<i>PXK</i>locus in systemic lupus erythematosus: fine mapping and functional analysis reveals novel susceptibility gene<i>ABHD6</i>

Oparina, N. Yu.; Delgado-Vega, Angélica M.; Martínez-Bueno, Manuel; Magro-Checa, César; García-Fernández, Carlos; Ortega‐Castro, Rafaela; Pons-Estel, Bernardo A.; D’Alfonso, Sandra; Sebastiani, Gian Domenico; Witte, Torsten; Lauwerys, Bernard; Endreffy, E.; Kovács, László; Escudero, Alejandro; López‐Pedrera, Chary; Vasconcelos, Carlos; Silva, Ana Martins; Frostegård, Johan; Truedsson, Lennart; Martı́n, Javier; Raya, Enrique; Ortego-Centeno, Norbérto; Aguirre, María Ángeles; Garrido, Enrique de Ramón; Palma, María Jesús Castillo; Alarcón‐Riquelme, Marta E.; Kozyrev, Sergey V.

doi:10.1136/annrheumdis-2013-204909

Cited by 25 publications

(20 citation statements)

References 41 publications

(46 reference statements)

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“…Higher expression of ABHD6 in PBMCs defines an SLE endophenotype An overexpression of ABHD6 in SLE patients was suggested in the previous study, which first identified polymorphisms of ABHD6 as the PXK-locus associated predisposition for SLE (7). To examine this, we recruited a cohort of SLE patients and checked the expression of ABHD6 in PBMCs and found that there is significant overexpression of ABHD6 in SLE patients (n = 90, female = 86, male = 4), as compared with healthy controls (n = 76, female = 32, male = 44) ( Fig.…”

Section: Resultsmentioning

confidence: 96%

“…Genome-wide association studies have linked multiple genomic loci with SLE susceptibility, although direct pathogenetic role of very few of them have been reported, apart from the genes directly linked to induction and response of type I IFNs (5,6). A recent genome-wide association study had reported association of a novel gene, a/b-hydrolase domain-containing 6 (ABHD6), with SLE susceptibility (7).…”

Section: Cutting Edge: Dysregulated Endocannabinoid-rheostat For Plasmentioning

confidence: 99%

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Cutting Edge: Dysregulated Endocannabinoid-Rheostat for Plasmacytoid Dendritic Cell Activation in a Systemic Lupus Endophenotype

Rahaman

Bhattacharya

Liu

et al. 2019

The Journal of Immunology

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Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, characterized by loss of tolerance toward self nuclear Ags. Systemic induction of type I IFNs plays a pivotal role in SLE, a major source of type I IFNs being the plasmacytoid dendritic cells (pDCs). Several genes have been linked with susceptibility to SLE in genome-wide association studies. We aimed at exploring the role of one such gene, α/β-hydrolase domain-containing 6 (ABHD6), in regulation of IFN-α induction in SLE patients. We discovered a regulatory role of ABHD6 in human pDCs through modulating the local abundance of its substrate, the endocannabinoid 2-arachidonyl glycerol (2-AG), and elucidated a hitherto unknown cannabinoid receptor 2 (CB2)–mediated regulatory role of 2-AG on IFN-α induction by pDCs. We also identified an ABHD6High SLE endophenotype wherein reduced local abundance of 2-AG relieves the CB2-mediated steady-state resistive tuning on IFN-α induction by pDCs, thereby contributing to SLE pathogenesis.

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Section: Resultsmentioning

confidence: 96%

Section: Cutting Edge: Dysregulated Endocannabinoid-rheostat For Plasmentioning

confidence: 99%

Cutting Edge: Dysregulated Endocannabinoid-Rheostat for Plasmacytoid Dendritic Cell Activation in a Systemic Lupus Endophenotype

Rahaman

Bhattacharya

Liu

et al. 2019

The Journal of Immunology

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“…Refining candidate genes in IBD and autoimmune/autoinflammatory disease-associated risk loci has advanced by exome-sequencing studies, fine mapping of high confidence risk loci, and eQTL analysis (27, 59–61). However, the major integrative analyses with eQTLs, such as those for rheumatoid arthritis (61), systemic lupus erythematosus (62), and multiple sclerosis (63), have used eQTLs defined in peripheral blood (64) or immune cell subsets (63, 65). eQTL mapping in neutrophils (66, 67), monocytes (10), and dendritic cells (68) has expanded by comparing resting cells with cells after immune stimulation.…”

