This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features!
Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log in
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Apr;13(3):268-74.
doi: 10.1038/gene.2011.84. Epub 2012 Jan 5.

Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene

Affiliations

Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene

S E Löfgren et al. Genes Immun. 2012 Apr.

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

CONFLICT OF INTEREST

Authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Linkage disequilibrium (LD) structure of the SNPs in the PTTG1-miR-146a region generated from HapMap (release 28) with Haploview v. 4.2. LD blocks (r2) were defined using the solid spine method.
Figure 2
Figure 2
Schematic representation of the PTTG1-miR146a genomic region and the position of the SNPs analyzed. Exons are shown as black bars and dotted line represents the intergenic region. The location of the two mature miRNA annotated in this region, miR-3142 and miR-146a, are indicated in the pri-miR-146a transcript. The positions of the four SNPs included in this study are indicated, together with the LD plot showing the linkage (r2) between them (generated with Haploview from our genotyping data, except for the LD between rs2277920-rs57095329 (*) that was extracted from 1000 genomes pilots for CEU and CHB+JPT).
Figure 3
Figure 3
PTTG1 and miR-146a gene expression analysis in PBMCs (a–e) and LCLs (f and g) from healthy donors, stratified by genotypes. No association was seen with PTTG1 expression (a) neither for rs2910164 with the primary transcript of miR-146a (e). As for corroboration of previous findings, rs2910164 correlated with miR-146a expression levels (c). Both mature and primary form of miR146a were significantly down-regulated in individuals’ homozygotes for the risk allele of rs2431697 (b and d). miR-146a expression analysis in LCLs also showed a trend of down-regulation of mat-miR146a (f) and statistically lower levels of pri-miR-146a (g) in cells from individuals homozygotes for the rs2431697 risk allele. Values correspond to means ±SEM error bars. Expression levels were normalized to 18S rRNA.

References

    1. Kontaki E, Boumpas DT. Innate immunity in systemic lupus erythematosus: sensing endogenous nucleic acids. J Autoimmun. 2010;35(3):206–11. - PubMed
    1. Ronnblom L, Alm GV. Systemic lupus erythematosus and the type I interferon system. Arthritis Res Ther. 2003;5(2):68–75. - PMC - PubMed
    1. Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610–5. - PMC - PubMed
    1. Baechler EC, Batliwalla FM, Reed AM, Peterson EJ, Gaffney PM, Moser KL, et al. Gene expression profiling in human autoimmunity. Immunol Rev. 2006;210:120–37. - PubMed
    1. Harley JB, Alarcon-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet. 2008;40(2):204–10. - PMC - PubMed

Publication types

Full text links
Nature Publishing Group full text link Nature Publishing Group Free PMC article
Cite

AltStyle によって変換されたページ (->オリジナル) /