Increased body mass index is linked to systemic inflammation through altered chromatin co-accessibility in human preadipocytes.

Obesity-induced adipose tissue dysfunction can cause low-grade inflammation and downstream obesity comorbidities. Although preadipocytes may contribute to this pro-inflammatory environment, the underlying mechanisms are unclear. We used human primary preadipocytes from body mass index (BMI) -discordant monozygotic (MZ) twin pairs to generate epigenetic (ATAC-sequence) and transcriptomic (RNA-sequence) data for testing whether increased BMI alters the subnuclear compartmentalization of open chromatin in the twins' preadipocytes, causing downstream inflammation. Here we show that the co-accessibility of open chromatin, i.e. compartmentalization of chromatin activity, is altered in the higher vs lower BMI MZ siblings for a large subset ( ~ 88.5 Mb) of the active subnuclear compartments. Using the UK Biobank we show that variants within these regions contribute to systemic inflammation through interactions with BMI on C-reactive protein. In summary, open chromatin co-accessibility in human preadipocytes is disrupted among the higher BMI siblings, suggesting a mechanism how obesity may lead to inflammation via gene-environment interactions.

Incidental Meckel's Diverticulum With Neuroendocrine Tumor.

Meckel's diverticulum (MD), the most common congenital disease of the small bowel, commonly presents with symptoms of painless rectal bleeding and intestinal obstruction. The treatment of symptomatic MD involves resection of the lesion regardless of patient age; however, the excision of asymptomatic and incidentally identified MDs in adults remain controversial. On one hand, the complications arising from MDs decrease with age, leading to a lower benefit than risk ratio with prophylactic resection. On the other hand, malignancies, such as neuroendocrine tumors, may arise over time from untreated MDs. This can lead to poor prognostic complications, such as liver or lymph node metastases. In this case report, we describe an incidental Meckel's diverticulum discovered during an exploratory laparotomy for acute sigmoid diverticulitis in an adult male. Later biopsy findings discovered the lesion to contain a grade 1 neuroendocrine tumor. Based on our literature review findings, resection of the incidental Meckel's diverticulum was a reasonable approach given the low complication risks of the procedure and the possibility of malignant transformation and progression.

A Case of Severe Disseminated Autoeczematization Secondary to Cellulitis.

Autoeczematization, the dissemination of a local eczematous reaction to a distal site, is closely associated with lower extremity edema. Our patient is a 50-year-old man with a past medical history of drug-induced lupus to hydralazine and recent bilateral cellulitis in his lower extremities. He was presented with complaints of vesicles on his palms and soles and a scaling rash that had spread over his torso, arms, and trunk. Laboratory studies found no evidence of an active rheumatological condition with complement C3 and C4 levels being normal and no anti-dsDNA, anti-histone, anti-Smith, anti-ribonucleoprotein (anti-RNP), anti-centromere, anti-neutrophil cytoplasmic antibodies (ANCA), anti-Ro, or anti-La antibodies present. Moreover, syphilis, HIV, gonorrhea, chlamydia, rickettsia antibody, and Borrelia burgdorferi antibody testing was negative suggesting a non-infectious etiology of the rash. Hypothesizing a dermatologic origin of the rash, a skin biopsy was performed that revealed intermittent foci of moderate hyperparakeratosis and mild hypergranulosis indicative of eczematous dermatitis. Unfortunately, treatment of the disseminated rash with 10 mg of daily oral prednisone and topical triamcinolone acetonide 0.1% ointment proved inefficient, and methotrexate therapy was advised. We posit that cellulitis, a soft tissue infection under the skin, is a potential cause of disruption of the skin barrier that leads to activation of autosensitized T cells. These activated T cells circulate to distal areas of the skin and may lead to autoeczematization. The treatment of these id reactions with corticosteroids - both topical and oral - may be insufficient at reducing dermatitis and require the application of systemic methotrexate or cyclosporine. Through this case, we demonstrate the importance of treating id reactions by stepping up the intensity of treatment due to the severity of autosensitization-driven eczema.

Recurrent Bacterial Infections in Cutaneous T-cell Lymphoma.

Cutaneous T-cell lymphoma (CTCL) is a dermatologically manifesting immune cell disorder. We present a case of a 76-year-old female with a past medical history of CTCL, presenting with cellulitis of the left foot. After diagnosis of CTCL, the patient was admitted multiple times for treatment of cutaneous and soft-tissue infections with methicillin-resistant Staphylococcus aureus. Her recurrent infection with S. aureus had led to treatment for sepsis and a below-knee amputation on the right during prior hospitalizations. On this admission, the patient was treated with intravenous vancomycin and cefepime as in-patient and oral linezolid as out-patient. Recent articles show that patients with CTCL have an increased tendency to harbor S. aureus, which leads to recurrent infections. Additionally, evidence suggests that S. aureus toxins aid the progression of CTCL by helping the cancer to escape immune regulation. Our patient demonstrates this unique relationship between CTCL and S. aureus, and moreover, we make a case that S. aureus infection in CTCL, as compared to that in other dermatitis, should be better managed to not exacerbate the disease.

