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Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus.

ABSTRACT: BACKGROUND:A major systemic lupus erythematosus (SLE) susceptibility locus lies within a common inversion polymorphism region (encompassing 3.8 - 4.5 ?Mb) located at 8p23. Initially implicated genes included FAM167A-BLK and XKR6, of which BLK received major attention due to its known role in B-cell biology. Recently, additional SLE risk carried in non-inverted background was also reported. OBJECTIVE AND METHODS:In this case -control study, we further investigated the 'extended' 8p23 locus (~ 4 ?Mb) where we observed multiple SLE signals and assessed these signals for their relation to the inversion affecting this region. The study involved a North American discovery data set (~ 1200 ?subjects) and a replication data set (> 10?000 ?subjects) comprising European-descent individuals. RESULTS:Meta-analysis of 8p23 SNPs, with p < 0.05 in both data sets, identified 51 genome-wide significant SNPs (p < 5.0 × 10-8). While most of these SNPs were related to previously implicated signals (XKR6-FAM167A-BLK subregion), our results also revealed two 'new' SLE signals, including SGK223-CLDN23-MFHAS1 (6.06 × 10-9 ? meta p ? 4.88 × 10-8) and CTSB (meta p = 4.87 × 10-8) subregions that are located > 2 Mb upstream and ~ 0.3 ?Mb downstream from previously reported signals. Functional assessment of relevant SNPs indicated putative cis-effects on the expression of various genes at 8p23. Additional analyses in discovery sample, where the inversion genotypes were inferred, replicated the association of non-inverted status with SLE risk and suggested that a number of SLE risk alleles are predominantly carried in non-inverted background. CONCLUSIONS:Our results implicate multiple (known+novel) SLE signals/genes at the extended 8p23 locus, beyond previously reported signals/genes, and suggest that this broad locus contributes to SLE risk through the effects of multiple genes/pathways.

SUBMITTER: Demirci FY

PROVIDER: S-EPMC5610905 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus.

Demirci F Yesim FY Wang Xingbin X Morris David L DL Feingold Eleanor E Bernatsky Sasha S Pineau Christian C Clarke Ann A Ramsey-Goldman Rosalind R Manzi Susan S Vyse Timothy J TJ Kamboh M I MI

Journal of medical genetics 20170313 6

<h4>Background</h4>A major systemic lupus erythematosus (SLE) susceptibility locus lies within a common inversion polymorphism region (encompassing 3.8 - 4.5 Mb) located at 8p23. Initially implicated genes included <i>FAM167A-BLK</i> and <i>XKR6</i>, of which <i>BLK</i> received major attention due to its known role in B-cell biology. Recently, additional SLE risk carried in non-inverted background was also reported.<h4>Objective and methods</h4>In this case -control study, we further investiga ...[more]

PMID: 28289186

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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

Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus.

Publications

Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus.

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