Corrigendum: Sex differences in the genetics of sarcoidosis across European and African ancestry populations.

[This corrects the article DOI: 10.3389/fmed.2023.1132799.].

Multiple Correspondence Analysis and HLA-Associations of Organ Involvement in a Large Cohort of African-American and European-American Patients with Sarcoidosis.

Sarcoidosis is a systemic granulomatous disease with predominant pulmonary involvement and vast heterogeneity of clinical manifestations and disease outcomes. African American (AA) patients suffer greater morbidity and mortality. Using Multiple Correspondence Analysis, we identified seven clusters of organ involvement in European American (EA; n = 385) patients which were similar to those previously described in a Pan-European (GenPhenReSa) and a Spanish cohort (SARCOGEAS). In contrast, AA (n = 987) had six, less well-defined and overlapping clusters with little similarity to the cluster identified in the EA cohort evaluated at the same U.S. institutions. Association of cluster membership with two-digit HLA-DRB1 alleles demonstrated ancestry-specific patterns of association and replicated known HLA effects.These results further support the notion that genetically influenced immune risk profiles, which differ based on ancestry, play a role in phenotypic heterogeneity. Dissecting such risk profiles will move us closer to personalized medicine for this complex disease.

Sex differences in the genetics of sarcoidosis across European and African ancestry populations.

Background: Sex differences in the susceptibility of sarcoidosis are unknown. The study aims to identify sex-dependent genetic variations in two clinical sarcoidosis phenotypes: Löfgren's syndrome (LS) and non-Löfgren's syndrome (non-LS). Methods: A meta-analysis of genome-wide association studies was conducted on Europeans and African Americans, totaling 10,103 individuals from three population-based cohorts, Sweden (n = 3,843), Germany (n = 3,342), and the United States (n = 2,918), followed by an SNP lookup in the UK Biobank (UKB, n = 387,945). A genome-wide association study based on Immunochip data consisting of 141,000 single nucleotide polymorphisms (SNPs) was conducted in the sex groups. The association test was based on logistic regression using the additive model in LS and non-LS sex groups independently. Additionally, gene-based analysis, gene expression, expression quantitative trait loci (eQTL) mapping, and pathway analysis were performed to discover functionally relevant mechanisms related to sarcoidosis and biological sex. Results: We identified sex-dependent genetic variations in LS and non-LS sex groups. Genetic findings in LS sex groups were explicitly located in the extended Major Histocompatibility Complex (xMHC). In non-LS, genetic differences in the sex groups were primarily located in the MHC class II subregion and ANXA11. Gene-based analysis and eQTL enrichment revealed distinct sex-specific gene expression patterns in various tissues and immune cell types. In LS sex groups, a pathway map related to antigen presentation machinery by IFN-gamma. In non-LS, pathway maps related to immune response lectin-induced complement pathway in males and related to maturation and migration of dendritic cells in skin sensitization in females were identified. Conclusion: Our findings provide new evidence for a sex bias underlying sarcoidosis genetic architecture, particularly in clinical phenotypes LS and non-LS. Biological sex likely plays a role in disease mechanisms in sarcoidosis.

Identification of Environmental Exposures Associated with Risk of Sarcoidosis in African Americans.

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.

USH2A Gene Mutations in Rabbits Lead to Progressive Retinal Degeneration and Hearing Loss.

Purpose: Mutations in USH2A gene are responsible for the greatest proportion of the Usher Syndrome (USH) population, among which more than 30% are frameshift mutations on exon 13. A clinically relevant animal model has been absent for USH2A-related vision loss. Here we sought to establish a rabbit model carrying USH2A frameshift mutation on exon 12 (human exon 13 equivalent). Methods: CRISPR/Cas9 reagents targeting the rabbit USH2A exon 12 were delivered into rabbit embryos to produce an USH2A mutant rabbit line. The USH2A knockout animals were subjected to a series of functional and morphological analyses, including acoustic auditory brainstem responses, electroretinography, optical coherence tomography, fundus photography, fundus autofluorescence, histology, and immunohistochemistry. Results: The USH2A mutant rabbits exhibit hyper-autofluorescent signals on fundus autofluorescence and hyper-reflective signals on optical coherence tomography images as early as 4 months of age, which indicate retinal pigment epithelium damage. Auditory brainstem response measurement in these rabbits showed moderate to severe hearing loss. Electroretinography signals of both rod and cone function were decreased in the USH2A mutant rabbits starting from 7 months of age and further decreased at 15 to 22 months of age, indicating progressive photoreceptor degeneration, which is confirmed by histopathological examination. Conclusions: Disruption of USH2A gene in rabbits is sufficient to induce hearing loss and progressive photoreceptor degeneration, mimicking the USH2A clinical disease. Translational Relevance: To our knowledge, this study presents the first mammalian model of USH2 showing the phenotype of retinitis pigmentosa. This study supports the use of rabbits as a clinically relevant large animal model to understand the pathogenesis and to develop novel therapeutics for Usher syndrome.

