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Background: Most epidemiological studies of hidradenitis suppurativa (HS) have described homogeneous patient populations., Objective: To characterize demographics, modifiable health behaviors, and comorbidities of HS patients within a diverse cohort., Methods: A retrospective cross-sectional study of 13,130 HS patients within a healthcare system was conducted., Results: A female sex bias of ∼3:1 in all racial/ethnic subgroups was observed. Black/African American (AA) patients had a lower age at HS diagnosis than White patients (37.1 years vs 39.4 years, P<0.001). A higher proportion of Black/AA females than White females with HS had BMI in the obese range (69.9% vs 56.5%; P=0.03). In contrast, fewer Black/African American males with HS had a BMI in the obese range compared to White males (51.4% vs. 61.0%; P<0.001). More Black/AA patients than White patients with HS had congestive heart failure (OR=2.10, CI=1.19-3.78; P<0.05), chronic pulmonary disease (OR=1.34; CI=1.02-1.78; P<0.05), diabetes with chronic complication (OR=1.73; CI=1.16-2.60; P<0.05), renal disease (OR=2.66; CI=1.67-4.34; P<0.05), and Charlson Comorbidity Index score ≥4 (OR=1.67; CI=1.09-2.58; P<0.05). Furthermore, male patients were more likely than female patients to have renal disease (OR=2.62; CI 1.66-4.14; P<0.05)., Limitations: A single-center study., Conclusion: Subgroups of HS patients had significant differences in demographics, risk factors, and comorbid conditions., (Copyright © 2024. Published by Elsevier Inc.)

Competing Interests: Conflicts of interest Dr Hamzavi is a consultant for AbbVie, Pfizer, Incyte, UCB, Boehringer Ingelheim, Sonoma, Union Therapeutics, Novartis, Jansen, Avita, and Galderma; investigator for Lenicura, Pfizer, Incyte, Avita, and L'Oréal/La Roche-Posay; and past president of the HS Foundation and Global Vitiligo Foundation. Dr Huggins has been an investigator for Arcutis, Avita, Clinuvel, Incyte, Pfizer, Mitsubishi, and The Immune Tolerance Network. He is also the Treasurer of the Global Vitiligo Foundation (GVF) and the chair of the GVF community committee and served on advisory boards for Incyte and Avita. Drs Young, Adrianto, Zhou, and Mi and authors Lu and Dai have no conflicts of interest to declare.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful nodules, abscesses, and scarring, predominantly affecting intertriginous regions and it is often underdiagnosed. This study aimed to utilize single cell RNA and cell-surface protein sequencing (CITE-Seq) to delineate the immune composition of circulating cells in Hidradenitis suppurativa (HS) peripheral blood compared to healthy controls. CITE-Seq was used to analyze the gene and protein expression profiles of peripheral blood mononuclear cells (PBMCs) from 9 HS and 29 healthy controls. The study identified significant differences cell composition between HS patients and healthy controls, including increased proportions of CD14+ and CD16+ monocytes, cDC2, plasmablasts, and proliferating CD4+ T cells in HS patients. Differential expression analysis revealed upregulation of inflammatory markers such as TNF, IL1B , and NF-κB in monocytes, as well as chemokines and cell adhesion molecules involved in immune cell recruitment and tissue infiltration. Pathway enrichment analysis highlighted the involvement of IL-17, IL-26 and TNF signaling pathways in HS pathogenesis. Machine learning identified key markers for diagnostics and therapeutic development. The findings also support the potential for machine learning models to aid in the diagnosis of HS based on immune cell markers. These insights may inform future therapeutic strategies targeting specific immune pathways in HS., Competing Interests: Conflict of Interest WL has received research grant funding from Abbvie, Amgen, Janssen, Leo, Novartis, Pfizer, Regeneron, and TRex Bio. CP has received honoraria and/or travel support from MSD, BMS, Pierre Fabre, MERCK, Sanofi, Almirall, AbbVie, Pelpharma, Amgen, DSD, Takeda, Pfizer, Novartis, Leo, Janssen, Astra Zeneca, and Boehringer Ingelheim. AW received honoraria and travel support from AbbVie, Amgen, Biogen, Janssen, Leo, Novartis, UCB and Sanofi. HN has received grant support from AbbVie; consulting fees from 23andme, Abbvie, Aristea Therapeutics, Nimbus Therapeutics, Medscape, Sonoma Biotherapeutics, DAVA Oncology, Boehringer Ingelheim, Union Chimique Belge’s (UCB) and Novartis; investigator fees from Pfizer; and holds shares in Radera, Inc. She is also an Associate Editor for JAMA Dermatology and Vice President of the Hidradenitis Suppurativa Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Objective: The objective of this study is to assess the effects of social determinants of health (SDOH) and race-ethnicity on readmission and to investigate the potential for geospatial clustering of patients with a greater burden of SDOH that could lead to a higher risk of readmission., Design: A retrospective study of inpatients at five hospitals within Henry Ford Health (HFH) in Detroit, Michigan from November 2015 to December 2018 was conducted., Setting: This study used an adult inpatient registry created based on HFH electronic health record data as the data source. A subset of the data elements in the registry was collected for data analyses that included readmission index, race-ethnicity, six SDOH variables and demographics and clinical-related variables., Participants: The cohort was composed of 248 810 admission patient encounters with 156 353 unique adult patients between the study time period. Encounters were excluded if they did not qualify as an index admission for all payors based on the Centers for Medicare and Medicaid Service definition., Main Outcome Measure: The primary outcome was 30-day all-cause readmission. This binary index was identified based on HFH internal data supplemented by external validated readmission data from the Michigan Health Information Network., Results: Race-ethnicity and all SDOH were significantly associated with readmission. The effect of depression on readmission was dependent on race-ethnicity, with Hispanic patients having the strongest effect in comparison to either African Americans or non-Hispanic whites. Spatial analysis identified ZIP codes in the City of Detroit, Michigan, as over-represented for individuals with multiple SDOH., Conclusions: There is a complex relationship between SDOH and race-ethnicity that must be taken into consideration when providing healthcare services. Insights from this study, which pinpoint the most vulnerable patients, could be leveraged to further improve existing models to predict risk of 30-day readmission for individuals in future work., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Keratoacanthoma (KA) is a common keratinocyte neoplasm that is regularly classified as a type of cutaneous squamous cell carcinoma (cSCC) despite demonstrating benign behavior. Differentiating KA from well-differentiated cSCC is difficult in many cases due to the substantial overlap of clinical and histological features. Currently, no reliable discriminating markers have been defined, and consequently, KAs are often treated similarly to cSCC, creating unnecessary surgical morbidity and healthcare costs. In this study, we used RNA sequencing to identify key differences in transcriptomes between KA and cSCC, which suggested divergent keratinocyte populations between each tumor. Imaging mass cytometry was then used to identify single-cell tissue characteristics, including cellular phenotype, frequency, topography, functional status, and interactions between KA and well-differentiated cSCC. We found that cSCC had significantly increased proportions of Ki67+ keratinocytes among tumor keratinocytes, which were dispersed significantly throughout non-basal keratinocyte communities. In cSCC, regulatory T-cells were more prevalent and held greater suppressive capacity. Furthermore, cSCC regulatory T-cells, tumor-associated macrophages, and fibroblasts had significant associations with Ki67 + keratinocytes as opposed to avoidances with KA, indicating a more immunosuppressive environment. Our data suggest that multicellular spatial features can serve as a foundation to enhance the histological discrimination of ambiguous KA and cSCC lesions., (Copyright © 2023. Published by Elsevier Inc.)

