Polymorphisms within the ARNT2 and CX3CR1 Genes Are Associated with the Risk of Developing Invasive Aspergillosis.

Invasive aspergillosis (IA) is a life-threatening infection that affects an increasing number of patients undergoing chemotherapy or allo-transplantation, and recent studies have shown that genetic factors contribute to disease susceptibility. In this two-stage, population-based, case-control study, we evaluated whether 7 potentially functional single nucleotide polymorphisms (SNPs) within the ARNT2 and CX3CR1 genes influence the risk of IA in high-risk hematological patients. We genotyped selected SNPs in a cohort of 500 hematological patients (103 of those had been diagnosed with proven or probable IA), and we evaluated their association with the risk of developing IA. The association of the most interesting markers of IA risk was then validated in a replication population, including 474 subjects (94 IA and 380 non-IA patients). Functional experiments were also performed to confirm the biological relevance of the most interesting markers. The meta-analysis of both populations showed that carriers of the ARNT2rs1374213G, CX3CR1rs7631529A, and CX3CR1rs9823718G alleles (where the RefSeq identifier appears as a subscript) had a significantly increased risk of developing IA according to a log-additive model (P value from the meta-analysis [PMeta] = 9.8 · 10-5, PMeta = 1.5 · 10-4, and PMeta =7.9 · 10-5, respectively). Haplotype analysis also confirmed the association of the CX3CR1 haplotype with AG CGG with an increased risk of IA (P = 4.0 · 10-4). Mechanistically, we observed that monocyte-derived macrophages (MDM) from subjects carrying the ARNTR2rs1374213G allele or the GG genotype showed a significantly impaired fungicidal activity but that MDM from carriers of the ARNT2rs1374213G and CX3CR1rs9823718G or CX3CR1rs7631529A alleles had deregulated immune responses to Aspergillus conidia. These results, together with those from expression quantitative trait locus (eQTL) data browsers showing a strong correlation of the CX3CR1rs9823718G allele with lower levels of CX3CR1 mRNA in whole peripheral blood (P = 2.46 · 10-7) and primary monocytes (P = 4.31 · 10-7), highlight the role of the ARNT2 and CX3CR1 loci in modulating and predicting IA risk and provide new insights into the host immune mechanisms involved in IA development.

Making sense of parameter estimation and model simulation in bioprocesses.

Most articles that report fitted parameters for kinetic models do not include meaningful statistical information. This study demonstrates the importance of reporting a complete statistical analysis and shows a methodology to perform it, using functionalities implemented in computational tools. As an example, alginate production is studied in a batch stirred-tank fermenter and modeled using the kinetic model proposed by Klimek and Ollis (1980). The model parameters and their 95% confidence intervals are estimated by nonlinear regression. The significance of the parameters value is checked using a hypothesis test. The uncertainty of the parameters is propagated to the output model variables through prediction intervals, showing that the kinetic model of Klimek and Ollis (1980) can simulate with high certainty the dynamic of the alginate production process. Finally, the results obtained in other studies are compared to show how the lack of statistical analysis can hold back a deeper understanding about bioprocesses.

Partition coefficients of methylated DNA bases obtained from free energy calculations with molecular electron density derived atomic charges.

