Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk

Lassen, Kara G.; McKenzie, Craig; Mari, Muriel; Murano, Tatsuro; Begun, Jakob; Baxt, Leigh A.; Goel, Gautam; Villablanca, Eduardo J.; Kuo, Szu Yu; Huang, Hailiang; Macia, Laurence; Bhan, Atul K.; Batten, Marcel; Daly, Mark J.; Reggiori, Fulvio; Mackay, Charles R.; Xavier, Ramnik J.

doi:10.1016/j.immuni.2016.05.007

Cited by 113 publications

(125 citation statements)

References 63 publications

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“…Notably, of the 622 genes in this sub-network, there were 102 (16.4%) IBD-associated genes, a 2.5-fold enrichment compared to the full intestinal network (hypergeometric P=7.6×10 −8 ). Importantly, LRRK2 was closely connected to GPR65 , a proton-sensing G-protein coupled receptor associated with IBD and altered lysosomal function (24) and to HLA-DPA1 , an α-subunit of the major histocompatibility complex protein/peptide-antigen receptor and a graft-versus-host disease antigen complex linked to both IBD(25) and PD (26). …”

Section: Resultsmentioning

confidence: 99%

“…SLC2A13 (solute carrier family 2 member 13) is a glucose transporter that is not expressed in the gut or the immune system and has not been previously linked to IBD, further suggesting that the observed 12q12 signal is driven by the LRRK2 gene. Intriguingly, LRRK2 was tightly linked with GPR65 , where the IBD-associated risk allele, I231L, is associated with impaired lysosomal function (24) and HLA-DPA1 , with variants in this locus linked to both IBD (25) and PD (26). …”

Section: Discussionmentioning

confidence: 99%

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Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

et al. 2018

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Crohn’s disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of non-synonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2,066 CD cases and 3,633 healthy controls. We detected association signals in the LRRK2 gene that conferred CD risk (N2081D variant, P=9.5×10−10) or protection (N551K variant, tagging R1398H-associated haplotype, P=3.3×10−8). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinson’s disease (PD), and healthy controls revealed extensive pleiotropy, with similar genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant is associated with increased kinase activity, whereas neither N551K nor R1398H on the protective haplotype altered kinase activity. R1398H, but not N551K, increased GTPase activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

et al. 2018

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“…We identified 34 gene pairs (36 unique genes) with significant changes in correlation from the healthy state to disease uninflamed and inflamed states (Supplemental Table 6). Recent studies offer insights into potential roles in IBD-relevant pathways for the proteins encoded by these genes, such as C1ORF106 in autophagy- dependent intracellular pathogen defense (37) and C5ORF30 in negative regulation of immune and inflammatory pathways (38), but the activities of many of the genes remain to be studied in the context of IBD or other immune-mediated diseases.…”

Section: Resultsmentioning

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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“…Our data now provide evidence that an inability to interpret the immune epigenome due to loss of SP140 contributes to IBD. Furthermore, it adds SP140 to a number of other IBD-associated genes ( NOD2 , ATG16L1 , GPR65 , and AIM2 ) that drive innate immunity in the intestine and whose loss or variation results in impaired barrier defense, decreased cytokine production, and an inability to maintain gut microbial balance, which ultimately enhances intestinal inflammation (26, 28–30, 51). …”

Section: Discussionmentioning

confidence: 99%

Maintenance of macrophage transcriptional programs and intestinal homeostasis by epigenetic reader SP140

et al. 2017

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Epigenetic “readers” that recognize defined posttranslational modifications on histones have become desirable therapeutic targets for cancer and inflammation. SP140 is one such bromodomain and plant homeodomain (PHD)–containing reader with immune-restricted expression, and single-nucleotide polymorphisms (SNPs) within SP140 associate with Crohn’s disease (CD). However, the function of SP140 and the consequences of disease-associated SP140 SNPs have remained unclear. We show that SP140 is critical for transcriptional programs that uphold the macrophage state. SP140 preferentially occupies promoters of silenced, lineage-inappropriate genes bearing the histone modification H3K27me3, such as the HOXA cluster in human macrophages, and ensures their repression. Depletion of SP140 in mouse or human macrophages resulted in severely compromised microbe-induced activation. We reveal that peripheral blood mononuclear cells (PBMCs) or B cells from individuals carrying CD-associated SNPs within SP140 have defective SP140 messenger RNA splicing and diminished SP140 protein levels. Moreover, CD patients carrying SP140 SNPs displayed suppressed innate immune gene signatures in a mixed population of PBMCs that stratified them from other CD patients. Hematopoietic-specific knockdown of Sp140 in mice resulted in exacerbated dextran sulfate sodium (DSS)–induced colitis, and low SP140 levels in human CD intestinal biopsies correlated with relatively lower intestinal innate cytokine levels and improved response to anti–tumor necrosis factor (TNF) therapy. Thus, the epigenetic reader SP140 is a key regulator of macrophage transcriptional programs for cellular state, and a loss of SP140 due to genetic variation contributes to a molecularly defined subset of CD characterized by ineffective innate immunity, normally critical for intestinal homeostasis.

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Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk

Cited by 113 publications

References 63 publications

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease

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

Maintenance of macrophage transcriptional programs and intestinal homeostasis by epigenetic reader SP140

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