Fine mapping and bioinformatic analysis of the DDX6-CXCR5 genetic risk association in Sjögren's Disease (SjD) and Systemic Lupus Erythematosus (SLE) identified five common SNPs with functional evidence in immune cell types: rs4938573, rs57494551, rs4938572, rs4936443, rs7117261. Functional interrogation of nuclear protein binding affinity, enhancer/promoter regulatory activity, and chromatin-chromatin interactions in immune, salivary gland epithelial, and kidney epithelial cells revealed cell type-specific allelic effects for all five SNPs that expanded regulation beyond effects on DDX6 and CXCR5 expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, including lnc-PHLDB1-1 . Collectively, functional characterization implicated the risk alleles of these SNPs as modulators of promoter and/or enhancer activities that regulate cell type-specific expression of DDX6 , CXCR5 , and lnc-PHLDB1-1 , among others. Further, these findings emphasize the importance of exploring the functional significance of SNPs in the context of complex chromatin architecture in disease-relevant cell types and tissues., Competing Interests: Competing Interests C.J.L.* and A.D.F. have an active collaborative research agreement with Janssen. E.B. has an active research collaboration with Pfizer. T.M. is employed as medical solutions lead in rheumatology at UCB. R.H.S. is a consultant for Jansen Pharmaceuticals. S.J.B. provided consultancy services for Abbvie, BMS, Galapagos, Iqvia, J&J, Kiniksa, and Novartis in 2020–2021. L.R. provided consultancy services for AstraZeneca. B.M.W. has active collaborative research agreements with Astellas Bio and Pfizer, Inc. M.R. received grants from Amgen, AstraZeneca, Bristol Myers-Squibb, Novartis, and Servier for clinical trials in Sjögren’s Syndrome and SLE. All other authors have reported that they have no competing interests to report.

Rationale: Sarcoidosis is a racially disparate granulomatous disease likely caused by environmental exposures, genes, and their interactions. Despite increased risk in African Americans, few environmental risk factor studies in this susceptible population exist. Objectives: To identify environmental exposures associated with the risk of sarcoidosis in African Americans and those that differ in effect by self-identified race and genetic ancestry. Methods: The study sample comprised 2,096 African Americans (1,205 with and 891 without sarcoidosis) compiled from three component studies. Unsupervised clustering and multiple correspondence analyses were used to identify underlying clusters of environmental exposures. Mixed-effects logistic regression was used to evaluate the association of these exposure clusters and the 51 single-component exposures with risk of sarcoidosis. A comparison case-control sample of 762 European Americans (388 with and 374 without sarcoidosis) was used to assess heterogeneity in exposure risk by race. Results: Seven exposure clusters were identified, five of which were associated with risk. The exposure cluster with the strongest risk association was composed of metals ( P  < 0.001), and within this cluster, exposure to aluminum had the highest risk (odds ratio, 3.30; 95% confidence interval [95% CI], 2.23-4.09; P  < 0.001). This effect also differed by race ( P  < 0.001), with European Americans having no significant association with exposure (odds ratio, 0.86; 95% CI, 0.56-1.33). Within African Americans, the increased risk was dependent on genetic African ancestry ( P  = 0.047). Conclusions: Our findings support African Americans having sarcoidosis environmental exposure risk profiles that differ from those of European Americans. These differences may underlie racially disparate incidence rates that are partially explained by genetic variation differing by African ancestry.

Unlike conventional αβT cells, invariant natural killer T (iNKT) cells complete their terminal differentiation to functional iNKT1/2/17 cells in the thymus. However, underlying molecular programs that guide iNKT subset differentiation remain unclear. Here, we profiled the transcriptomes of over 17,000 iNKT cells and the chromatin accessibility states of over 39,000 iNKT cells across four thymic iNKT developmental stages using single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) to define their developmental trajectories. Our study discovered novel features for iNKT precursors and different iNKT subsets and indicated that iNKT2 and iNKT17 lineage commitment may occur as early as stage 0 (ST0) by two distinct programs, while iNKT1 commitments may occur post ST0. Both iNKT1 and iNKT2 cells exhibit extensive phenotypic and functional heterogeneity, while iNKT17 cells are relatively homogenous. Furthermore, we identified that a novel transcription factor, Cbfβ, was highly expressed in iNKT progenitor commitment checkpoint, which showed a similar expression trajectory with other known transcription factors for iNKT cells development, Zbtb16 and Egr2, and could direct iNKT cells fate and drive their effector phenotype differentiation. Conditional deletion of Cbfβ blocked early iNKT cell development and led to severe impairment of iNKT1/2/17 cell differentiation. Overall, our findings uncovered distinct iNKT developmental programs as well as their cellular heterogeneity, and identified a novel transcription factor Cbfβ as a key regulator for early iNKT cell commitment., (© 2023. The Author(s).)