Partition coefficients serve in various areas as pharmacology and environmental sciences to predict the hydrophobicity of different substances. Recently, they have also been used to address the accuracy of force fields for various organic compounds and specifically the methylated DNA bases. In this study, atomic charges were derived by different partitioning methods (Hirshfeld and Minimal Basis Iterative Stockholder) directly from the electron density obtained by electronic structure calculations in a vacuum, with an implicit solvation model or with explicit solvation taking the dynamics of the solute and the solvent into account. To test the ability of these charges to describe electrostatic interactions in force fields for condensed phases, the original atomic charges of the AMBER99 force field were replaced with the new atomic charges and combined with different solvent models to obtain the hydration and chloroform solvation free energies by molecular dynamics simulations. Chloroform-water partition coefficients derived from the obtained free energies were compared to experimental and previously reported values obtained with the GAFF or the AMBER-99 force field. The results show that good agreement with experimental data is obtained when the polarization of the electron density by the solvent has been taken into account, and when the energy needed to polarize the electron density of the solute has been considered in the transfer free energy. These results were further confirmed by hydration free energies of polar and aromatic amino acid side chain analogs. Comparison of the two partitioning methods, Hirshfeld-I and Minimal Basis Iterative Stockholder (MBIS), revealed some deficiencies in the Hirshfeld-I method related to the unstable isolated anionic nitrogen pro-atom used in the method. Hydration free energies and partitioning coefficients obtained with atomic charges from the MBIS partitioning method accounting for polarization by the implicit solvation model are in good agreement with the experimental values. © 2018 Wiley Periodicals, Inc.

CymeR: cytometry analysis using KNIME, docker and R.

Summary: Here we present open-source software for the analysis of high-dimensional cytometry data using state of the art algorithms. Importantly, use of the software requires no programming ability, and output files can either be interrogated directly in CymeR or they can be used downstream with any other cytometric data analysis platform. Also, because we use Docker to integrate the multitude of components that form the basis of CymeR, we have additionally developed a proof-of-concept of how future open-source bioinformatic programs with graphical user interfaces could be developed. Availability and Implementation: CymeR is open-source software that ties several components into a single program that is perhaps best thought of as a self-contained data analysis operating system. Please see https://github.com/bmuchmore/CymeR/wiki for detailed installation instructions. Contact: brian.muchmore@genyo.es or marta.alarcon@genyo.es.

[Face protective patches do not reduce facial pressure ulcers in a simulated model of non-invasive ventilation]. / Uso de parches protectores faciales no reduce la presión facial en un modelo simulado de ventilación mecánica no invasiva.

Noninvasive ventilation (NIV) frequently involves the development of facial pressure ulcers (FPU). Its prevention considers the empirical use of protective patches between skin and mask, in order to reduce the pressure exerted by it. OBJECTIVES: To evaluate the effect of protective patches on the pressure exerted by the facial mask, and its impact on the programmed ventilatory parameters. METHOD: Bilevel NIV simulated model using full face mask in phantom with a physiological airway (ALS PRO +) in supine position. Forehead, chin and cheekbones pressure were measured using 3 types of standard protective patches versus a control group using pressure sensors (Interlinks Electronics®). The values obtained with the protective patches-mask model were evaluated in the programmed variables maximum inspiratory flow (MIF)), expired tidal volume (Vte) and positive inspiratory pressure (IPAP), with Trilogy 100 ventilator, Respironics®. The programming and recording of the variables was carried out in 8 opportunities in each group by independent operators. RESULTS: There was no decrease in facial pressure with any of the protective patches compared to the control group. Moltopren increased facial pressure at all support points (p < 0.001), increased leakage, it decreased MIF, Vte and IPAP (p < 0.001). Hydrocolloid patches increased facial pressure only in the left cheekbone, increased leakage and decreased MIF. Polyurethane patches did not produce changes in facial pressure or ventilatory variables. CONCLUSION: The use of protective patches of moltopren, hydrocolloid and polyurethane transparent did not contribute to the decrease of the facial pressure. A deleterious effect of the moltopren and hydrocolloid patches was observed on the administration of ventilatory variables, concluding that the non-use of the protective patches allowed a better administration of the programmed parameters.

The SLE variant Ala71Thr of BLK severely decreases protein abundance and binding to BANK1 through impairment of the SH3 domain function.