Exacerbation of Secondary Cold Agglutinin Syndrome in the Setting of SARS-CoV-2.

In this report, we present a case of exacerbation of cold agglutinin syndrome (CAS) potentially due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. An 83-year-old female with a history of cold agglutinin hemolytic anemia presented with shortness of breath, productive cough, worsening orthopnea, darkening fingers and urine, and jaundice. Laboratory investigations found elevated white blood cells (WBC) and total bilirubin, severely low hemoglobin, and positive direct Coombs test. Moreover, SARS-CoV-2 RNA was also found to be positive in a sample from the nasal swab by reverse transcription-polymerase chain reaction (RT-PCR), indicating exacerbation of CAS secondary to viral coronavirus 2019 (COVID-19) infection. A treatment regime for SARS-CoV-2 consisting of five days of remdesivir and seven days of dexamethasone 6 mg IV was initiated, resulting in significant improvement in the patient's condition.

Treatment of Elsberg Syndrome Causes Fever of Unknown Origin Attributable to Drug Reaction.

A 56-year-old male with a history of non-adherence to HIV anti-retroviral therapy (ART) presented with Elsberg syndrome - varicella reactivation causing fever, painful dermatomal rash, weakness of bilateral lower extremities, and urinary and bowel dysfunction. On the third day of hospitalization, the patient developed altered mental status. An investigation for encephalitis and myelitis revealed a CD4 count of 150 cells/uL, viral load of about 150,000 copies/mL, and MRI of the lumbar spine demonstrating thickening of the cauda equina. Cerebrospinal fluid (CSF) from lumbar puncture confirmed the presence of varicella-zoster virus (VZV). Treatment with acyclovir for 21 days was initiated. However, the patient developed a persistent fever. Evaluation for the source of the fever resulted in identification of anti-viral therapy as the cause. In conclusion, the present report provides a unique example of acyclovir-induced fever developed on treatment of Elsberg syndrome.

The causal effect of obesity on prediabetes and insulin resistance reveals the important role of adipose tissue in insulin resistance.

Reverse causality has made it difficult to establish the causal directions between obesity and prediabetes and obesity and insulin resistance. To disentangle whether obesity causally drives prediabetes and insulin resistance already in non-diabetic individuals, we utilized the UK Biobank and METSIM cohort to perform a Mendelian randomization (MR) analyses in the non-diabetic individuals. Our results suggest that both prediabetes and systemic insulin resistance are caused by obesity (p = 1.2×10-3 and p = 3.1×10-24). As obesity reflects the amount of body fat, we next studied how adipose tissue affects insulin resistance. We performed both bulk RNA-sequencing and single nucleus RNA sequencing on frozen human subcutaneous adipose biopsies to assess adipose cell-type heterogeneity and mitochondrial (MT) gene expression in insulin resistance. We discovered that the adipose MT gene expression and body fat percent are both independently associated with insulin resistance (p≤0.05 for each) when adjusting for the decomposed adipose cell-type proportions. Next, we showed that these 3 factors, adipose MT gene expression, body fat percent, and adipose cell types, explain a substantial amount (44.39%) of variance in insulin resistance and can be used to predict it (p≤2.64×10-5 in 3 independent human cohorts). In summary, we demonstrated that obesity is a strong determinant of both prediabetes and insulin resistance, and discovered that individuals' adipose cell-type composition, adipose MT gene expression, and body fat percent predict their insulin resistance, emphasizing the critical role of adipose tissue in systemic insulin resistance.

Novel Lipid Long Intervening Noncoding RNA, Oligodendrocyte Maturation-Associated Long Intergenic Noncoding RNA, Regulates the Liver Steatosis Gene Stearoyl-Coenzyme A Desaturase As an Enhancer RNA.

The global obesity epidemic is driving the concomitant rise in nonalcoholic fatty liver disease (NAFLD). To identify new genes involved in central liver functions, we examined liver RNA-sequence data from 259 patients who underwent morbidly obese bariatric surgery. Of these patients, 84 had normal liver histology, 40 simple steatosis, 43 nonalcoholic steatohepatitis, and the remaining 92 patients had varying degrees of NAFLD based on liver histology. We discovered oligodendrocyte maturation-associated long intergenic noncoding RNA (OLMALINC), a long intervening noncoding RNA (lincRNA) in a human liver co-expression network (n = 75 genes) that was strongly associated with statin use and serum triglycerides (TGs). OLMALINC liver expression was highly correlated with the expression of known cholesterol biosynthesis genes and stearoyl-coenzyme A desaturase (SCD). SCD is the rate-limiting enzyme in monounsaturated fatty acids and a key TG gene that is known to be up-regulated in liver steatosis and NAFLD and resides adjacent to OLMALINC on the human chromosome 10q24.31. Next, we functionally demonstrated that OLMALINC regulates SCD as an enhancer-RNA (eRNA), thus describing the first lincRNA that functions as an eRNA to regulate lipid metabolism. Specifically, we show that OLMALINC promotes liver expression of SCD in cis through regional chromosomal DNA-DNA looping interactions. Conclusion: The primate-specific lincRNA OLMALINC is a novel epigenetic regulator of the key TG and NAFLD gene SCD.