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that can manifest with abscesses, sinus tracts, and scarring in the intertriginous areas of the body. HS is characterized by immune dysregulation, featuring elevated levels of myeloid cells, T helper (Th) cells, and pro-inflammatory cytokines, particularly those involved in Th1- and Th17-mediated immunity. In most epidemiological studies, HS shows a strong female sex bias, with reported female-to-male ratios estimated at roughly 3:1, suggesting that sex-related factors contribute to HS pathophysiology. In this article, we review the role of intrinsic and extrinsic factors that contribute to immunological differences between the sexes and postulate their role in the female sex bias observed in HS. We discuss the effects of hormones, X chromosome dosage, genetics, the microbiome, and smoking on sex-related differences in immunity to postulate potential immunological mechanisms in HS pathophysiology. Future studies are required to better characterize sex-biased factors that contribute to HS disease presentations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Young, Dimitrion, Zhou, Adrianto and Mi.)

Invariant natural killer T (iNKT) cells are innate-like T cells that are abundant in liver sinusoids and play a critical role in tumor immunity. However, the role of iNKT cells in pancreatic cancer liver metastasis (PCLM) has not been fully explored. In this study, we employed a hemi-spleen pancreatic tumor cell injection mouse model of PCLM, a model that closely mimics clinical conditions in humans, to explore the role of iNKT cells in PCLM. Activation of iNKT cells with α-galactosylceramide (αGC) markedly increased immune cell infiltration and suppressed PCLM progression. Via single cell RNA sequencing (scRNA-seq) we profiled over 30,000 immune cells from normal liver and PCLM with or without αGC treatment and were able to characterize the global changes of the immune cells in the tumor microenvironment upon αGC treatment, identifying a total of 12 subpopulations. Upon treatment with αGC, scRNA-Seq and flow cytometry analyses revealed increased cytotoxic activity of iNKT/NK cells and skewing CD4 T cells towards a cytotoxic Th1 profile and CD8 T cells towards a cytotoxic profile, characterized by higher proliferation and reduced exhaustion marker PD1 expression. Moreover, αGC treatment excluded tumor associated macrophages. Lastly, imaging mass cytometry analysis uncovered the reduced epithelial to mesenchymal transition related markers and increased active CD4 and CD8 T cells in PCLM with αGC treatment. Overall, our findings uncover the protective function of activated iNKT cells in pancreatic cancer liver metastasis through increased NK and T cell immunity and decreased tumor associated macrophages., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background The renal mechanisms involved in the maintenance of human hypertension and resistance to treatment are not well understood. Animal studies suggest that chronic renal inflammation contributes to hypertension. We studied cells shed in first-morning urine samples from individuals who were hypertensive who exhibited difficult-to-control blood pressure (BP). We performed bulk RNA sequencing of these shed cells to develop transcriptome-wide associations with BP. We also analyzed nephron-specific genes and used an unbiased bioinformatic approach to find signaling pathways activated in difficult-to-control hypertension. Methods and Results Participants who completed the SPRINT (Systolic Blood Pressure Intervention Trial) at a single trial site were recruited, and cells shed in first-morning urine samples collected. A total of 47 participants were divided into 2 groups based on hypertension control. The BP-difficult group (n=29) had systolic BP>140 mm Hg, >120 mm Hg after intensive treatment for hypertension, or required more than the median number of antihypertensive drugs used in SPRINT. The easy-to-control BP group (n=18) comprised the remainder of the participants. A total of 60 differentially expressed genes were identified with a >2-fold change in the BP-difficult group. In BP-difficult participants, 2 of the most upregulated genes were associated with inflammation: Tumor Necrosis Factor Alpha Induced Protien 6 (fold change, 7.76; P =0.006) and Serpin Family B Member 9 (fold change, 5.10; P =0.007). Biological pathway analysis revealed an overrepresentation of inflammatory networks, including interferon signaling, granulocyte adhesion and diapedesis, and Janus Kinase family kinases in the BP-difficult group ( P <0.001). Conclusions We conclude that transcriptomes from cells shed in first-morning urine identify a gene expression profile in difficult-to-control hypertension that associates with renal inflammation.

Objective: Sjögren's disease (SjD) is an autoimmune disease characterised by inflammatory destruction of exocrine glands. Patients with autoantibodies to Ro/SSA (SjD Ro+ ) exhibit more severe disease. Long non-coding RNAs (lncRNAs) are a functionally diverse class of non-protein-coding RNAs whose role in autoimmune disease pathology has not been well characterised., Methods: Whole blood RNA-sequencing (RNA-seq) was performed on SjD cases (n=23 Ro/SSA negative (SjD Ro- ); n=27 Ro/SSA positive (SjD Ro+ ) and healthy controls (HCs; n=27). Bioinformatics and pathway analyses of differentially expressed (DE) transcripts (log 2 fold change ≥2 or ≤0.5; p adj <0.05) were used to predict lncRNA function. LINC01871 was characterised by RNA-seq analyses of HSB-2 cells with CRISPR-targeted LINC01871 deletion ( LINC01871 -/ - ) and in vitro stimulation assays., Results: Whole blood RNA-seq revealed autoantibody-specific transcription profiles and disproportionate downregulation of DE transcripts in SjD cases relative to HCs. Sixteen DE lncRNAs exhibited correlated expression with the interferon (IFN)-regulated gene, RSAD2 , in SjD Ro+ (r≥0.65 or ≤-0.6); four antisense lncRNAs exhibited IFN-regulated expression in immune cell lines. LINC01871 was upregulated in all SjD cases. RNA-seq and pathway analyses of LINC01871 -/ - cells implicated roles in cytotoxic function, differentiation and IFNγ induction. LINC01871 was induced by IFNγ in a myeloid cell line and regulated by calcineurin/NFAT pathway and T cell receptor (TCR) signalling in primary human T cells., Conclusion: LINC01871 influences expression of many immune cell genes and growth factors, is IFNγ inducible, and regulated by calcineurin signalling and TCR ligand engagement. Altered LINC01871 expression may influence the dysregulated T cell inflammatory pathways implicated in SjD., Competing Interests: Competing interests: KS is a current employee of Janssen. ADF and CJL have an active collaborative research agreement with Janssen. All other authors have reported that they have no competing interests to report., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Hidradenitis suppurativa (HS) is a multifactorial chronic skin disease characterized by inflammation around the hair follicles commonly affecting intertriginous areas. The underlying pathogenesis of HS and its molecular mechanisms are largely understudied. Genetic studies in families have identified variants within the γ-secretase complex associated with HS; however, no definitive genotype-phenotype correlations have been made. The lack of knowledge regarding the intersection of genetics, immunology and environmental risk factors is a major obstacle to improving treatment for patients with HS. This article provides an overview of the role of race, genetics, and immunology in HS to provide insight into the multiple factors influencing the pathophysiology of HS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vellaichamy, Amin, Dimitrion, Hamzavi, Zhou, Adrianto and Mi.)

