Expression of DDX11 and DNM1L at the 12p11 Locus Modulates Systemic Lupus Erythematosus Susceptibility.

Mohammad Saeed,Eduardo Collantes Estévez,Chary López-Pedrera,Laura Muñoz-Barrera,Alejandra María Patiño-Trives,María Ángeles Aguirre,Alejandro Ibáñez-Costa

doi:10.3390/ijms22147624

Abstract

Objectives: This study employed genetic and functional analyses using OASIS meta-analysis of multiple existing GWAS and gene-expression datasets to identify novel SLE genes. Methods: Four hundred and ten genes were mapped using SNIPPER to 30 SLE GWAS loci and investigated for expression in three SLE GEO-datasets and the Cordoba GSE50395-dataset. Blood eQTL for significant SNPs in SLE loci and STRING for functional pathways of differentially expressed genes were used. Confirmatory qPCR on SLE monocytes was performed. The entire 12p11 locus was investigated for genetic association using two additional GWAS. Expression of 150 genes at this locus was assessed. Based on this significance, qPCRs for DNM1L and KRAS were performed. Results: Fifty genes were differentially expressed in at least two SLE GEO-datasets, with all probes directionally aligned. DDX11, an RNA helicase involved in genome stability, was downregulated in both GEO and Cordoba datasets. The most significant SNP, rs3741869 in OASIS locus 12p11.21, containing DDX11, was a cis-eQTL regulating DDX11 expression. DDX11 was found repressed. The entire 12p11 locus showed three association peaks. Gene expression in GEO datasets identified DNM1L and KRAS, besides DDX11. Confirmatory qPCR validated DNM1L as an SLE susceptibility gene. DDX11, DNM1L and KRAS interact with each other and multiple known SLE genes including STAT1/STAT4 and major components of IFN-dependent gene expression, and are responsible for signal transduction of cytokines, hormones, and growth-factors, deregulation of which is involved in SLE-development. Conclusion: A genomic convergence approach with OASIS analysis of multiple GWAS and expression datasets identified DDX11 and DNM1L as novel SLE-genes, the expression of which is altered in monocytes from SLE patients. This study lays the foundation for understanding the pathogenic involvement of DDX11 and DNM1L in SLE by identifying them using a systems-biology approach, while the 12p11 locus harboring these genes was previously missed by four independent GWAS.

Highlights

SNIPPER located 410 genes (Table S1) in 30 Systemic lupus erythematosus (SLE) loci identified by OASIS 2, and these were tested in three GEO expression datasets
The most important finding of this study was the identification of DDX11 and DNM1L as SLE
The most significant SNP, rs3741869, in OASIS locus 19 containing the gene DDX11, was a cis-eQTL regulating the expression of DDX11

Summary

Introduction

Systemic lupus erythematosus (SLE) is a complex disorder manifesting as a syndrome [1]. In SLE, identification of susceptibility genes is of great relevance for understanding specific pathobiological mechanisms and expanding the number of molecular targets for clinical testing and drug discovery. Despite the identification of a large number of genes in multiple SLE genome-wide association studies (GWAS) and candidate gene studies, together they explain only 15 to 30% of SLE heritability [2,3,4]. It is possible that several loci of modest significance remain to be discovered due to the complex, syndromic nature of SLE, along with other GWAS limitations.

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Conclusion