Section: Discussionmentioning

confidence: 99%

Characterization of candidate genes in inflammatory bowel disease–associated risk loci

Peloquin¹,

Goel²,

Kong³

et al. 2016

JCI Insight

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GWAS have linked SNPs to risk of inflammatory bowel disease (IBD), but a systematic characterization of disease-associated genes has been lacking. Prior studies utilized microarrays that did not capture many genes encoded within risk loci or defined expression quantitative trait loci (eQTLs) using peripheral blood, which is not the target tissue in IBD. To address these gaps, we sought to characterize the expression of IBD-associated risk genes in disease-relevant tissues and in the setting of active IBD. Terminal ileal (TI) and colonic mucosal tissues were obtained from patients with Crohn’s disease or ulcerative colitis and from healthy controls. We developed a NanoString code set to profile 678 genes within IBD risk loci. A subset of patients and controls were genotyped for IBD-associated risk SNPs. Analyses included differential expression and variance analysis, weighted gene coexpression network analysis, and eQTL analysis. We identified 116 genes that discriminate between healthy TI and colon samples and uncovered patterns in variance of gene expression that highlight heterogeneity of disease. We identified 107 coexpressed gene pairs for which transcriptional regulation is either conserved or reversed in an inflammation-independent or -dependent manner. We demonstrate that on average approximately 60% of disease-associated genes are differentially expressed in inflamed tissue. Last, we identified eQTLs with either genotype-only effects on expression or an interaction effect between genotype and inflammation. Our data reinforce tissue specificity of expression in disease-associated candidate genes, highlight genes and gene pairs that are regulated in disease-relevant tissue and inflammation, and provide a foundation to advance the understanding of IBD pathogenesis.

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“…Inhibition of ABHD6 also increases 2-AG signaling through CB1 receptors in the CNS (77, 78). ABHD6 also has significant functions outside of the CNS e.g., (79, 80), which will complicate the application of ABHD6-based therapies to CNS disorders. ABHD12 is the other major hydrolytic enzyme suggested to be involved in the hydrolysis of 2-AG in brain.…”

Section: Endocannabinoid Degradationmentioning

confidence: 99%

An Introduction to the Endogenous Cannabinoid System

Mackie

2016

Biological Psychiatry

927

729

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The endocannabinoid system (ECS) is a widespread neuromodulatory system that plays important roles in central nervous system (CNS) development, synaptic plasticity, and the response to endogenous and environmental insults. The ECS is comprised of cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes responsible for the synthesis and degradation of the endocannabinoids. The most abundant cannabinoid receptor is the CB1 cannabinoid receptors, however CB2 cannabinoid receptors, transient receptor potential (TRP) channels, and peroxisome proliferator activated receptors (PPAR’s) are also engaged by some cannabinoids. Exogenous cannabinoids, such as tetrahydrocannabinol, produce their biological effects through their interactions with cannabinoid receptors. 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (anandamide) are the best-studied endogenous cannabinoids. Despite similarities in chemical structure, 2-AG and anandamide are synthesized and degraded by distinct enzymatic pathways, which impart fundamentally different physiological and pathophysiological roles to these two endocannabinoids. Because of the pervasive social use of cannabis and the involvement of endocannabinoids in a multitude of biological processes, much has been learned about the physiological and pathophysiological roles of the ECS. This review will provide an introduction to the ECS with an emphasis on its role in synaptic plasticity and how the ECS is perturbed in schizophrenia.

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PXKlocus in systemic lupus erythematosus: fine mapping and functional analysis reveals novel susceptibility geneABHD6

Abstract: These results confirm the genetic association of the locus 3p14.3 with SLE in Europeans and point to the ABHD6 and not PXK, as the major susceptibility gene in the region. We suggest a pathogenic mechanism mediated by the upregulation of ABHD6 in individuals carrying the SLE-risk variants.

Cited by 25 publications

References 41 publications

Cutting Edge: Dysregulated Endocannabinoid-Rheostat for Plasmacytoid Dendritic Cell Activation in a Systemic Lupus Endophenotype

Cutting Edge: Dysregulated Endocannabinoid-Rheostat for Plasmacytoid Dendritic Cell Activation in a Systemic Lupus Endophenotype

Characterization of candidate genes in inflammatory bowel disease–associated risk loci

An Introduction to the Endogenous Cannabinoid System

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