Rapid, robust, and accurate biomass compositional analyses are required in the bioenergy industry to accurately determine the chemical composition of biomass feedstocks. A stacked regression ensemble approach using near infrared spectroscopic method was developed for the quantitative determination of glucan, xylan, lignin, ash, and extract in biomass feedstocks. A comprehensive comparison of the performance of various machine learning techniques including support vector regression (linear and radial), least absolute shrinkage and selection operator (LASSO), ridge regression, elastic net, partial least squares, random forests, recursive partitioning and regression trees, gradient boosting, and gaussian process regression was assessed in the training set data (n = 188). The predictive performance of the aforementioned machine learning approaches was then compared with stacked regression, an ensemble learning algorithm which collates the performance of the abovementioned machine learning regression techniques. Results show that the stacked regression primarily outperformed other machine learning techniques (Root mean square error of prediction (RMSEP) average =1.660%wt,R 2 =0.907) across all five constituents in the validation set data (n = 81). Further results also show that the RMSEP of the stacked ensemble technique is significantly different than that of the partial least squares (PLS) approach in predicting glucan, ash, lignin, and extract components in biomass samples. The stacked ensemble learning approach offers an alternative method for a more accurate prediction of biomass compositions than the traditional PLS technique., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Invariant natural killer T cell (iNKT) subsets are differentially distributed in various immune organs. However, it remains unclear whether iNKT cells exhibit phenotypical and functional differences in different peripheral organs and how thymic iNKT cells emigrate to peripheral organs. Here, we used single-cell RNA-seq to map iNKT cells from peripheral organs. iNKT1 cells from liver, spleen, and lymph node appear to have distinct phenotypic profiles and functional capabilities. However, iNKT17 transcriptomes were comparable across peripheral organs. In addition, by integrating data with a thymic iNKT cell study, we uncovered a transient population of recent thymic emigrants, a cluster of peripheral iNKT cells with high expression of transcription factor Kruppel-like factor 2 (Klf2). Deletion of Klf2 led to a severe impairment of iNKT differentiation and migration. Our study revealed that iNKT subsets are uniquely distributed in peripheral organs with some inter-local tissue variation, especially for iNKT1 cell, and identified Klf2 as a rheostat for iNKT cell migration and differentiation., (© 2022. The Author(s).)

Sjögren's disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren's cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands., (© 2022. The Author(s).)

Enzalutamide, a second-generation antiandrogen, is commonly prescribed for the therapy of advanced prostate cancer, but enzalutamide-resistant, lethal, or incurable disease invariably develops. To understand the molecular mechanism(s) behind enzalutamide resistance, here, we comprehensively analyzed a range of prostate tumors and clinically relevant models by gene expression array, immunohistochemistry, and Western blot, which revealed that enzalutamide-resistant prostate cancer cells and tumors overexpress the pseudokinase, Tribbles 2 (TRIB2). Inhibition of TRIB2 decreases the viability of enzalutamide-resistant prostate cancer cells, suggesting a critical role of TRIB2 in these cells. Moreover, the overexpression of TRIB2 confers resistance in prostate cancer cells to clinically relevant doses of enzalutamide, and this resistance is lost upon inhibition of TRIB2. Interestingly, we found that TRIB2 downregulates the luminal markers androgen receptor and cytokeratin 8 in prostate cancer cells but upregulates the neuronal transcription factor BRN2 (Brain-2) and the stemness factor SOX2 (SRY-box 2) to induce neuroendocrine characteristics. Finally, we show that inhibition of either TRIB2 or its downstream targets, BRN2 or SOX2, resensitizes resistant prostate cancer cells to enzalutamide. Thus, TRIB2 emerges as a potential new regulator of transdifferentiation that confers enzalutamide resistance in prostate cancer cells via a mechanism involving increased cellular plasticity and lineage switching., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Readmission is an increasingly important focus for improvement regarding quality, value, and patient burden in our surgical patient population. We hypothesized that inpatient harm events increase the likelihood of readmission in surgical patients. We created a system-wide inpatient registry with 30-day readmission. A surgical subset was created, and harm events were tracked through the electronic health record system. Between 2015 and 2017, 37,048 surgical patient encounters met inclusion criterion. A total of 2,887 patients (7.69%) were readmitted. After multiple logistic regression of the highly significant harm measures, seven harm measures remained statistically significant (p < .05). Those with the three highest odds ratios were mucosal pressure ulcer, Clostridium difficile, and glucose <40. Incorporating harm measures to the traditional risk, predictive model for 30-day readmission improved our model performance (area under the ROC curve from 0.68 to 0.71). This study demonstrated that inpatient hospital-based harm events can be electronically monitored and used to predict 30-day readmission., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 National Association for Healthcare Quality.)

Purpose : Identify genes associated with ocular sarcoidosis (OS). Methods : We genotyped 1.1 million genetic variants to identify significant OS associations, defined as those that achieved p < 5 × 10 -8 in a genome-wide comparison of OS cases to healthy controls in our European- or African-American cohorts (EA, AA). Potential functional roles of all associated variants were assessed. Results : Eight significant non-HLA variants were found in AA OS cases compared to healthy controls and confirmed as at least suggestive when comparing OS to non-OS cases. Seven of these were within MAGI1 and include transcription factor binding sites and expression quantitative trait loci. Our EA cohort, while showing similar effect sizes at variants within MAGI1 , had no significant variants. Association analysis of HLA-DRB1 alleles confirmed association to OS in EA to *04:01. Conclusion : Our results support organ-specific genetic risk in OS in a compelling candidate, MAGI1 , known to be associated with barrier function and autoimmunity.