The B-lymphocyte kinase (BLK) gene is associated genetically with several human autoimmune diseases including systemic lupus erythematosus. We recently described that the genetic risk is given by two haplotypes: one covering several strongly linked single-nucleotide polymorphisms within the promoter of the gene that correlated with low transcript levels, and a second haplotype that includes a rare nonsynonymous variant (Ala71Thr). Here we show that this variant, located within the BLK SH3 domain, is a major determinant of protein levels. In vitro analyses show that the 71Thr isoform is hyperphosphorylated and promotes kinase activation. As a consequence, BLK is ubiquitinated, its proteasomal degradation enhanced and the average life of the protein is reduced by half. Altogether, these findings suggest that an intrinsic autoregulatory mechanism previously unappreciated in BLK is disrupted by the 71Thr substitution. Because the SH3 domain is also involved in protein interactions, we sought for differences between the two isoforms in trafficking and binding to protein partners. We found that binding of the 71Thr variant to the adaptor protein BANK1 is severely reduced. Our study provides new insights on the intrinsic regulation of BLK activation and highlights the dominant role of its SH3 domain in BANK1 binding.

The microphysics of collisionless shock waves.

Collisionless shocks, that is shocks mediated by electromagnetic processes, are customary in space physics and in astrophysics. They are to be found in a great variety of objects and environments: magnetospheric and heliospheric shocks, supernova remnants, pulsar winds and their nebulæ, active galactic nuclei, gamma-ray bursts and clusters of galaxies shock waves. Collisionless shock microphysics enters at different stages of shock formation, shock dynamics and particle energization and/or acceleration. It turns out that the shock phenomenon is a multi-scale non-linear problem in time and space. It is complexified by the impact due to high-energy cosmic rays in astrophysical environments. This review adresses the physics of shock formation, shock dynamics and particle acceleration based on a close examination of available multi-wavelength or in situ observations, analytical and numerical developments. A particular emphasis is made on the different instabilities triggered during the shock formation and in association with particle acceleration processes with regards to the properties of the background upstream medium. It appears that among the most important parameters the background magnetic field through the magnetization and its obliquity is the dominant one. The shock velocity that can reach relativistic speeds has also a strong impact over the development of the micro-instabilities and the fate of particle acceleration. Recent developments of laboratory shock experiments has started to bring some new insights in the physics of space plasma and astrophysical shock waves. A special section is dedicated to new laser plasma experiments probing shock physics.

Genetic analysis of the pathogenic molecular sub-phenotype interferon-alpha identifies multiple novel loci involved in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by inflammation of multiple organ systems and dysregulated interferon responses. SLE is both genetically and phenotypically heterogeneous, greatly reducing the power of case-control studies in SLE. Elevated circulating interferon-alpha (IFN-α) is a stable, heritable trait in SLE, which has been implicated in primary disease pathogenesis. About 40-50% of patients have high IFN-α, and high levels correspond with clinical differences. To study genetic heterogeneity in SLE, we performed a case-case study comparing patients with high vs low IFN-α in over 1550 SLE cases, including genome-wide association study and replication cohorts. In meta-analysis, the top associations in European ancestry were protein kinase, cyclic GMP-dependent, type I (PRKG1) rs7897633 (P(Meta) = 2.75 × 10(-8)) and purine nucleoside phosphorylase (PNP) rs1049564 (P(Meta) = 1.24 × 10(-7)). We also found evidence for cross-ancestral background associations with the ankyrin repeat domain 44 (ANKRD44) and pleckstrin homology domain containing, family F member 2 gene (PLEKHF2) loci. These loci have not been previously identified in case-control SLE genetic studies. Bioinformatic analyses implicated these loci functionally in dendritic cells and natural killer cells, both of which are involved in IFN-α production in SLE. As case-control studies of heterogeneous diseases reach a limit of feasibility with respect to subject number and detectable effect size, the study of informative pathogenic sub-phenotypes becomes an attractive strategy for genetic discovery in complex disease.

Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study.