Novel HLA associations with outcomes of Mycobacterium tuberculosis exposure and sarcoidosis in individuals of African ancestry using nearest-neighbor feature selection.

Tuberculosis and sarcoidosis are inflammatory diseases characterized by granulomas that may occur in any organ but are often found in the lung. The panoply of classical human leukocyte antigen (HLA) alleles associated with occurrence and/or severity of both diseases varies considerably across studies. This heterogeneity of results, due to variation in factors like ancestry and disease subphenotype, as well as the use of simple modeling strategies to elucidate likely complex relationships, has made conclusions about underlying commonalities difficult. Here we perform HLA association analyses in individuals of African ancestry, using a greater resolution to include subphenotypes of disease and employing more comprehensive analytical techniques. Using a novel application of nearest-neighbor feature selection to score allelic importance, we investigated HLA allele association with Mycobacterium tuberculosis exposure outcomes in the first analysis of both latent Mycobacterium tuberculosis infection and active disease compared with those who, despite long-term exposure to active index cases, have neither positive diagnostic tests nor display clinical symptoms. We also compared persistent to resolved sarcoidosis. This led to the identification of novel HLA associations and evidence of main effects and interaction effects. We found strikingly similar main effects and interaction effects at HLA-DRB1, -DQB1, and -DPB1 in those resistant to tuberculosis (either latent or active) and persistent sarcoidosis.

Genome-Wide Association Study of Ocular Sarcoidosis Confirms HLA Associations and Implicates Barrier Function and Autoimmunity in African Americans.

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.

Isolated Pulmonary Valve Endocarditis.

Infective endocarditis involving the right side of the heart is typically associated with IV drug abuse and chronic indwelling catheters which commonly involve the tricuspid valve. Isolated pulmonary valve endocarditis (PVE) is a rare clinical entity. We report a rare case of a young woman with a history of end-stage renal disease (ESRD) on hemodialysis through tunneled catheter presenting with persistent coagulase-negative staphylococcus (CoNS) epidermidis bacteremia despite being on appropriate treatment with IV vancomycin for two weeks. Because of the persistent bacteremia, a transesophageal echocardiogram was performed and it revealed a thickened pulmonary valve with 1.8 cm vegetation in the left posterior cusp. She was successfully treated with IV daptomycin course for a total of six weeks. The recommended management for PVE is usually medical treatment with IV antibiotics gauged according to sensitivities of the cultures. Our article highlights the fact that the decision to manage it medically versus surgically can propose a challenge as the guidelines are not very robust.

Sarcoidosis: Pitfalls and Challenging Mimickers.

Sarcoidosis, a systemic granulomatous disease of unknown etiology, may mimic other conditions at presentation often resulting in delayed diagnosis. These conditions include infections, neoplasms, autoimmune, cardiovascular, and drug-induced diseases. This review highlights the most common sarcoidosis mimics that often lead to pitfalls in diagnosis and delay in appropriate treatment. Prior to invasive testing and initiating immunosuppressants (commonly corticosteroids), it is important to exclude sarcoid mimickers.

Myocardial contractile patterns predict future cardiac events in sarcoidosis.

The poor prognosis of cardiac sarcoidosis (CS) underscores the need for risk stratification. We evaluated 84 consecutive sarcoidosis patients who were referred for echocardiographic studies for cardiac symptoms or abnormal electrocardiograms. In 54 patients without previous diagnosis of CS or other known structural heart disease, 13 reached endpoints during (median) 24 months follow up. Significantly impaired peak systolic longitudinal strain in their original echocardiograms were identified in 13 of 17 left ventricular segments, clustering in the free wall, interventricular septum and apex. The regional (including 13 clustered segments) peak systolic longitudinal strain (RPSLS) were significantly impaired in patients with endpoints, compared with those without [(-11.4 ± 4.45) vs. (-18.7 ± 3.76) %, P < 0.00001]. Cox multivariate regression analysis revealed that RPSLS was independently associated with endpoints (HR 1.24; 95% CI 1.08-1.42, P = 0.002). Receiver operating characteristic curve suggested a cut-off RPSLS value of -15.0% (84.6% sensitivity and 86.8% specificity) to predict the occurrence of endpoints. Impaired RPSLS correlates with risk of adverse cardiac events in patients with extra-cardiac sarcoidosis.

