Dataset Information

Discovery of a novel genetic susceptibility locus on X chromosome for systemic lupus erythematosus.

ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease affecting predominantly females. To discover additional genetic risk variants for SLE on the X chromosome, we performed a follow-up study of our previously published genome-wide association study (GWAS) data set in this study.Twelve single nucleotide polymorphisms (SNPs) within novel or unpublished loci with P-value < 1.00 × 10(-02) were selected for genotype with a total of 2,442 cases and 2,798 controls(including 1,156 cases and 2,330 controls from central China, 1,012 cases and 335 controls from southern China and 274 cases and 133 controls from northern China) using Sequenom Massarry system. Associaton analyses were performed using logistic regression with sample region as a covariate through PLINK 1.07 software.Combined analysis in discovery and central validation dataset discovered a novel locus rs5914778 within LINC01420 associated with SLE at genome-wide significance (P = 1.00 × 10(-08); odds ratio (OR) = 1.32). We also confirmed rs5914778 in the southern Chinese sample cohort (P = 5.31 × 10(-05); OR = 1.51), and meta-analysis of the samples from the discovery, central and southern validations regions provided robust evidence for the association of rs5914778 (P = 5.26 × 10(-12); OR = 1.35). However, this SNP did not show association with SLE in the northern sample (P = 0.33). Further analysis represent the association of northern was significantly heterogeneous compared to central and southern respectively.Our study increases the number of established susceptibility loci for SLE in Han Chinese population and has further demonstrated the important role of X-linked genetic risk variants in the pathogenesis of SLE in Chinese Han population.

SUBMITTER: Zhu Z

PROVIDER: S-EPMC4669597 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Discovery of a novel genetic susceptibility locus on X chromosome for systemic lupus erythematosus.

Zhu Zhengwei Z Liang Zhuoyuan Z Liany Herty H Yang Chao C Wen Leilei L Lin Zhiming Z Sheng Yujun Y Lin Yan Y Ye Lei L Cheng Yuyan Y Chang Yan Y Liu Lu L Yang Lulu L Shi Yinjuan Y Shen Changbing C Zhou Fusheng F Zheng Xiaodong X Zhu Jun J Liang Bo B Ding Yantao Y Zhou Yi Y Yin Xianyong X Tang Huayang H Zuo Xianbo X Sun Liangdan L Bei Jin-Xin JX Liu Jianjun J Yang Sen S Yang Wanling W Cui Yong Y Zhang Xuejun X

Arthritis research & therapy 20151203

<h4>Introduction</h4>Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease affecting predominantly females. To discover additional genetic risk variants for SLE on the X chromosome, we performed a follow-up study of our previously published genome-wide association study (GWAS) data set in this study.<h4>Methods</h4>Twelve single nucleotide polymorphisms (SNPs) within novel or unpublished loci with P-value < 1.00 × 10(-02) were selected for genotype with a total of 2,442 c ...[more]

PMID: 26635088

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Project description:This study employed genetic and functional analyses using OASIS meta-analysis of multiple existing GWAS and gene-expression datasets to identify novel SLE genes. 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. 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. 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.

Dataset Information

Discovery of a novel genetic susceptibility locus on X chromosome for systemic lupus erythematosus.

Publications

Discovery of a novel genetic susceptibility locus on X chromosome for systemic lupus erythematosus.

Similar Datasets

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