Alveolar macrophages (AMs) derived from embryonic precursors seed the lung before birth and self-maintain locally throughout adulthood, but are regenerated by bone marrow (BM) under stress conditions. However, the regulation of AM development and maintenance remains poorly understood. Here, we show that histone deacetylase 3 (HDAC3) is a key epigenetic factor required for AM embryonic development, postnatal homeostasis, maturation, and regeneration from BM. Loss of HDAC3 in early embryonic development affects AM development starting at E14.5, while loss of HDAC3 after birth affects AM homeostasis and maturation. Single-cell RNA sequencing analyses reveal four distinct AM sub-clusters and a dysregulated cluster-specific pathway in the HDAC3-deficient AMs. Moreover, HDAC3-deficient AMs exhibit severe mitochondrial oxidative dysfunction and deteriorative cell death. Mechanistically, HDAC3 directly binds to Pparg enhancers, and HDAC3 deficiency impairs Pparg expression and its signaling pathway. Our findings identify HDAC3 as a key epigenetic regulator of lung AM development and homeostasis.

Vα24-invariant human natural killer T (NKT) cells comprise a unique subset of CD1d-restricted T cells with potent immune regulatory function and are involved in the development of a variety of human diseases. However, the lack of comprehensive molecular subset identities limits their objective classification and clinical application. Using unbiased single-cell RNA sequencing (scRNA-seq) of over 4000 unstimulated and 7000 stimulated human peripheral blood NKT cells, we identified four and five clusters of NKT cells from each NKT group, respectively. Our study uncovers multiple previously unrecognized NKT subsets with potential functional specificities, including a cluster of NKT cells with regulatory T cell property. Flow cytometry and Ingenuity Pathway Analysis confirmed the existence of these NKT populations and indicated the related functional capacities. Our study provides the unbiased and more comprehensive molecular identities of human NKT subsets, which will eventually lead the way to tailored therapies targeting selected NKT subsets., (Copyright © 2020 Zhou, Adrianto, Wang, Wu, Datta and Mi.)

Triple negative breast cancers (TNBCs) are molecularly heterogeneous, and the link between their aggressiveness with African ancestry is not established. We investigated primary TNBCs for gene expression among self-reported race (SRR) groups of African American (AA, n = 42) and European American (EA, n = 33) women. RNA sequencing data were analyzed to measure changes in genome-wide expression, and we utilized logistic regressions to identify ancestry-associated gene expression signatures. Using SNVs identified from our RNA sequencing data, global ancestry was estimated. We identified 156 African ancestry-associated genes and found that, compared to SRR, quantitative genetic analysis was a more robust method to identify racial/ethnic-specific genes that were differentially expressed. A subset of African ancestry-specific genes that were upregulated in TNBCs of our AA patients were validated in TCGA data. In AA patients, there was a higher incidence of basal-like two tumors and altered TP53, NFB1, and AKT pathways. The distinct distribution of TNBC subtypes and altered oncologic pathways show that the ethnic variations in TNBCs are driven by shared genetic ancestry. Thus, to appreciate the molecular diversity of TNBCs, tumors from patients of various ancestral origins should be evaluated.

The etiology of many complex diseases involves both environmental exposures and inherited genetic predisposition as well as interactions between them. Gene-environment-wide interaction studies (GEWIS) provide a means to identify the interactions between genetic variation and environmental exposures that underlie disease risk. However, current GEWIS methods lack the capability to adjust for the potentially complex correlations in studies with varying degrees of relationships (both known and unknown) among individuals in admixed populations. We developed novel generalized estimating equation (GEE) based methods-GEE-adaptive and GEE-joint-to account for phenotypic correlations due to kinship while accounting for covariates, including, measures of genome-wide ancestry. In simulation studies of admixed individuals, both methods controlled family-wise error rates, an advantage over the case-only approach. They demonstrated higher power than traditional case-control methods across a wide range of underlying alternative hypotheses, especially where both marginal and interaction effects were present. We applied the proposed method to conduct a GEWIS of a known sarcoidosis risk factor (insecticide exposure) and risk of sarcoidosis in African Americans and identified two novel loci with suggestive evidence of G × E interaction., (© 2019 Wiley Periodicals, Inc.)

Current models propose that group 2 innate lymphoid cells (ILC2s) are generated in the bone marrow. Here, we demonstrate that subsets of these cells can differentiate from multipotent progenitors and committed T cell precursors in the thymus, both in vivo and in vitro. These thymic ILC2s exit the thymus, circulate in the blood, and home to peripheral tissues. Ablation of E protein transcription factors greatly promotes the ILC fate while impairing B and T cell development. Consistently, a transcriptional network centered on the ZBTB16 transcription factor and IL-4 signaling pathway is highly up-regulated due to E protein deficiency. Our results show that ILC2 can still arise from what are normally considered to be committed T cell precursors, and that this alternative cell fate is restrained by high levels of E protein activity in these cells. Thymus-derived lung ILC2s of E protein-deficient mice show different transcriptomes, proliferative properties, and cytokine responses from wild-type counterparts, suggesting potentially distinct functions., (© 2019 Qian et al.)

Objectives: Microbial infections and mucosal dysbiosis influence morbidity in patients with systemic lupus erythematosus (SLE). In the oral cavity, periodontal bacteria and subgingival plaque dysbiosis provide persistent inflammatory stimuli at the mucosal surface. This study was undertaken to evaluate whether exposure to periodontal bacteria influences disease parameters in SLE patients., Methods: Circulating antibodies to specific periodontal bacteria have been used as surrogate markers to determine an ongoing bacterial burden, or as indicators of past exposure to the bacteria. Banked serum samples from SLE patients in the Oklahoma Lupus Cohort were used to measure antibody titres against periodontal pathogens (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Treponema denticola) and commensals (Capnocytophaga ochracea, and Streptococcus gordonii) by ELISA. Correlations between anti-bacterial antibodies and different clinicalparameters of SLE including, autoantibodies (anti-dsDNA, anti-SmRNP, anti-SSA/Ro and anti-SSB/La), complement, and disease activity (SLEDAI and BILAG) were studied., Results: SLE patients had varying amounts of antibodies to different oral bacteria. The antibody titres against A. actinomycetemcomitans, P. gingivalis, T. denticola, and C. ochracea were higher in patients positive for anti-dsDNA antibodies, and they showed significant correlations with anti-dsDNA titres and reduced levels of complement. Among the periodontal pathogens, only antibodies to A. actinomycetemcomitans were associated with higher disease activity., Conclusions: Our results suggest that exposure to specific pathogenic periodontal bacteria influences disease activity in SLE patients. These findings provide a rationale for assessing and improving periodontal health in SLE patients, as an adjunct to lupus therapies.

