Nina Y Oparina1, Angelica M Delgado-Vega2, Manuel Martinez-Bueno3, César Magro-Checa4, Concepción Fernández5, Rafaela Ortega Castro6, Bernardo A Pons-Estel7, Sandra D'Alfonso8, Gian Domenico Sebastiani9, Torsten Witte10, Bernard R Lauwerys11, Emoke Endreffy12, László Kovács13, Alejandro Escudero6, Chary López-Pedrera6, Carlos Vasconcelos14, Berta Martins da Silva14, Johan Frostegård15, Lennart Truedsson16, Javier Martin17, Enrique Raya4, Norberto Ortego-Centeno5, Maria de Los Angeles Aguirre6, Enrique de Ramón Garrido18, María-Jesús Castillo Palma19, Marta E Alarcon-Riquelme20, Sergey V Kozyrev1. 1. Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. 2. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. 3. Centro de Genómica e Investigación Oncológica (GENYO). Pfizer-Universidad de Granada-Junta de Andalucía, PTS, Granada, Spain. 4. Department of Rheumatology, Hospital Universitario San Cecilio, Granada, Spain. 5. Unidad de Enfermedades Autoimmunes Sistémicas, UGC Medicina Interna, Hospital Universitario San Cecilio, Granada, Spain. 6. Servicio de Reumatologia, Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica IMIBIC, Córdoba, Spain. 7. Department of Rheumatology, Sanatorio Parque, Rosario, Argentina. 8. Department of Health Sciences and IRCAD, University of Eastern Piedmont, Novara, Italy. 9. Unità Operativa Complessa Reumatología, Azienda Ospedaliera San Camillo- Forlanini, Roma, Italy. 10. Hannover Medical School, Hannover, Germany. 11. Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Bruxells, Belgium. 12. Department of Pediatrics and Health Center, University of Szeged, Szeged, Hungary. 13. Department of Rheumatology, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary. 14. Centro Hospitalar do Porto/Hospital Santo Antonio and UMIB/ICBAS, Porto, Portugal. 15. IMM, Unit of Immunology and Chronic disease, Karolinska Institutet, Stockholm, Sweden. 16. Department of Laboratory Medicine, Section of M.I.G., Lund University, Lund, Sweden. 17. Instituto de Biomedicina y Parasitología López Neyra, CSIC, Armilla, Spain. 18. Department of Medicine, Hospital Carlos Haya, Málaga, Spain. 19. Department of Internal Medicine, Hospital Universitario Virgen del Rocío, Seville, Spain. 20. Centro de Genómica e Investigación Oncológica (GENYO). Pfizer-Universidad de Granada-Junta de Andalucía, PTS, Granada, Spain Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Abstract
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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 SLEpatients 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Samuel E Vaughn; Corinne Foley; Xiaoming Lu; Zubin H Patel; Erin E Zoller; Albert F Magnusen; Adrienne H Williams; Julie T Ziegler; Mary E Comeau; Miranda C Marion; Stuart B Glenn; Adam Adler; Nan Shen; Swapan Nath; Anne M Stevens; Barry I Freedman; Betty P Tsao; Chaim O Jacob; Diane L Kamen; Elizabeth E Brown; Gary S Gilkeson; Graciela S Alarcón; John D Reveille; Juan-Manuel Anaya; Judith A James; Kathy L Moser; Lindsey A Criswell; Luis M Vilá; Marta E Alarcón-Riquelme; Michelle Petri; R Hal Scofield; Robert P Kimberly; Rosalind Ramsey-Goldman; Young Binjoo; Jeongim Choi; Sang-Cheol Bae; Susan A Boackle; Timothy J Vyse; Joel M Guthridge; Bahram Namjou; Patrick M Gaffney; Carl D Langefeld; Kenneth M Kaufman; Jennifer A Kelly; Isaac T W Harley; John B Harley; Leah C Kottyan Journal: Front Genet Date: 2015-01-08 Impact factor: 4.599
Authors: James Bentham; David L Morris; Deborah S Cunninghame Graham; Christopher L Pinder; Philip Tombleson; Timothy W Behrens; Javier Martín; Benjamin P Fairfax; Julian C Knight; Lingyan Chen; Joseph Replogle; Ann-Christine Syvänen; Lars Rönnblom; Robert R Graham; Joan E Wither; John D Rioux; Marta E Alarcón-Riquelme; Timothy J Vyse Journal: Nat Genet Date: 2015-10-26 Impact factor: 38.330