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A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus.

ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (P<1 × 10(-4)). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P=0.0004) and UBCH7 protein expression (P=0.0068). The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.

SUBMITTER: Wang S

PROVIDER: S-EPMC3411915 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus.

Wang S S Adrianto I I Wiley G B GB Lessard C J CJ Kelly J A JA Adler A J AJ Glenn S B SB Williams A H AH Ziegler J T JT Comeau M E ME Marion M C MC Wakeland B E BE Liang C C Kaufman K M KM Guthridge J M JM Alarcón-Riquelme M E ME Alarcón G S GS Anaya J-M JM Bae S-C SC Kim J-H JH Joo Y B YB Boackle S A SA Brown E E EE Petri M A MA Ramsey-Goldman R R Reveille J D JD Vilá L M LM Criswell L A LA Edberg J C JC Freedman B I BI Gilkeson G S GS Jacob C O CO James J A JA Kamen D L DL Kimberly R P RP Martin J J Merrill J T JT Niewold T B TB Pons-Estel B A BA Scofield R H RH Stevens A M AM Tsao B P BP Vyse T J TJ Langefeld C D CD Harley J B JB Wakeland E K EK Moser K L KL Montgomery C G CG Gaffney P M PM

Genes and immunity 20120405 5

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune fu ...[more]

PMID: 22476155

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Project description:Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P ?=?1.34×10(-8), OR ?=?1.22, CI 95% ?=?1.14-1.30; rs2004640: P ?=?4.60×10(-7), OR ?=?0.84, CI 95% ?=?0.78-0.90; rs10488631: P ?=?7.53×10(-20), OR ?=?1.63, CI 95% ?=?1.47-1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P ?=?0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P ?=?9.04×10(-22), OR ?=?1.75, CI 95% ?=?1.56-1.97) better explained the observed association (likelihood P-value ?=?1.48×10(-4)), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific.

Dataset Information

A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus.

Publications

A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus.

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