Background: Hirschsprung disease (HSCR) is a heterogeneous genetic disorder characterized by absence of ganglion cells along the intestines resulting in functional bowel obstruction. Mutations in neuregulin 1 (NRG1) gene have been implicated in some cases of intestinal aganglionosis. This study aims to investigate the contribution of the NRG1 gene to HSCR development in an Indonesian population., Methods: We analyzed the entire coding region of the NRG1 gene in 54 histopathologically diagnosed HSCR patients., Results: All patients were sporadic non-syndromic HSCR with 53/54 (98%) short-segment and 1/54 (2%) long-segment patients. NRG1 gene analysis identified one rare variant, c.397G > C (p.V133 L), and three common variants, rs7834206, rs3735774, and rs75155858. The p.V133 L variant was predicted to reside within a region of high mammalian conservation, overlapping with the promoter and enhancer histone marks of relevant tissues such as digestive and smooth muscle tissues and potentially altering the AP-4&#95;2, BDP1&#95;disc3, Egr-1&#95;known1, Egr-1&#95;known4, HEN1&#95;2 transcription factor binding motifs. This p.V133 L variant was absent in 92 non-HSCR controls. Furthermore, the rs7834206 polymorphism was associated with HSCR by case-control analysis (p = 0.037)., Conclusions: This study is the first report of a NRG1 rare variant associated with HSCR patients of South-East Asian ancestry and provides further insights into the contribution of NRG1 in the molecular genetic pathogenesis of HSCR.

Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.

Innate lymphoid cells (ILCs) are important regulators in various immune responses. The current paradigm states that all newly made ILCs originate from common lymphoid progenitors in the bone marrow. Id2, an inhibitor of E protein transcription factors, is indispensable for ILC differentiation. Unexpectedly, we found that ectopically expressing Id1 or deleting two E protein genes in the thymus drastically increased ILC2 counts in the thymus and other organs where ILC2 normally reside. Further evidence suggests a thymic origin of these mutant ILC2s. The mutant mice exhibit augmented spontaneous infiltration of eosinophils and heightened responses to papain in the lung and increased ability to expulse the helminth parasite, Nippostrongylus brasiliensis These results prompt the questions of whether the thymus naturally has the capacity to produce ILC2s and whether E proteins restrain such a potential. The abundance of ILC2s in Id1 transgenic mice also offers a unique opportunity for testing the biological functions of ILC2s., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Sarcoidosis is a complex disease of unknown etiology characterized by the presence of granulomatous inflammation. Though various immune system pathways have been implicated in disease, the relationship between the genetic determinants of sarcoidosis and other inflammatory disorders has not been characterized. Herein, we examined the degree of genetic pleiotropy common to sarcoidosis and other inflammatory disorders to identify shared pathways and disease systems pertinent to sarcoidosis onset. To achieve this, we quantify the association of common variant polygenic risk scores from nine complex inflammatory disorders with sarcoidosis risk. Enrichment analyses of genes implicated in pleiotropic associations were further used to elucidate candidate pathways. In European-Americans, we identify significant pleiotropy between risk of sarcoidosis and risk of asthma (R 2 =2.03%; P=8.89 × 10 -9 ), celiac disease (R 2 =2.03%; P=8.21 × 10 -9 ), primary biliary cirrhosis (R 2 =2.43%; P=2.01 × 10 -10 ) and rheumatoid arthritis (R 2 =4.32%; P=2.50 × 10 -17 ). These associations validate in African Americans only after accounting for the proportion of genome-wide European ancestry, where we demonstrate similar effects of polygenic risk for African-Americans with the highest levels of European ancestry. Variants and genes implicated in European-American pleiotropic associations were enriched for pathways involving interleukin-12, interleukin-27 and cell adhesion molecules, corroborating the hypothesized immunopathogenesis of disease.

Methods of estimating allele frequencies from data on unrelated and related individuals are described in this chapter. For samples of unrelated individuals with simple codominant markers, the natural estimators of allele frequencies can be used. For genetic data on related individuals, maximum likelihood estimation (MLE) can be applied to compute allele frequencies. Factors that influence allele frequencies in populations are also explained.

Rationale: Sarcoidosis is a multisystem disease of unknown cause. Löfgren's syndrome (LS) is a characteristic subgroup of sarcoidosis that is associated with a good prognosis in sarcoidosis. However, little is known about its genetic architecture or its broader phenotype, non-LS sarcoidosis., Objectives: To address the genetic architecture of sarcoidosis phenotypes, LS and non-LS., Methods: An association study in a white Swedish cohort of 384 LS, 664 non-LS, and 2,086 control subjects, totaling 3,134 subjects using a fine-mapping genotyping platform was conducted. Replication was performed in four independent cohorts, three of white European descent (Germany, n = 4,975; the Netherlands, n = 613; and Czech Republic, n = 521), and one of black African descent (United States, n = 1,657), totaling 7,766 subjects., Measurements and Main Results: A total of 727 LS-associated variants expanding throughout the extended major histocompatibility complex (MHC) region and 68 non-LS-associated variants located in the MHC class II region were identified and confirmed. A shared overlap between LS and non-LS defined by 17 variants located in the MHC class II region was found. Outside the MHC region, two LS-associated loci, in ADCY3 and between CSMD1 and MCPH1, were observed and replicated., Conclusions: Comprehensive and integrative analyses of genetics, transcription, and pathway modeling on LS and non-LS indicates that these sarcoidosis phenotypes have different genetic susceptibility, genomic distributions, and cellular activities, suggesting distinct molecular mechanisms in pathways related to immune response with a common region.

