Functional characterization of genetic polymorphisms (IFI16, MNDA AND AIM2) associated with SLE disease

Abstract

Sytemic lupus erythematosus (SLE)is a an autoimmune disease that affects multiple organs. In this study, we applied case-control association study including pooling genome association (GWA) and candidate gene association studies to search for SNPs associated with SLE susceptibility and/or severity. We could not identify any SNPs with distinct p-value or odds ratio from our pooling GWA result due to limited power. However,the GWA result compared with known candidate gene suggested that TNFb, HLA,TNXB and TNFSAIP3 gene are important candidate genes in Thai population giving positive association with p-value(by t-test)less than 0.0001. We selected new candidate genes from SLE major susceptibility loci in chromosome 1 as a model for individual genotyping results showed that the allele frequency patterns of SNPs in NOS1AP, IFIX(PYHIN1), TLR5, CD1D genes from individual genotyping were similay to the patterns from pooling approach. We selected IFIX for further study in candidate gene’s part. Beside IFIX, we also focus on MNDA, IFI16 and AIM2 genes which located in the same region and are all IFN-inducible genes. They are important SLE susceptibility genes due to several reasons including 1)genetic mapping from lupus murine model and 2) an upregulated IFN-inducible gene in patients with SLE from microarray studies and 3)IFI16 was identified as new autoantigen for with SLE. We genotyped 10 SNPs from these 4 genes in 200 patients with SLE vs.200 normal controls. From our association results, we found that SNP within IFIX(rs856084, OR=1.37,95%cl=1.01-1.87)and IFI16(rs866484, OR=1.37,95% Cl=1.03-1.82 และrs1772414,OR=1.41,95%Cl=1.06-1.88)are independently important. To clarify the of IFIX16 gene, more extensive study using dense SNPs and increasing sample sizes required in future study. In order to better understand functions of these genes,we studied the expression ofMNDA,IFIX16 and AIM2 genes from various cell types in patients with SLE compared to healthy controls. We found the increasing of IFN-inducible genes in leukocytes from patients with SLE,but not in lymphocytes and kidney. These results may indicate the importance of these genes in SLE development via expression in other white blood cell subsets such as monocytes. The negative finding of lyhese genes in kidney indicates that they might not be important in renal pathology.