Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene.
A recent genome-wide association study revealed a variant (rs2431697) in an intergenic region, between the pituitary tumor-transforming 1 (PTTG1) and microRNA (miR-146a) genes, associated with systemic lupus erythematosus (SLE) susceptibility. Here, we analyzed with a case-control design this variant and other candidate polymorphisms in this region together with expression analysis in order to clarify to which gene this association is related. The single-nucleotide polymorphisms (SNPs) rs2431697, rs2910164 and rs2277920 were genotyped by TaqMan assays in 1324 SLE patients and 1453 healthy controls of European ancestry. Genetic association was statistically analyzed using Unphased. Gene expression of PTTG1, the miRNAs miR-3142 and primary and mature forms of miR-146a in peripheral blood mononuclear cells (PBMCs) were assessed by quantitative real-time PCR. Of the three variants analyzed, only rs2431697 was genetically associated with SLE in Europeans. Gene expression analysis revealed that this SNP was not associated with PTTG1 expression levels, but with the microRNA-146a, where the risk allele correlates with lower expression of the miRNA. We replicated the genetic association of rs2341697 with SLE in a case-control study in Europeans and demonstrated that the risk allele of this SNP correlates with a downregulation of the miRNA 146a, potentially important in SLE etiology.
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
S E
SE
Löfgren
J
J
Frostegård
L
L
Truedsson
B A
BA
Pons-Estel
S
S
D'Alfonso
T
T
Witte
B R
BR
Lauwerys
E
E
Endreffy
L
L
Kovács
C
C
Vasconcelos
B
B
Martins da Silva
S V
SV
Kozyrev
M E
ME
Alarcón-Riquelme
D000483:Alleles; D016022:Case-Control Studies; D005060:Europe; D005786:Gene Expression Regulation; D023061:Gene Order; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000208:ethnology / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D064249:Securin; D044465:White People / Q000235:genetics*
C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human