Autotaxin may play a Critical Role between the Genetic Risk Factors and Pathogenesis of SLE in Plasmacytoid Dendritic Cells

The importance of autotaxin, which catalyzes the production of lysophospholipids, has recently been recognized in various diseases including cancer and autoimmune diseases. We herein report our analysis of autotaxin in systemic lupus erythematosus (SLE), utilizing data from ImmuNexUT, a comprehensive database consisting of transcriptome data and expression quantitative trait locus (eQTL) data of immune cells from patients with immune-mediated disorders. Autotaxin was elevated in the serum of SLE patients, and the expression of ENPP2, which encodes autotaxin, is elevated in plasmacytoid dendritic cells (pDCs) of SLE patients compared to healthy controls. In weighted correlation network analysis, ENPP2 belonged to a module that correlated with disease activity. This module was enriched in interferon-associated genes and included genes whose expression is influenced by SNPs associated with SLE, suggesting that it is a key module connecting genetic risk factors of SLE with disease pathogenesis. The increased expression of ENPP2 in pDCs from SLE patients may be due to increased expression of interferon-associated genes and increased binding of STAT3 complexes to the regulatory region of ENPP2. Thus, autotaxin may play a critical role in connecting genetic risk factors of SLE to disease pathogenesis in pDCs.

Download Full-text

Chromatin architecture in addiction circuitry elucidates biological mechanisms underlying cigarette smoking and alcohol use traits.

10.1101/2021.03.18.436046 ◽

2021 ◽

Author(s):

Nancy Y.A Sey ◽

Benxia Hu ◽

Marina Iskhakova ◽

Huaigu Sun ◽

Neda Shokrian ◽

...

Keyword(s):

Risk Factors ◽

Alcohol Use ◽

Cigarette Smoking ◽

Genetic Risk ◽

Target Genes ◽

Association Studies ◽

Critical Role ◽

Genetic Risk Factors ◽

Genome Wide Association Studies ◽

Risk Genes

Cigarette smoking and alcohol use are among the most prevalent substances used worldwide and account for a substantial proportion of preventable morbidity and mortality, underscoring the public health significance of understanding their etiology. Genome-wide association studies (GWAS) have successfully identified genetic variants associated with cigarette smoking and alcohol use traits. However, the vast majority of risk variants reside in non-coding regions of the genome, and their target genes and neurobiological mechanisms are unknown. Chromosomal conformation mappings can address this knowledge gap by charting the interaction profiles of risk-associated regulatory variants with target genes. To investigate the functional impact of common variants associated with cigarette smoking and alcohol use traits, we applied Hi-C coupled MAGMA (H-MAGMA) built upon cortical and midbrain dopaminergic neuronal Hi-C datasets to GWAS summary statistics of nicotine dependence, cigarettes per day, problematic alcohol use, and drinks per week. The identified risk genes mapped to key pathways associated with cigarette smoking and alcohol use traits, including drug metabolic processes and neuronal apoptosis. Risk genes were highly expressed in cortical glutamatergic, midbrain dopaminergic, GABAergic, and serotonergic neurons, suggesting them as relevant cell types in understanding the mechanisms by which genetic risk factors influence cigarette smoking and alcohol use. Lastly, we identified pleiotropic genes between cigarette smoking and alcohol use traits under the assumption that they may reveal substance-agnostic, shared neurobiological mechanisms of addiction. The number of pleiotropic genes was ~26-fold higher in dopaminergic neurons than in cortical neurons, emphasizing the critical role of ascending dopaminergic pathways in mediating general addiction phenotypes. Collectively, brain region- and neuronal subtype-specific 3D genome architecture refines neurobiological hypotheses for smoking, alcohol, and general addiction phenotypes by linking genetic risk factors to their target genes.

Download Full-text

Genetic Risk Factors for Thrombosis in Systemic Lupus Erythematosus

The Journal of Rheumatology ◽

10.3899/jrheum.111451 ◽

2012 ◽

Vol 39 (8) ◽

pp. 1603-1610 ◽

Cited By ~ 17

Author(s):

RACHEL KAISER ◽

YONGHONG LI ◽

MONICA CHANG ◽

JOSEPH CATANESE ◽

ANN B. BEGOVICH ◽

...

