Gene-gene interactions of IRF5, STAT4, IKZF1 and ETS1 in systemic lupus erythematosus.
Interferon (IFN) activation signaling and T helper 17 (Th17)-cell/B-cell regulation play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). Several studies have provided convincing evidence that polymorphisms in IRF5, STAT4, IKZF1 and ETS1 from these pathways may be involved in SLE by affecting gene expression or epistasis. We analyzed the genetic interaction in known SLE susceptibility loci from the four genes in northern Han Chinese. A total of 946 northern Han Chinese participated in this study (370 unrelated SLE patients and 576 healthy controls). Subjects underwent genotyping for the single-nucleotide polymorphisms (SNPs) rs2004640 in IRF5, rs7574865 in STAT4, rs4917014 in IKZF1 and rs1128334 in ETS1 by use of a TaqMan SNP genotyping assay and direct sequencing. Gene-gene interaction analysis involved direct counting, multifactor dimensionality reduction (MDR) and linear regression analysis. SLE patients and controls differed in allele frequencies of rs7574865, rs1128334 (P < 0.001) and rs4917014 (P < 0.01). Direct counting revealed that the frequency of risk homozygote combinations was higher for SLE patients than controls (P < 0.01). Furthermore, 2-, 3- and 4-way gene-gene epistasis in SLE was confirmed by parametric methods and MDR analysis. Gene expression analysis partially supported the findings. Our study confirmed the association of the IFN pathway or Th17/B-cells and the pathogenesis of SLE, and gene-gene interaction in this pathway may increase the risk of SLE.
Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, Shandong University School of Medicine, Jinan, China; Department of Medical Genetics and Cell Biology, Ningxia Medical University, Yinchuan, China.
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J
Dang
S
S
Shan
J
J
Li
H
H
Zhao
Q
Q
Xin
Y
Y
Liu
X
X
Bian
Q
Q
Liu
D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D004843:Epistasis, Genetic / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D050835:Interferon Regulatory Factors / Q000235:genetics*; D007372:Interferons / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000208:ethnology / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D060888:Real-Time Polymerase Chain Reaction; D050797:STAT4 Transcription Factor / Q000235:genetics*; D058504:Th17 Cells / Q000276:immunology; D055815:Young Adult
C494041:ETS1 protein, human; C497239:IKZF1 protein, human; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D051740:Ikaros Transcription Factor; D007372:Interferons
Th17/B cell regulation; genetic interaction; interferon-I pathway; single-nucleotide polymorphisms; systemic lupus erythematosus