ATF6B

Sarcoidosis is a heterogenous, multisystemic inflammatory disease that primarily affects lungs. In this study, we multiplex genotyped 18 single-nucleotide polymorphisms (SNPs) to replicate the findings from previous genome-wide association studies (GWAS) and candidate gene studies, and extended analyses to different clinical manifestations (Lofgren syndrome and chest X-ray [CXR] stages) including treatment response among West-Slavonic subjects (564 sarcoidosis patients and 301 healthy controls). We confirm the replication (with Bonferroni correction) of ANXA11 rs1049550 as protective variant for sarcoidosis (odds ratio [OR]=0.71, p=1.33×10^-3), non-LS (OR=0.66, p=2.71×10^-4) and CXR stages 2-4 (OR=0.62, p=7.48×10^-5) compared to controls in West-Slavonic population. We also validate the association of risk variants C6orf10 rs3129927 (OR=2.61, p=2.60×10^-8), TNFA rs1800629 (OR=1.56, p=6.65×10^-4), ATF6B rs3130288 (OR=2.75, p=1.06×10^-9) and HLA-DQA1 rs2187668 (OR=1.74, p=8.83×10^-4) with sarcoidosis compared to controls. For sub-phenotypes compared to controls, risk variants C6orf10 rs3129927 (OR=5.35, p=1.07×10^-12), TNFA rs1800629 (OR=2.66, p=5.94×10^-7), ATF6B rs3130288 (OR=5.24, p=5.21×10^-13), LRRC16A rs9295661 (OR=2.97, p=4.29×10^-4), HLA-DQA1 rs2187668 (OR=3.14, p=1.09×10^-6) and HLA-DRA rs3135394 (OR=5.23, p=8.25×10^-13) were associated with LS while C6orf10 rs3129927 (OR=1.96, p=4.27×10^-4) and ATF6B rs3130288 (OR=2.15, p=3.36×10^-5) were associated with non-LS. For CXR stages compared to controls, C6orf10 rs3129927 (OR=3.67, p=3.63×10^-11), TNFA rs1800629 (OR=1.84, p=1.32×10^-4), ATF6B rs3129927 (OR=3.63, p=1.82×10^-11), HLA-DQA1 rs2187668 (OR=2.13, p=9.59×10^-5) and HLA-DRA rs3135394 (OR=3.42, p=3.45×10^-10) were risk variants for early CXR stages 0-1 while C6orf10 rs3129927 (OR=1.99, p=5.51×10^-4), ATF6B rs3129927 (OR=2.23, p=3.52×10^-5) and HLA-DRA rs3135394 (OR=1.85, p=2.00×10^-3) were risk variants for advanced CXR stages 2-4. The present findings nominate gene variants as plausible prognostic markers for clinical phenotypes, treatment response and disease resolution/progression and may form the basis for establishing genotype-phenotype relationships in patients with sarcoidosis among West-Slavonic population.

A woman in her 20s presented with headache and back pain and was found to have a left renal mass with bony metastases. She underwent nephrectomy, and on histopathology was initially diagnosed with stage 4 clear cell sarcoma of the kidney. She underwent palliative radiation and chemotherapy; however, the disease progressed and she came to our centre. We started her on second-line chemotherapy and submitted her tissue blocks for review. Due to her age and lack of sclerotic stroma in the tissue, we had our doubts about the diagnosis and hence, tissue sample was submitted for next-generation sequencing (NGS). NGS detected an EWSR1::CREBL1 fusion, clinching the final diagnosis of sclerosing epithelioid fibrosarcoma of the kidney, a singular diagnosis rarely reported in the literature. Currently, the patient is post her third line of chemotherapy, is on maintenance, and is doing well and has resumed her daily activities.

The death of oral keratinocytes is a crucial step in the emergence of recurrent aphthous stomatitis (RAS, also known as aphthae or aphthous ulcers). Since there are no experimental models available to research aphthous ulcers, little is understood about this process. We hypothesize that saliva can be a data bank of information that offers insights on epithelial damage.

In this case-crossover study, we assessed the salivary proteome of patients with RAS (n = 36) in the presence and absence of ulcers using discovery proteomics and bioinformatics. Additionally, we contrasted these patterns with those of healthy individuals (n = 31) who had no prior aphthous ulceration.

Salivary proteome showed that during the ulcerative phase, controlled cell death was downregulated. Due to its ability to distinguish between individuals with and without ulcers, the ATF6B protein raises the possibility that endoplasmic reticulum (ER) stress is responsible for the damage that leads to the death of oral keratinocytes. The high abundance of TRAP1 and ERN1 matches with this biological discovery. The type of death is immunogenic, according to the functional data found in a cell death database.

We identified a cellular process that can lead to the death of oral keratinocytes in the etiopathogenesis process of RAS. Future studies should be conducted to identify what is responsible for the increase in ER stress signaling that would lead to an anti-cell death response.