title: PXK locus in systemic lupus erythematosus: fine mapping and functional analysis reveals novel susceptibility gene ABHD6.
abstract: OBJECTIVE
  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.
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Nina Y
authors.initials: NY
authors.lastname: Oparina
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Angelica M
authors.initials: AM
authors.lastname: Delgado-Vega
authors.affiliation: Centro de Genómica e Investigación Oncológica (GENYO). Pfizer-Universidad de Granada-Junta de Andalucía, PTS, Granada, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Martinez-Bueno
authors.affiliation: Department of Rheumatology, Hospital Universitario San Cecilio, Granada, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Magro-Checa
authors.affiliation: Unidad de Enfermedades Autoimmunes Sistémicas, UGC Medicina Interna, Hospital Universitario San Cecilio, Granada, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Fernández
authors.affiliation: Servicio de Reumatologia, Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica IMIBIC, Córdoba, Spain.
authors.forename: Rafaela Ortega
authors.initials: RO
authors.lastname: Castro
authors.affiliation: Department of Rheumatology, Sanatorio Parque, Rosario, Argentina.
authors.forename: Bernardo A
authors.initials: BA
authors.lastname: Pons-Estel
authors.affiliation: Department of Health Sciences and IRCAD, University of Eastern Piedmont, Novara, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: D'Alfonso
authors.affiliation: Unità Operativa Complessa Reumatología, Azienda Ospedaliera San Camillo- Forlanini, Roma, Italy.
authors.forename: Gian Domenico
authors.initials: GD
authors.lastname: Sebastiani
authors.affiliation: Hannover Medical School, Hannover, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Witte
authors.affiliation: Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Bruxells, Belgium.
authors.forename: Bernard R
authors.initials: BR
authors.lastname: Lauwerys
authors.affiliation: Department of Pediatrics and Health Center, University of Szeged, Szeged, Hungary.
authors.forename: Emoke
authors.initials: E
authors.lastname: Endreffy
authors.affiliation: Department of Rheumatology, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Kovács
authors.affiliation: Servicio de Reumatologia, Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica IMIBIC, Córdoba, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Escudero
authors.affiliation: Servicio de Reumatologia, Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica IMIBIC, Córdoba, Spain.
authors.forename: Chary
authors.initials: C
authors.lastname: López-Pedrera
authors.affiliation: Centro Hospitalar do Porto/Hospital Santo Antonio and UMIB/ICBAS, Porto, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Vasconcelos
authors.affiliation: Centro Hospitalar do Porto/Hospital Santo Antonio and UMIB/ICBAS, Porto, Portugal.
authors.forename: Berta Martins
authors.initials: BM
authors.lastname: da Silva
authors.affiliation: IMM, Unit of Immunology and Chronic disease, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Frostegård
authors.affiliation: Department of Laboratory Medicine, Section of M.I.G., Lund University, Lund, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Truedsson
authors.affiliation: Instituto de Biomedicina y Parasitología López Neyra, CSIC, Armilla, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.affiliation: Department of Rheumatology, Hospital Universitario San Cecilio, Granada, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Raya
authors.affiliation: Unidad de Enfermedades Autoimmunes Sistémicas, UGC Medicina Interna, Hospital Universitario San Cecilio, Granada, Spain.
authors.forename: Norberto
authors.initials: N
authors.lastname: Ortego-Centeno
authors.affiliation: Servicio de Reumatologia, Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica IMIBIC, Córdoba, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: de Los Angeles Aguirre
authors.affiliation: Department of Medicine, Hospital Carlos Haya, Málaga, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: de Ramón Garrido
authors.affiliation: Department of Internal Medicine, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: María-Jesús Castillo
authors.initials: MJ
authors.lastname: Palma
authors.affiliation: 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.
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcon-Riquelme
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Kozyrev
mesh_terms: D017398:Alternative Splicing; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002900:Chromosomes, Human, 1-3; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008994:Monoacylglycerol Lipases / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C508327:PXK protein, human; D017346:Protein Serine-Threonine Kinases; C540878:ABHD6 protein, human; D008994:Monoacylglycerol Lipases
keywords: Autoimmune Diseases; Gene Polymorphism; Systemic Lupus Erythematosus