Reverse gene-environment interaction approach to identify variants influencing body-mass index in humans.

Identifying gene-environment interactions (GxEs) contributing to human cardiometabolic disorders is challenging. Here we apply a reverse GxE candidate search by deriving candidate variants from promoter-enhancer interactions that respond to dietary fatty acid challenge through altered chromatin accessibility in human primary adipocytes. We then test all variants residing in the lipid-responsive open chromatin sites within adipocyte promoter-enhancer contacts for interaction effects between the genotype and dietary saturated fat intake on body mass index (BMI) in the UK Biobank. We discover 14 novel GxE variants in 12 lipid-responsive promoters, including well-known lipid genes (LIPE, CARM1, and PLIN2) and novel genes, such as LDB3, for which we provide further functional and integrative genomics evidence. We further identify 24 GxE variants in enhancers, totaling 38 new GxE variants for BMI in the UK Biobank, demonstrating that molecular genomics data produced in physiologically relevant contexts can discover new functional GxE mechanisms in humans.

Author Correction: Integration of human adipocyte chromosomal interactions with adipose gene expression prioritizes obesity-related genes from GWAS.

In the original version of this Article, Supplementary Table 10 contained incorrect primer sequences for the mobility shift assay for SNP rs4776984. These errors have now been fixed and the corrected version of the Supplementary Information PDF is available to download from the HTML version of the Article.

Integration of human adipocyte chromosomal interactions with adipose gene expression prioritizes obesity-related genes from GWAS.

Increased adiposity is a hallmark of obesity and overweight, which affect 2.2 billion people world-wide. Understanding the genetic and molecular mechanisms that underlie obesity-related phenotypes can help to improve treatment options and drug development. Here we perform promoter Capture Hi-C in human adipocytes to investigate interactions between gene promoters and distal elements as a transcription-regulating mechanism contributing to these phenotypes. We find that promoter-interacting elements in human adipocytes are enriched for adipose-related transcription factor motifs, such as PPARG and CEBPB, and contribute to heritability of cis-regulated gene expression. We further intersect these data with published genome-wide association studies for BMI and BMI-related metabolic traits to identify the genes that are under genetic cis regulation in human adipocytes via chromosomal interactions. This integrative genomics approach identifies four cis-eQTL-eGene relationships associated with BMI or obesity-related traits, including rs4776984 and MAP2K5, which we further confirm by EMSA, and highlights 38 additional candidate genes.

Molecular Characterization of the Lipid Genome-Wide Association Study Signal on Chromosome 18q11.2 Implicates HNF4A-Mediated Regulation of the TMEM241 Gene.

OBJECTIVE: We recently identified a locus on chromosome 18q11.2 for high serum triglycerides in Mexicans. We hypothesize that the lead genome-wide association study single-nucleotide polymorphism rs9949617, or its linkage disequilibrium proxies, regulates 1 of the 5 genes in the triglyceride-associated region. APPROACH AND RESULTS: We performed a linkage disequilibrium analysis and found 9 additional variants in linkage disequilibrium (r(2)>0.7) with the lead single-nucleotide polymorphism. To select the variants for functional analyses, we annotated the 10 variants using DNase I hypersensitive sites, transcription factor and chromatin states and identified rs17259126 as the lead candidate variant for functional in vitro validation. Using luciferase transcriptional reporter assay in liver HepG2 cells, we found that the G allele exhibits a significantly lower effect on transcription (P<0.05). The electrophoretic mobility shift and ChIPqPCR (chromatin immunoprecipitation coupled with quantitative polymerase chain reaction) assays confirmed that the minor G allele of rs17259126 disrupts an hepatocyte nuclear factor 4 α-binding site. To find the regional candidate gene, we performed a local expression quantitative trait locus analysis and found that rs17259126 and its linkage disequilibrium proxies alter expression of the regional transmembrane protein 241 (TMEM241) gene in 795 adipose RNAs from the Metabolic Syndrome In Men (METSIM) cohort (P=6.11×10(-07)-5.80×10(-04)). These results were replicated in expression profiles of TMEM241 from the Multiple Tissue Human Expression Resource (MuTHER; n=856). CONCLUSIONS: The Mexican genome-wide association study signal for high serum triglycerides on chromosome 18q11.2 harbors a regulatory single-nucleotide polymorphism, rs17259126, which disrupts normal hepatocyte nuclear factor 4 α binding and decreases the expression of the regional TMEM241 gene. Our data suggest that decreased transcript levels of TMEM241 contribute to increased triglyceride levels in Mexicans.