Isolated extraocular orbital mass: a rare presentation of sarcoidosis.

We report a case of orbital sarcoidosis in a 66 year old male who presented with one month history of right eye swelling and intermittent diplopia. MRI revealed an enhancing infiltrative soft tissue mass in the inferior aspect of the right orbit and biopsy of the mass demonstrated non-necrotizing granulomas. Chest CT scan was normal and PET scan showed no other organ involvement. He was treated with tapering doses of prednisone over six months. Although relapse occurred while tapering prednisone to 20 mg per day, he responded well to the addition of azathioprine with complete resolution of visual difficulties and orbital the mass on repeat MRI. Sarcoidosis, presenting as an isolated orbital mass is rare, can be successfully treated and should be included in differential diagnosis.

High-Density Genetic Mapping Identifies New Susceptibility Variants in Sarcoidosis Phenotypes and Shows Genomic-driven Phenotypic Differences.

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.

Walking the tightrope: Using quantitative Doppler echocardiography to optimize ventricular filling pressures in patients hospitalized for acute heart failure.

Acutely decompensated heart failure (HF), one of the most common reasons for hospitalization, places an intense economic pressure on the health care system and adversely affects outcome of HF patients. Due to lack of reliable clinical tools to assess and monitor hemodynamics, accurate judgment on cardiac preload remains a challenge and complicates current inpatient HF management. In this review, we discuss the emerging role of real-time quantitative Doppler echocardiography (DE) in identifying inappropriate cardiac preload, monitoring volume status during the management, and improving quality of care in patients with acute HF. We illustrate the utilization of DE in common clinical scenarios, propose stepwise algorithms to effectively utilize serial quantitative DE in the bedside care, and discuss obstacles and prospects of quantitative DE utilization in HF management. These efforts will further prompt the development of multi-center prospective studies to define and validate the specific roles of quantitative DE in reducing hospitalization time and improving outcome of HF patients.

Novel pharmacotherapy of sarcoidosis.

Sarcoidosis is a multisystem granulomatous disease of unknown etiology that most commonly affects the lungs. Treatment of sarcoidosis can be challenging as it is often difficult to measure disease activity and distinguish active inflammation from fibrosis. Identifying the inflammatory mediators in sarcoidosis has led to the development and use of novel therapeutic agents. The goal of pharmacotherapy is to decrease granuloma accumulation, ameliorate symptoms and improve organ function. Systemic corticosteroids remain the first line treatment. Other immunosuppressive agents may be considered for the patients who respond poorly to corticosteroids or who experience significant adverse effects. An overview of pharmacotherapy of sarcoidosis is provided here.

Fine mapping of chromosome 15q25 implicates ZNF592 in neurosarcoidosis patients.

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).

Comparing Hospitalist-Resident to Hospitalist-Midlevel Practitioner Team Performance on Length of Stay and Direct Patient Care Cost.

BACKGROUND: A perception exists that residents are more costly than midlevel providers (MLPs). Since graduate medical education (GME) funding is a key issue for teaching programs, hospitals should conduct cost-benefit analyses when considering staffing models. OBJECTIVE: Our aim was to compare direct patient care costs and length of stay (LOS) between resident and MLP inpatient teams. METHODS: We queried the University HealthSystems Consortium clinical database (UHC CDB) for 13 553 "inpatient" discharges at our institution from July 2010 to June 2013. Patient assignment was based on bed availability rather than "educational value." Using the UHC CDB data, discharges for resident and MLP inpatient teams were compared for observed and expected LOS, direct cost derived from hospital charges, relative expected mortality (REM), and readmissions. We also compared patient satisfaction for physician domain questions using Press Ganey data. Bivariate analysis was performed for factors associated with differences between the 2 services using χ(2) analysis and Student t test for categorical and continuous variables, respectively. RESULTS: During the 3-year period, while REM was higher on the hospitalist-resident services (P < .001), LOS was shorter by 1.26 days, and per-patient direct costs derived from hospital charges were lower by $617. Patient satisfaction scores for the physician-selected questions were higher for resident teams. There were no differences in patient demographics, daily discharge rates, readmissions, or deaths. CONCLUSIONS: Resident teams are economically more efficient than MLP teams and have higher patient satisfaction. The findings offer guidance when considering GME costs and inpatient staffing models.

Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk.

RATIONALE: Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far. OBJECTIVES: To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci. METHODS: Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single-nucleotide polymorphisms. MEASUREMENTS AND MAIN RESULTS: Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3. CONCLUSIONS: Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics.

Association of HLA-DRB1 with Sarcoidosis Susceptibility and Progression in African Americans.

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.