A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10(-4) < P < 4.15 × 10(-2)), where we further identified a five-marker haplotype (rs12141731-rs2949655-rs16859085-rs12144621-rs858554; G-G-A-G-A; P(hap) = 2.12 × 10(-5)) that exceeded the most associated single SNP rs858554 (minor allele frequency in controls = 13%; P = 4.99 × 10(-4), odds ratio = 1.32) in significance. Imputation and subsequent association analysis showed evidence of association (P < 0.05) at 27 additional SNPs within intron 1. Cross-ethnic meta-analysis, assuming an additive genetic model adjusted for population proportions, showed five SNPs with significant P-values (1.40 × 10(-3) < P< 3.97 × 10(-2)), with one (rs704848) remaining significant after Bonferroni correction (P(meta) = 2.66 × 10(-2)). Our study independently confirms and extends the association of SLE with CD247, which is shared by various autoimmune disorders and supports a common T-cell-mediated mechanism.

Lupus in Latin-American patients: lessons from the GLADEL cohort.

The need for comprehensive published epidemiologic and clinical data from Latin American systemic lupus erythematosus (SLE) patients motivated the late Dr Alarcón-Segovia and other Latin American professionals taking care of these patients to spearhead the creation of the G: rupo L: atino A: mericano D: e E: studio del L: upus (GLADEL) cohort in 1997. This inception cohort recruited a total of 1480 multiethnic (Mestizo, African-Latin American (ALA), Caucasian and other) SLE patients diagnosed within two years from the time of enrollment from 34 Latin American centers with expertise in the diagnosis and management of this disease. In addition to the initial 2004 description of the cohort, GLADEL has contributed to improving our knowledge about the course and outcome of lupus in patients from this part of the Americas. The major findings from this cohort are highlighted in this review. They have had important clinical implications for the adequate care of SLE patients both in Latin America and worldwide where these patients may have emigrated.

[High flow nasal cannula in infants: Experience in a critical patient unit]. / Cánula nasal de alto flujo en lactantes: experiencia en una unidad de paciente crítico.

INTRODUCTION: The high flow nasal cannula (HFNC) is a method of respiratory support that is increasingly being used in paediatrics due to its results and safety. OBJECTIVE: To determine the efficacy of HFNC, as well as to evaluate the factors related to its failure and complications associated with its use in infants. PATIENTS AND METHOD: An analysis was performed on the demographic, clinical, blood gas, and radiological data, as well as the complications of patients connected to a HFNC in a critical care unit between June 2012 and September 2014. A comparison was made between the patients who failed and those who responded to HFNC. A failure was considered as the need for further respiratory support during the first 48hours of connection. The Kolmogorov Smirnov, Mann-Whitney U, chi squared and the Exact Fisher test were used, as well as correlations and a binary logistic regression model for P≤.05. RESULTS: The study included 109 patients, with a median age and weight: 1 month (0.2-20 months) and 3.7kg (2-10kg); 95 percentile: 3.7 months and 5.7kg, respectively. The most frequent diagnosis and radiological pattern was bronchiolitis (53.2%) and interstitial infiltration (56%). Around 70.6% responded. There was a significant difference between failure and response in the diagnosis (P=.013), radiography (P=018), connection context (P<.0001), pCO2 (median 40.7mmHg [15.4-67 mmHg] versus 47.3mmHg [28.6-71.3mmHg], P=.004) and hours on HFNC (median 60.75hrs [5-621.5 hrs] versus 10.5hrs [1-29 hrs], P<.0001). The OR of the PCO2 ≥ 55mmHg for failure was 2.97 (95% CI; 1.08-8.17; P=.035). No patient died and no complications were recorded. CONCLUSION: The percentage success observed was similar to that published. In this sample, the failure of HFNC was only associated with an initial pCO2 ≥ 55mmHg. On there being no complications reported as regards it use, it is considered safe, although a randomised, controlled, multicentre study is required to compare and contrast these results.

GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region.