Keyword(s):

Risk Factors ◽

Systemic Lupus Erythematosus ◽

Venous Thrombosis ◽

Lupus Erythematosus ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Antiphospholipid Antibody ◽

Systemic Lupus ◽

Discovery Cohort ◽

Thrombosis Risk

Objective.Thrombosis is a serious complication of systemic lupus erythematosus (SLE). We investigated whether genetic variants implicated in thrombosis pathways are associated with thrombosis among 2 ethnically diverse SLE cohorts.Methods.Our discovery cohort consisted of 1698 patients with SLE enrolled in the University of California, San Francisco, Lupus Genetics Project and our replication cohort included 1361 patients with SLE enrolled in the PROFILE cohort. Patients fulfilled American College of Rheumatology SLE criteria, and data relevant to thrombosis were available. Thirty-three single nucleotide polymorphisms (SNP) previously shown to be associated with risk of deep venous thrombosis in the general population or implicated in thrombosis pathways were genotyped and tested for association with thrombosis in bivariate allelic analyses. SNP with p < 0.1 in the bivariate analyses were further tested in multivariable logistic regression models adjusted for age, sex, disease duration, antiphospholipid antibody status, smoking, nephritis, and medications.Results.In the discovery cohort, 23% of patients with SLE experienced a thrombotic event. SNP in the following genes demonstrated association with thrombosis risk overall in the discovery or replication cohorts and were assessed using metaanalytic methods: factor V Leiden (FVL) rs6025 (OR 1.85, p = 0.02) and methylenetetrahydrofolate reductase (MTHFR) rs1801133 (OR 0.75, p = 0.04) in whites, and fibrinogen gamma (FGG) rs2066865 (OR 1.91, p = 0.01) in Hispanic Americans. SNP in these genes showed association with venous thrombosis risk in whites: MTHFR rs1801131 (OR 1.51, p = 0.01), MTHFR rs1801133 (OR 0.70, p = 0.04), FVL rs6025 (OR 2.69, p = 0.002), and FGG rs2066865 (OR 1.49, p = 0.02) in whites. A SNP in FGG rs2066865 (OR 2.19, p = 0.003) demonstrated association with arterial thrombosis risk in Hispanics.Conclusion.Our results implicate specific genetic risk factors for thrombosis in patients with SLE and suggest that genetic risk for thrombosis differs across ethnic groups.

Download Full-text

Clinical and genetic risk factors of herpes zoster in patients with systemic lupus erythematosus

Rheumatology International ◽

10.1007/s00296-003-0403-3 ◽

2003 ◽

Vol 25 (2) ◽

pp. 97-102 ◽

Cited By ~ 15

Author(s):

Tae-Young Kang ◽

Hye-Soon Lee ◽

Tae-Hwan Kim ◽

Jae-Bum Jun ◽

Dae-Hyun Yoo

Keyword(s):

Risk Factors ◽

Systemic Lupus Erythematosus ◽

Herpes Zoster ◽

Lupus Erythematosus ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Systemic Lupus

Download Full-text

Complete deficiencies of complement C4A and C4B including 2-bp insertion in codon 1213 are genetic risk factors of systemic lupus erythematosus in Thai populations

Journal of Autoimmunity ◽

10.1016/j.jaut.2005.04.004 ◽

2005 ◽

Vol 25 (1) ◽

pp. 77-84 ◽

Cited By ~ 18

Author(s):

Wannaporn Ittiprasert ◽

Surasak Kantachuvesiri ◽

Kanok Pavasuthipaisit ◽

Orawan Verasertniyom ◽

Lulin Chaomthum ◽

...

Keyword(s):

Risk Factors ◽

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Systemic Lupus

Download Full-text

Clinical and genetic risk factors for pneumonia in systemic lupus erythematosus

Arthritis & Rheumatism ◽

10.1002/art.22804 ◽

2007 ◽

Vol 56 (8) ◽

pp. 2679-2686 ◽

Cited By ~ 34

Author(s):

Brent W. Kinder ◽

Michelle M. Freemer ◽

Talmadge E. King ◽

Raymond F. Lum ◽

Joanne Nititham ◽

...

Keyword(s):

Risk Factors ◽

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Systemic Lupus

Download Full-text

Update on genetic risk factors for systemic lupus erythematosus and rheumatoid arthritis

Current Opinion in Rheumatology ◽

10.1097/00002281-200003000-00001 ◽

2000 ◽

Vol 12 (2) ◽

pp. 85-90 ◽

Cited By ~ 9

Author(s):

Lindsey A. Criswell ◽

Christopher I. Amos

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Systemic Lupus

Download Full-text

Current advances in lupus genetic and genomic studies in Asia

Lupus ◽

10.1177/0961203310376639 ◽

2010 ◽

Vol 19 (12) ◽

pp. 1374-1383 ◽

Cited By ~ 16

Author(s):

YJ Yuan ◽

XB Luo ◽

N. Shen

Keyword(s):

Risk Factors ◽

Ethnic Groups ◽

Lupus Erythematosus ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Disease Genes ◽