Objective: To evaluate serum cytokine profiles for their utility to determine the heterogeneous responses to interferon (IFN)-β treatment in patients with multiple sclerosis (MS)., Methods: Patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome receiving de novo IFN-β treatment were included in this prospective, observational study. Number of relapses and changes in disability were assessed 2 years prior to and 2 years after initiation of treatment. Sera were collected at baseline and after 3 months on therapy. Cytokine levels in sera were assessed by Luminex multiplex assays. Baseline cytokine profiles were grouped by hierarchical clustering analysis. Demographic features, changes in cytokines, and clinical outcome were then assessed in the clustered patient groups., Results: A total of 157 patients were included in the study and clustered into 6 distinct subsets by baseline cytokine profiles. These subsets differed significantly in their clinical and biological response to IFN-β therapy. Two subsets were associated with patients who responded poorly to therapy. Two other subsets, associated with a good response to therapy, showed a significant reduction in relapse rates and no worsening of disability. Each subset also had differential changes in cytokine levels after 3 months of IFN-β treatment., Conclusions: There is heterogeneity in the immunologic pathways of the RRMS population, which correlates with IFN-β response.

Neurosarcoidosis is a clinical subtype of sarcoidosis characterized by the presence of granulomas in the nervous system. Here, we report a highly significant association with a variant (rs75652600, P = 3.12 × 10(-8), odds ratios = 4.34) within a zinc finger gene, ZNF592, from an imputation-based fine-mapping study of the chromosomal region 15q25 in African-Americans with neurosarcoidosis. We validate the association with ZNF592, a gene previously shown to cause cerebellar ataxia, in a cohort of European-Americans with neurosarcoidosis by uncovering low-frequency variants with a similar risk effect size (chr15:85309284, P = 0.0021, odds ratios = 5.36).

HLA-DRB1 is a sarcoidosis risk gene, and the *03:01 allele is strongly associated with disease resolution in European sarcoidosis cases. Whereas the HLA-DRB1 variation is associated with sarcoidosis susceptibility in African Americans, DRB1 risk alleles are not as well defined, and associations with disease resolution have not been studied. Associations between genotyped and imputed HLA-DRB1 alleles and disease susceptibility/resolution were evaluated in a sample of 1,277 African-American patients with sarcoidosis and 1,467 control subjects. In silico binding assays were performed to assess the functional significance of the associated alleles. Increased disease susceptibility was associated with the HLA-DRB1 alleles *12:01 (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.65-2.69; P = 3.2 × 10(-9)) and *11:01 (OR, 1.69; 95% CI, 1.42-2.01; P = 3.0 × 10(-9)). The strongest protective association was found with *03:01 (OR, 0.56; 95% CI, 0.44-0.73; P = 1.0 × 10(-5)). The African-derived allele *03:02 was associated with decreased risk of persistent radiographic disease (OR, 0.52; 95% CI, 0.37-0.72; P = 1.3 × 10(-4)), a finding consistent across the three component studies comprising the analytic sample. The DRB1*03:01 association with disease persistence was dependent upon local ancestry, with carriers of at least one European allele at DRB1 at a decreased risk of persistent disease (OR, 0.36; 95% CI, 0.14-0.94; P = 0.037). Results of in silico binding analyses showed that DRB1*03:01 consistently demonstrated the highest binding affinities for six bacterial peptides previously found in sarcoidosis granulomas, whereas *12:01 displayed the lowest binding affinities. This study has identified DRB1*03:01 and *03:02 as novel alleles associated with disease susceptibility and course in African Americans. Further investigation of DRB1*03 alleles may uncover immunologic factors that favor sarcoidosis protection and resolution among African Americans.

Background: Adapter trimming and removal of duplicate reads are common practices in next-generation sequencing pipelines. Sequencing reads ambiguously mapped to repetitive and low complexity regions can also be problematic for accurate assessment of the biological signal, yet their impact on sequencing data has not received much attention. We investigate how trimming the adapters, removing duplicates, and filtering out reads overlapping low complexity regions influence the significance of biological signal in RNA- and ChIP-seq experiments., Methods: We assessed the effect of data processing steps on the alignment statistics and the functional enrichment analysis results of RNA- and ChIP-seq data. We compared differentially processed RNA-seq data with matching microarray data on the same patient samples to determine whether changes in pre-processing improved correlation between the two. We have developed a simple tool to remove low complexity regions, RepeatSoaker, available at https://github.com/mdozmorov/RepeatSoaker, and tested its effect on the alignment statistics and the results of the enrichment analyses., Results: Both adapter trimming and duplicate removal moderately improved the strength of biological signals in RNA-seq and ChIP-seq data. Aggressive filtering of reads overlapping with low complexity regions, as defined by RepeatMasker, further improved the strength of biological signals, and the correlation between RNA-seq and microarray gene expression data., Conclusions: Adapter trimming and duplicates removal, coupled with filtering out reads overlapping low complexity regions, is shown to increase the quality and reliability of detecting biological signals in RNA-seq and ChIP-seq data.

Objective: Systemic lupus erythematosus (SLE) is a complex and multifactorial autoimmune disease with striking clinical, immunologic, and genetic heterogeneity, despite nearly ubiquitous antinuclear antibody (ANA) production. Multiple gene polymorphisms have been associated with the disease, but these individually account for only a very small percentage of overall SLE risk. In earlier studies, constitutive expression of the DNA-binding protein AT-rich-interactive domain 3A (ARID3a) in transgenic mouse B lymphocyte lineage cells led to spontaneous ANA production and preferential development of B cells associated with production of polyreactive antibodies. Therefore, we undertook this study to determine whether ARID3a was overexpressed in B lymphocytes of SLE patients and whether ARID3a expression was associated with disease severity., Methods: A cross-section of SLE patients, rheumatoid arthritis patients, and age- and sex-matched controls was analyzed longitudinally for lupus disease activity, numbers of ARID3a+ peripheral blood mononuclear B cells from multiple B cell subsets, and immunoglobulin and cytokine levels., Results: Fifty of 115 SLE patients (43%) had dramatically increased numbers of ARID3a+ B cells compared to healthy controls. ARID3a was not expressed in naive B cells of healthy controls, but was abundant in these precursors of antibody-secreting cells in SLE patients. Total numbers of ARID3a+ B cells correlated with increased disease activity as defined by SLE Disease Activity Index scores in individuals assessed at 3 time points., Conclusion: These findings identify B cell anomalies in SLE that allow stratification of patient samples based on ARID3a expression and implicate ARID3a as a potential marker of CD19+ B lymphocytes correlated with disease activity., (Copyright © 2014 by the American College of Rheumatology.)

