Advanced

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

Oparina, Nina Y.; Delgado-Vega, Angelica M.; Martinez-Bueno, Manuel; Magro-Checa, Cesar; Fernandez, Concepcion; Ortega Castro, Rafaela; Pons-Estel, Bernardo A.; D'Alfonso, Sandra; Sebastiani, Gian Domenico and Witte, Torsten, et al. (2015) In Annals of the Rheumatic Diseases 74(3). p.14-14
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
@article{dc8a029c-a647-4e15-96b0-bfa0352264d7,
  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.},
  author       = {Oparina, Nina Y. and Delgado-Vega, Angelica M. and Martinez-Bueno, Manuel and Magro-Checa, Cesar and Fernandez, Concepcion and Ortega Castro, Rafaela and Pons-Estel, Bernardo A. and D'Alfonso, Sandra and Sebastiani, Gian Domenico and Witte, Torsten and Lauwerys, Bernard R. and Endreffy, Emoke and Kovacs, Laszlo and Escudero, Alejandro and Lopez-Pedrera, Chary and Vasconcelos, Carlos and da Silva, Berta Martins and Frostegard, Johan and Truedsson, Lennart and Martin, Javier and Raya, Enrique and Ortego-Centeno, Norberto and de los Angeles Aguirre, Maria and de Ramon Garrido, Enrique and Castillo Palma, Maria-Jesus and Alarcon-Riquelme, Marta E. and Kozyrev, Sergey V.},
  issn         = {1468-2060},
  language     = {eng},
  number       = {3},
  pages        = {14--14},
  publisher    = {British Medical Association},
  series       = {Annals of the Rheumatic Diseases},
  title        = {PXK locus in systemic lupus erythematosus: fine mapping and functional analysis reveals novel susceptibility gene ABHD6},
  url          = {http://dx.doi.org/10.1136/annrheumdis-2013-204909},
  volume       = {74},
  year         = {2015},
}