Asian Populations ◽

Genetic Components ◽

Genomic Studies ◽

Interferon Pathway

The genetic components in systemic lupus erythematosus (SLE) have long been established, however, it has been unclear for many years whether the same genetic risk factors for SLE are shared across different ethnic groups. Over the past few years, a number of genetic and genomic studies have been conducted in Asian populations to address this question. These studies have demonstrated that genetic heterogeneity does exist in SLE across different ethnic groups. With these studies, it has been established that a number of genes associated with SLE in Caucasians are also risk factors in Asians: HLA class II genes, STAT4, BANK1, BLK, IRF5, TNFSF4, ITGAM, etc., while there are also novel genetic risk factors identified by these studies in Asians, for instance, the ETS1 and WDFY4 in Chinese. For the genomic studies, the interferon signature has been confirmed as a major lupus molecular phenotype in Asians the same as in Caucasians; microRNA expression profiling and its novel role in regulating the interferon pathway has been first revealed in Asians. Further understanding of the function of lupus disease genes and delineating the key molecular pathway(s) will enhance the development of novel therapeutic targets and biomarkers for individualized clinical management for lupus patients.

Download Full-text

Neuronal ROS-induced glial lipid droplet formation is altered by loss of Alzheimer’s disease–associated genes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2112095118 ◽

2021 ◽

Vol 118 (52) ◽

pp. e2112095118

Author(s):

Matthew J. Moulton ◽

Scott Barish ◽

Isha Ralhan ◽

Jinlan Chang ◽

Lindsey D. Goodman ◽

...

Keyword(s):

Risk Factors ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Risk ◽

Critical Role ◽

Lipid Synthesis ◽

Genetic Risk Factors ◽

Lipid Transfer ◽

Neuroprotective Effects ◽

Disease Associated Genes

A growing list of Alzheimer’s disease (AD) genetic risk factors is being identified, but the contribution of each variant to disease mechanism remains largely unknown. We have previously shown that elevated levels of reactive oxygen species (ROS) induces lipid synthesis in neurons leading to the sequestration of peroxidated lipids in glial lipid droplets (LD), delaying neurotoxicity. This neuron-to-glia lipid transport is APOD/E-dependent. To identify proteins that modulate these neuroprotective effects, we tested the role of AD risk genes in ROS-induced LD formation and demonstrate that several genes impact neuroprotective LD formation, including homologs of human ABCA1, ABCA7, VLDLR, VPS26, VPS35, AP2A, PICALM, and CD2AP. Our data also show that ROS enhances Aβ42 phenotypes in flies and mice. Finally, a peptide agonist of ABCA1 restores glial LD formation in a humanized APOE4 fly model, highlighting a potentially therapeutic avenue to prevent ROS-induced neurotoxicity. This study places many AD genetic risk factors in a ROS-induced neuron-to-glia lipid transfer pathway with a critical role in protecting against neurotoxicity.

Download Full-text

Circulating dendritic cells of multiple sclerosis patients are proinflammatory and their frequency is correlated with MS-associated genetic risk factors

Multiple Sclerosis Journal ◽

10.1177/1352458513505352 ◽

2013 ◽

Vol 20 (5) ◽

pp. 548-557 ◽

Cited By ~ 18

Author(s):

Kristof Thewissen ◽

Amber H Nuyts ◽

Nathalie Deckx ◽

Bart Van Wijmeersch ◽

Guy Nagels ◽

...

Keyword(s):

Risk Factors ◽

Multiple Sclerosis ◽

Dendritic Cells ◽

Genetic Risk ◽

Ex Vivo ◽

Study Groups ◽

Genetic Risk Factors ◽

Healthy Controls ◽

Multiple Sclerosis Patients

Background: The role of the adaptive immune system and more specifically T cells in the pathogenesis of multiple sclerosis (MS) has been studied extensively. Emerging evidence suggests that dendritic cells (DCs), which are innate immune cells, also contribute to MS. Objectives: This study aimed to characterize circulating DC populations in MS and to investigate the contribution of MS-associated genetic risk factors to DCs. Methods: Ex vivo analysis of conventional (cDCs) and plasmacytoid DCs (pDCs) was carried out on peripheral blood of MS patients ( n = 110) and age- and gender-matched healthy controls ( n = 112). Results: Circulating pDCs were significantly decreased in patients with chronic progressive MS compared to relapsing–remitting MS and healthy controls. While no differences in cDCs frequency were found between the different study groups, HLA-DRB1*1501+ MS patients and patients not carrying the protective IL-7Rα haplotype 2 have reduced frequencies of circulating cDCs and pDCs, respectively. MS-derived DCs showed enhanced IL-12p70 production upon TLR ligation and had an increased expression of the migratory molecules CCR5 and CCR7 as well as an enhanced in vitro chemotaxis. Conclusion: DCs in MS are in a pro-inflammatory state, have a migratory phenotype and are affected by genetic risk factors, thereby contributing to pathogenic responses.

Download Full-text