Association of a functional polymorphism in the 3'-untranslated region of SPI1 with systemic lupus erythematosus.

Abstract

OBJECTIVE:

SPI1, also referred to as PU.1, is an Ets family transcription factor that interacts with IRF2, IRF4, and IRF8. In view of the significance of the type I interferon pathway in systemic lupus erythematosus (SLE), this study was undertaken to investigate a possible association between SPI1 polymorphisms and SLE.

METHODS:

A case-control association study was performed using 6 tag single-nucleotide polymorphisms (SNPs), as well as a SNP located upstream of SPI1 previously found to be associated with acute myelogenous leukemia, in 400 Japanese patients with SLE and 450 healthy controls. Resequencing of all exons and known regulatory regions was performed to identify functional polymorphisms. Association of genotype and SPI1 expression was examined using the GENEVAR database and reporter assays.

RESULTS:

A significant association was detected in 2 SNPs in intron 2 (rs10769258 and rs4752829) (P = 0.005 and P = 0.008, respectively, under the dominant model). The association was stronger in patients with nephropathy. Resequencing identified a potentially functional polymorphism in the 3'-untranslated region (3'-UTR), rs1057233, which was in strong linkage disequilibrium with the SNPs in intron 2. The number of risk alleles at rs1057233 was strongly correlated with SPI1 messenger RNA (mRNA) level in the database analysis (P = 0.0002), and was confirmed by a reporter assay. Interestingly, rs1057233 alters a target sequence for microRNA hsa-miR-569 (miR-569). Transfection experiments demonstrated that miR-569 inhibits expression of a reporter construct with the 3'-UTR sequence containing the nonrisk allele but not the risk allele.

CONCLUSION:

Our findings indicate that a SNP in the 3'-UTR of SPI1 is associated with elevated SPI1 mRNA level and with susceptibility to SLE.

• Authors: Koki Hikami, Aya Kawasaki, Ikue Ito, Minori Koga, Satoshi Ito, Taichi Hayashi, Isao Matsumoto, Akito Tsutsumi, Makio Kusaoi, Yoshinari Takasaki, Hiroshi Hashimoto, Tadao Arinami, Takayuki Sumida, Naoyuki Tsuchiya
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 63 Issue 3 Pg. 755-63 (Mar 2011) ISSN: 1529-0131 [Electronic] United States
• PMID: 21360505 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 by the American College of Rheumatology.

Chemical References

• 3' Untranslated Regions
• MicroRNAs
• Proto-Oncogene Proteins
• Trans-Activators
• proto-oncogene protein Spi-1

Topics

• 3' Untranslated Regions (genetics)
• Adult
• Asian People (genetics, statistics & numerical data)
• Female
• Genes, Reporter (genetics)
• Genetic Predisposition to Disease (ethnology, genetics)
• Genotype
• Humans
• Linkage Disequilibrium
• Lupus Erythematosus, Systemic (ethnology, genetics)
• Male
• MicroRNAs (genetics)
• Middle Aged
• Polymorphism, Single Nucleotide (genetics)
• Proto-Oncogene Proteins (genetics)
• Risk Factors
• Trans-Activators (genetics)
• Transfection
• Young Adult