Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus

Bentham, James; Morris, David L.; Graham, Deborah S. Cunninghame; Pinder, Christopher L.; Tombleson, Philip; Behrens, Timothy W.; Martı́n, Javier; Fairfax, Benjamin P.; Knight, Julian C.; Chen, Lingyan; Replogle, Joseph M.; Syvänen, Ann Christine; Rönnblom, Lars; Graham, Robert; Wither, Joan E.; Rioux, John D.; Alarcón‐Riquelme, Marta E.; Vyse, Timothy J.

doi:10.1038/ng.3434

Cited by 830 publications

(772 citation statements)

References 76 publications

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“…We also found cluster-specific expression of several poorly annotated SLE susceptibility genes, including WDFY4, CXorf21, and TMEM39A. Interestingly, many of the SLE GWAS genes are transcription factors, supporting the notion that aberrantly regulated gene expression networks in multiple cell types contribute to SLE 38 . Our analysis identified both innate and adaptive immune cell subsets in which these transcription factors (ARID5B, CIITA, ETS, IKZF1, IKZF2, IRF7, IRF8 and PRDM1) are expressed.…”

Section: Cluster-specific Expression Of Genes Associated With Diseasementioning

confidence: 51%

The immune cell landscape in kidneys of lupus nephritis patients

Arazi

Rao

Berthier

et al. 2018

Preprint

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Lupus nephritis is a potentially fatal autoimmune disease, whose current treatment is ineffective and often toxic. To gain insights into disease mechanisms, we analyzed kidney samples from lupus nephritis patients and healthy controls using single-cell RNA-seq. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid, T, NK and B cells, demonstrating both pro-inflammatory and resolving responses. We found evidence of local activation of B cells correlated with an age-associated B cell signature, and of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, pointing to potential therapeutic targets. Gene expression of immune cells in urine and kidney was highly correlated, suggesting urine may be a surrogate for kidney biopsies. Our results provide a first comprehensive view of the complex network of leukocytes active in lupus nephritis kidneys.

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Section: Cluster-specific Expression Of Genes Associated With Diseasementioning

confidence: 51%

The immune cell landscape in kidneys of lupus nephritis patients

Arazi

Rao

Berthier

et al. 2018

Preprint

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“…Additionally, we uncovered several novel loci that either fell just below genome-wide significance (P < 5Â10 À8 ) or were not independently replicated. In this follow-up study, we augmented our previous data with an additional cohort from Hong Kong and performed in silico replication together with published cohorts of European and Chinese descent (4,5). The added statistical power of the meta-analysis with nine cohorts allowed us to independently replicate five candidate loci above genome-wide significance.…”

Section: Introductionmentioning

confidence: 99%

“…Disease severity, morbidity and mortality are highest in individuals of non-European descent (1). To date, more than ten genome-wide association studies (GWAS) and historical candidate gene studies have identified diverse risk loci (2)(3)(4). However, these SLE candidate genes taken together are insufficient to explain the entire heritability of SLE.…”

Section: Introductionmentioning

confidence: 99%

Confirmation of five novel susceptibility loci for Systemic Lupus Erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci

et al. 2017

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We recently identified ten novel SLE susceptibility loci in Asians and uncovered several additional suggestive loci requiring further validation. This study aimed to replicate five of these suggestive loci in a Han Chinese cohort from Hong Kong, followed by meta-analysis (11,656 cases and 23,968 controls) on previously reported Asian and European populations, and to perform bioinformatic analyses on all 82 reported SLE loci to identify shared regulatory signatures. We performed a battery of analyses for these five loci, as well as joint analyses on all 82 SLE loci. All five loci passed genome-wide significance: MYNN Received: September 7, 2016. Revised: January 12, 2017. Accepted: January 13, 2017 ) of cis-genes. Transcription factor binding sites for p53, MEF2A and E2F1 were significantly (P < 0.05) over-represented in SLE loci, consistent with apoptosis playing a critical role in SLE. Enrichment analysis revealed common pathways, gene ontology, protein domains, and cell type-specific expression. In summary, we provide evidence of five novel SLE susceptibility loci. Integrated bioinformatics using all 82 loci revealed that SLE susceptibility loci share many gene regulatory features, suggestive of conserved mechanisms of SLE etiopathogenesis.

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“…13, 2017; enriched for ceQTLs but not for reQTLs. Most notably, systemic lupus erythematosus (SLE) GWAS signals 19 were very strongly and significantly enriched among reQTLs with no enrichment in ceQTLs, suggesting that innate immune response to pathogens may be a particularly important environmental modifier of genetic predisposition to SLE, while playing a smaller role in the genetic architecture of e.g.…”

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confidence: 99%

Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations

Kim-Hellmuth

Bechheim

Puetz

et al. 2017

Preprint

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The immune system plays a major role in human health and disease, and understanding genetic causes of interindividual variability of immune responses is vital. We isolated monocytes from 134 genotyped individuals, stimulated the cells with three defined microbe-associated molecular patterns (LPS, MDP, and pppdsRNA), and profiled the transcriptome at three time points. After mapping expression quantitative trait loci (eQTL), we identified 417 response eQTLs (reQTLs) with differing effect between the conditions. We characterized the dynamics of genetic regulation on early and late immune response, and observed an enrichment of reQTLs in distal cis-regulatory elements. Response eQTLs are also enriched for recent positive selection with an evolutionary trend towards enhanced immune response. Finally, we uncover novel reQTL effects in multiple GWAS loci, and show a stronger enrichment of response than constant eQTLs in GWAS signals of several autoimmune diseases. This demonstrates the importance of infectious stimuli modifying genetic predisposition to disease. Main TextAn increasingly popular approach to identify genetic factors affecting interindividual variation in immune response is mapping expression quantitative trait loci (eQTLs) -variants that associate to gene expression -and to identify so-called response eQTLs (reQTLs) where the eQTL effect differs between immune stimuli [1][2][3][4][5][6] .Such genetic variants can impact the transcriptional response to infection, and also represent genetic effects that are modified by the infectious environment via gene-byenvironment interactions. In this study, we create a data set of a large number of . CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/116376 doi: bioRxiv preprint first posted online Mar. 13, 2017; -3 -immune stimulus conditions, with monocytes activated with microbial ligands for three different pattern recognition receptor (PRR) families at two different time points, next to the baseline condition.To examine the time course of innate immune responses, we first profiled gene expression in monocytes of five individuals using Human HT-12 v4 Expression BeadChips (Illumina) at six time points after stimulation with three prototypical microbial ligands: Lipopolysaccharide (LPS) was used to activate TLR4, muramyl-dipeptide (MDP) to stimulate NOD2, and 5'-triphosphate RNA (RNA) to activate RIG-I. Hierarchical clustering revealed early differentially expressed (DE) genes at 45 and 90 minutes after stimulation and late DE genes between 3 and 24 hours ( Supplementary Fig. 1). For the full eQTL cohort, we analyzed primary monocytes isolated from 134 healthy male individuals (185 before quality control), which were either untreated (baseline) or stimulated with the same three pathogenderived stimuli, and gene expression was profiled after 90 ...

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Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus

Cited by 830 publications

References 76 publications

The immune cell landscape in kidneys of lupus nephritis patients

The immune cell landscape in kidneys of lupus nephritis patients

Confirmation of five novel susceptibility loci for Systemic Lupus Erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci

Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations

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