PXK locus in systemic lupus erythematosus: fine mapping and functional analysis reveals novel susceptibility gene ABHD6

• Published in: Annals of the rheumatic diseases Vol. 74; no. 3; p. e14
• Main Authors: Oparina, Nina Y, Delgado-Vega, Angelica M, Martinez-Bueno, Manuel, Magro-Checa, César, Fernández, Concepción, Castro, Rafaela Ortega, Pons-Estel, Bernardo A, D'Alfonso, Sandra, Sebastiani, Gian Domenico, Witte, Torsten, Lauwerys, Bernard R, Endreffy, Emoke, Kovács, László, Escudero, Alejandro, López-Pedrera, Chary, Vasconcelos, Carlos, da Silva, Berta Martins, Frostegård, Johan, Truedsson, Lennart, Martin, Javier, Raya, Enrique, Ortego-Centeno, Norberto, de Los Angeles Aguirre, Maria, de Ramón Garrido, Enrique, Palma, María-Jesús Castillo, Alarcon-Riquelme, Marta E, Kozyrev, Sergey V
• Format: Journal Article
• Language: English
• Published: England 01.03.2015
• Subjects: Alternative Splicing; Case-Control Studies; Chromosome Mapping; Chromosomes, Human, 1-3; Clinical Medicine; European Continental Ancestry Group - genetics; Genetic Predisposition to Disease; Haplotypes; Humans; Intracellular Signaling Peptides and Proteins - genetics; Klinisk medicin; Linkage Disequilibrium - genetics; Lupus Erythematosus, Systemic - genetics; Medical and Health Sciences; Medicin och hälsovetenskap; Monoacylglycerol Lipases - genetics; Nerve Tissue Proteins - genetics; Polymorphism, Single Nucleotide; Protein-Serine-Threonine Kinases - genetics; Reumatologi och inflammation; Rheumatology and Autoimmunity; RNA, Messenger - genetics; Systemic Lupus Erythematosus; Gene Polymorphism; Autoimmune Diseases
• ISSN: 0003-4967; 1468-2060; 1468-2060
• DOI: 10.1136/annrheumdis-2013-204909

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. 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. 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. 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.