the genetic association of the locus 3p14.3 with SLE in Europeans and point to the ABHD6 and not PXK, as the major susceptibility gene in the region. We suggest a pathogenic mechanism mediated by the upregulation of ABHD6 in individuals carrying the SLE-risk variants.

  • Systemic Lupus Erythematosus
  • Gene Polymorphism
  • Autoimmune Diseases

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