In a genome-wide association study (GWAS) of individuals of European ancestry afflicted with systemic lupus erythematosus (SLE) the extensive utilization of imputation, step-wise multiple regression, lasso regularization and increasing study power by utilizing false discovery rate instead of a Bonferroni multiple test correction enabled us to identify 13 novel non-human leukocyte antigen (HLA) genes and confirmed the association of four genes previously reported to be associated. Novel genes associated with SLE susceptibility included two transcription factors (EHF and MED1), two components of the NF-κB pathway (RASSF2 and RNF114), one gene involved in adhesion and endothelial migration (CNTN6) and two genes involved in antigen presentation (BIN1 and SEC61G). In addition, the strongly significant association of multiple single-nucleotide polymorphisms (SNPs) in the HLA region was assigned to HLA alleles and serotypes and deconvoluted into four primary signals. The novel SLE-associated genes point to new directions for both the diagnosis and treatment of this debilitating autoimmune disease.

MHC associations with clinical and autoantibody manifestations in European SLE.

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease affecting multiple organ systems and characterized by autoantibody formation to nuclear components. Although genetic variation within the major histocompatibility complex (MHC) is associated with SLE, its role in the development of clinical manifestations and autoantibody production is not well defined. We conducted a meta-analysis of four independent European SLE case collections for associations between SLE sub-phenotypes and MHC single-nucleotide polymorphism genotypes, human leukocyte antigen (HLA) alleles and variant HLA amino acids. Of the 11 American College of Rheumatology criteria and 7 autoantibody sub-phenotypes examined, anti-Ro/SSA and anti-La/SSB antibody subsets exhibited the highest number and most statistically significant associations. HLA-DRB1*03:01 was significantly associated with both sub-phenotypes. We found evidence of associations independent of MHC class II variants in the anti-Ro subset alone. Conditional analyses showed that anti-Ro and anti-La subsets are independently associated with HLA-DRB1*0301, and that the HLA-DRB1*03:01 association with SLE is largely but not completely driven by the association of this allele with these sub-phenotypes. Our results provide strong evidence for a multilevel risk model for HLA-DRB1*03:01 in SLE, where the association with anti-Ro and anti-La antibody-positive SLE is much stronger than SLE without these autoantibodies.

The dual effect of the lupus-associated polymorphism rs10516487 on BANK1 gene expression and protein localization.

Numerous loci have been found genetically associated with complex diseases, but only in a few cases has the functional variant and the molecular mechanism behind it been identified. Recently, the association of the BANK1 gene with systemic lupus erythematosus (SLE) was described. Here, we investigated the role of the associated polymorphisms on gene function and found that SNP rs17266594 located in the branch point consensus sequence has negligible effect on splicing or gene expression. The non-synonymous SNP rs10516487 located in exon 2 influenced splicing efficiency by creating an exonic splicing enhancer site for the SRp40 factor. Further, this same SNP generates protein isoforms with differential and measurable self-association properties. The full-length protein isoform containing the R61 variant forms larger protein scaffold complexes in the cell cytoplasm compared with the protective BANK1-61H variant. We also observed that, contrary to the full-length isoforms, the short Δ2 isoform of BANK1 displays a homogeneous cytoplasmic distribution, underscoring the potential role of the exon 2-coded protein domain in the scaffolding function of BANK1. We provide evidence that the non-synonymous SNP rs10516487 (G>A; R61H) shows a dual nature by first, influencing mRNA splicing and consequently the quantity of protein, and, second, by producing a risk variant-containing protein isoform with increased potential for multimerization.

Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene.

