61 0

Synergistic activation of NF-kappa B by TNFAIP3 (A20) reduction and UBE2L3 (UBCH7) augment that synergistically elevate lupus risk

Synergistic activation of NF-kappa B by TNFAIP3 (A20) reduction and UBE2L3 (UBCH7) augment that synergistically elevate lupus risk
Autoimmune disease; Cytokine; Epistasis; Gene-gene interaction; Gene polymorphism; Inflammatory disease; Rheumatic disease; Synergistic interaction; Systemic lupus erythematosus; TNFR pathway
Issue Date
ARTHRITIS RESEARCH & THERAPY, v. 22, no. 1, article no. 93
Background Systemic lupus erythematosus (SLE) is an autoimmune inflammatory rheumatic disease. SLE susceptibility is affected by multiple genetic elements, environmental factors, and their interactions. We aimed in this study to statistically and functionally characterize a gene-gene interaction (epistasis) recently documented to affect SLE risk. Methods Two single-nucleotide polymorphisms, rs2230926 in TNFAIP3 (A20) gene and rs131654 in UBE2L3 (UBCH7) gene, were genotyped in all 3525 Korean participants, and their SLE risk association and epistasis were statistically analyzed by calculating odds ratio (OR), 95% confidence interval (CI), and P values in genotype comparisons between 1318 SLE patients and 2207 healthy controls. Furthermore, their effects on gene functions were assessed by comparatively examining separate and combined effects of TNFAIP3 and UBE2L3 knockdowns on NF-kappa B transcription factor activity in human cells. Results SLE susceptibility is associated with TNFAIP3 rs2230926 (OR = 1.9, 95% CI 1.6-2.4, P = 8.6 x 10(-11)) and UBE2L3 rs131654 (OR = 1.2, 95% CI 1.1-1.4, P = 1.1 x 10(-4)) in a Korean population of this study. Their risk-associated alleles synergistically elevate SLE susceptibility in both multivariate logistic regression analysis (ORinteraction = 1.6, P = 0.0028) and genotype-stratified analysis (ORinteraction = 2.4), confirming the synergistic TNFAIP3-UBE2L3 interaction in SLE risk. Additionally, the SLE-susceptible alleles confer decreased TNFAIP3 expression (P = 1.1 x 10(-6), n = 610) and increased UBE2L3 expression (P = 9.5 x 10(-11), n = 475), respectively, in B cell analysis of the International HapMap Project individuals with adjustment for ethnicity. Furthermore, when compared with TNFAIP3 non-knockdown and UBE2L3 knockdown in human HeLa cells, TNFAIP3 knockdown and UBE2L3 non-knockdown synergistically increase three cytokines, CCL2, CXCL8 (IL8), and IL6, all regulated by NF-kappa B in the human TNFR signaling pathway. Conclusions A synergistic interaction between TNFAIP3 and UBE2L3 genes is observed in SLE risk, as being evident in comparison of genotype distributions between SLE patients and controls. Additionally, the synergistic gene-gene interaction is functionally validated, as TNFAIP3 reduction and UBE2L3 augment exert synergism in activation of NF-kappa B and subsequent induction of inflammatory cytokines. Accordingly, SLE inflammation and risk could be synergistically alleviated by TNFAIP3 upregulation and UBE2L3 downregulation.
1478-6354; 1478-6362
Appears in Collections:
COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
Files in This Item:
There are no files associated with this item.
RIS (EndNote)
XLS (Excel)


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.