Genome-wide association studies (GWAS) that draw samples from multiple studies with a mixture of relationship structures are becoming more common. Analytical methods exist for using mixed-sample data, but few methods have been proposed for the analysis of genotype-by-environment (G×E) interactions. Using GWAS data from a study of sarcoidosis susceptibility genes in related and unrelated African Americans, we explored the current analytic options for genotype association testing in studies using both unrelated and family-based designs. We propose a novel method-generalized least squares (GLX)-to estimate both SNP and G×E interaction effects for categorical environmental covariates and compared this method to generalized estimating equations (GEE), logistic regression, the Cochran-Armitage trend test, and the WQLS and MQLS methods. We used simulation to demonstrate that the GLX method reduces type I error under a variety of pedigree structures. We also demonstrate its superior power to detect SNP effects while offering computational advantages and comparable power to detect G×E interactions versus GEE. Using this method, we found two novel SNPs that demonstrate a significant genome-wide interaction with insecticide exposure-rs10499003 and rs7745248, located in the intronic and 3' UTR regions of the FUT9 gene on chromosome 6q16.1., (© 2014 WILEY PERIODICALS, INC.)

Background: The expense of human leukocyte antigen (HLA) allele genotyping has motivated the development of imputation methods that use dense single nucleotide polymorphism (SNP) genotype data and the region's haplotype structure, but the performance of these methods in admixed populations (such as African Americans) has not been adequately evaluated. We compared genotype-based-derived from both genome-wide genotyping and targeted sequencing-imputation results to existing allele data for HLA-DRB1, -DQB1, and -DPB1., Results: In European Americans, the newly-developed HLA Genotype Imputation with Attribute Bagging (HIBAG) method outperformed HLA*IMP:02. In African Americans, HLA*IMP:02 performed marginally better than HIBAG pre-built models, but HIBAG models constructed using a portion of our African American sample with both SNP genotyping and four-digit HLA class II allele typing had consistently higher accuracy than HLA*IMP:02. However, HIBAG was significantly less accurate in individuals heterozygous for local ancestry (p ≤0.04). Accuracy improved in models with equal numbers of African and European chromosomes. Variants added by targeted sequencing and SNP imputation further improved both imputation accuracy and the proportion of high quality calls., Conclusion: Combining the HIBAG approach with local ancestry and dense variant data can produce highly-accurate HLA class II allele imputation in African Americans.

Sarcoidosis is a complex, multi-organ granulomatous disease with a likely genetic component. West African ancestry confers a higher risk for sarcoidosis than European ancestry. Admixture mapping provides the most direct method to locate genes that underlie such ethnic variation in disease risk. We sought to identify genetic risk variants within four previously-identified ancestry-associated regions-6p24.3-p12.1, 17p13.3-13.1, 2p13.3-q12.1, and 6q23.3-q25.2-in a sample of 2,727 African Americans. We used logistic regression fit by generalized estimating equations and the MIX score statistic to determine which variants within ancestry-associated regions were associated with risk and responsible for the admixture signal. Fine mapping was performed by imputation, based on a previous genome-wide association study; significant variants were validated by direct genotyping. Within the 6p24.3-p12.1 locus, the most significant ancestry-adjusted SNP was rs74318745 (p = 9.4*10-11), an intronic SNP within the HLA-DRA gene that did not solely explain the admixture signal, indicating the presence of more than a single risk variant within this well-established sarcoidosis risk region. The locus on chromosome 17p13.3-13.1 revealed a novel sarcoidosis risk SNP, rs6502976 (p = 9.5*10-6), within intron 5 of the gene X-linked Inhibitor of Apoptosis Associated Factor 1 (XAF1) that accounted for the majority of the admixture linkage signal. Immunohistochemical expression studies demonstrated lack of expression of XAF1 and a corresponding high level of expression of its downstream target, X-linked Inhibitor of Apoptosis (XIAP) in sarcoidosis granulomas. In conclusion, ancestry and association fine mapping revealed a novel sarcoidosis susceptibility gene, XAF1, which has not been identified by previous genome-wide association studies. Based on the known biology of the XIAP/XAF1 apoptosis pathway and the differential expression patterns of XAF1 and XIAP in sarcoidosis granulomas, we suggest that this pathway may play a role in the maintenance of sarcoidosis granulomas.

The genetic factors underlying the pathogenesis of lupus nephritis associated with systemic lupus erythematosus are largely unknown, although animal studies indicate that nuclear factor (NF)-κB is involved. We reported previously that a knockin mouse expressing an inactive form of ABIN1 (ABIN1[D485N]) develops lupus-like autoimmune disease and demonstrates enhanced activation of NF-κB and mitogen-activated protein kinases in immune cells after toll-like receptor stimulation. In the current study, we show that ABIN1[D485N] mice develop progressive GN similar to class III and IV lupus nephritis in humans. To investigate the clinical relevance of ABIN1 dysfunction, we genotyped five single-nucleotide polymorphisms in the gene encoding ABIN1, TNIP1, in samples from European-American, African American, Asian, Gullah, and Hispanic participants in the Large Lupus Association Study 2. Comparing cases of systemic lupus erythematosus with nephritis and cases of systemic lupus erythematosus without nephritis revealed strong associations with lupus nephritis at rs7708392 in European Americans and rs4958881 in African Americans. Comparing cases of systemic lupus erythematosus with nephritis and healthy controls revealed a stronger association at rs7708392 in European Americans but not at rs4958881 in African Americans. Our data suggest that variants in the TNIP1 gene are associated with the risk for lupus nephritis and could be mechanistically involved in disease development via aberrant regulation of NF-κB and mitogen-activated protein kinase activity.