A recent genome-wide association study revealed a variant (rs2431697) in an intergenic region, between the pituitary tumor-transforming 1 (PTTG1) and microRNA (miR-146a) genes, associated with systemic lupus erythematosus (SLE) susceptibility. Here, we analyzed with a case-control design this variant and other candidate polymorphisms in this region together with expression analysis in order to clarify to which gene this association is related. The single-nucleotide polymorphisms (SNPs) rs2431697, rs2910164 and rs2277920 were genotyped by TaqMan assays in 1324 SLE patients and 1453 healthy controls of European ancestry. Genetic association was statistically analyzed using Unphased. Gene expression of PTTG1, the miRNAs miR-3142 and primary and mature forms of miR-146a in peripheral blood mononuclear cells (PBMCs) were assessed by quantitative real-time PCR. Of the three variants analyzed, only rs2431697 was genetically associated with SLE in Europeans. Gene expression analysis revealed that this SNP was not associated with PTTG1 expression levels, but with the microRNA-146a, where the risk allele correlates with lower expression of the miRNA. We replicated the genetic association of rs2341697 with SLE in a case-control study in Europeans and demonstrated that the risk allele of this SNP correlates with a downregulation of the miRNA 146a, potentially important in SLE etiology.

Role of MYH9 and APOL1 in African and non-African populations with lupus nephritis.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and organ damage. Lupus nephritis (LN) is one of the most severe manifestations of SLE. Multiple studies reported associations between renal diseases and variants in the non-muscle myosin heavy chain 9 (MYH9) and the neighboring apolipoprotein L 1 (APOL1) genes. We evaluated 167 variants spanning MYH9 for association with LN in a multiethnic sample. The two previously identified risk variants in APOL1 were also tested for association with LN in European-Americans (EAs) (N = 579) and African-Americans (AAs) (N = 407). Multiple peaks of association exceeding a Bonferroni corrected P-value of P < 2.03 × 10(-3) were observed between LN and MYH9 in EAs (N = 4620), with the most pronounced association at rs2157257 (P = 4.7 × 10(-4), odds ratio (OR) = 1.205). A modest effect with MYH9 was also detected in Gullah (rs8136069, P = 0.0019, OR = 2.304). No association between LN and MYH9 was found in AAs, Asians, Amerindians or Hispanics. This study provides the first investigation of MYH9 in LN in non-Africans and of APOL1 in LN in any population, and presents novel insight into the potential role of MYH9 in LN in EAs.

A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (P<1 × 10(-4)). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P=0.0004) and UBCH7 protein expression (P=0.0068). The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.

Association study of IRAK-M and SIGIRR genes with SLE in a large European-descent population.

OBJECTIVE: The aim of this study was to evaluate the relevance of genetic variants of interleukin receptor-associated kinase-M (IRAK-M) (rs11465955, rs1624395, rs1152888 and rs1370128) and single immunoglobulin IL1-1R-related molecule (SIGIRR) (rs3210908) genes in systemic lupus erythematosus (SLE) in four independent European-descent populations. METHODS: Our study population consisted of a total of 2033 SLE patients and 2357 healthy controls from Spain, Germany, Italy and Argentina. The genotyping was performed using a polymerase chain reaction (PCR) system with pre-developed TaqMan allelic discrimination assay. Genetic association between the genotyped markers was determined by PLINK v1.07. RESULTS: After a meta-analysis including these four populations, a trend of association between rs11465955 (P(meta) (-analysis) = 0.06), rs1370128 (P(meta) (-analysis) = 0.07) and rs1624395 (P(meta) (-analysis) = 0.06) polymorphisms was found. However, these differences did not reach statistical significance. In addition, we did not find any association between SLE and the rs1152888 IRAK-M (P(meta) (-analysis) = 0.13) and the rs3210908 SIGIRR (P(meta) (-analysis) = 0.40) polymorphisms after the meta-analysis. No evidence of association with IRAK-M haplotypes was found. CONCLUSION: These results suggest that the tested variations of IRAK-M and SIGIRR genes do not confer a relevant role in the susceptibility to SLE in European-descent populations.

Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3'-5' exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi-Goutières syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in ∼8370 patients with SLE and ∼7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)>10%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P=0.0008, OR=1.73, 95% CI=1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P=2.99E-13, OR=5.2, 95% CI=3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis.