ABSTRACT
Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.
Subject(s)
Dual Specificity Phosphatase 1/genetics , Eczema/diagnosis , Eczema/genetics , Receptor, Notch4/genetics , Sodium-Hydrogen Exchangers/genetics , Cytokine Receptor Common beta Subunit , Dual Specificity Phosphatase 1/chemistry , Dual Specificity Phosphatase 1/metabolism , Gene Expression , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Humans , Matrix Attachment Region Binding Proteins , Polymorphism, Single Nucleotide , Rare Diseases/genetics , Receptor, Notch4/chemistry , Receptor, Notch4/metabolism , Sodium-Hydrogen Exchangers/chemistry , Sodium-Hydrogen Exchangers/metabolismABSTRACT
Introduction Starting out with its discovery as small notches on fly wings, Neurogenic Locus Notch Homolog 4 (Notch4) signaling has been sparked as unique pathway implicated in cellular multiplication, differentiation, and regulation of stem cells. Its aberrant activation causes arrays of cancers including breast cancer. Objectives The aim of the present study was to evaluate the immunohistochemical expression level of Notch4 and its subcellular localization in invasive breast carcinoma. The correlation between Notch4 expression and both of clinicopathological parameters and immunohistochemical-based subtypes of studied cases was also assessed. Methods and materials Immunohistochemical expression of Notch4 receptor was examined in 60 specimens of paraffin-embedded sections of invasive breast cancer. Normal and hyperplastic breast tissue adjacent to carcinoma cells was also included in the study. Results There was a significant increase in the expression level of Notch4 protein in breast cancer, compared to that of normal breast tissue and hyperplastic breast lesions. Also, there was a statistical significant correlation between Notch4 expression level and tumor size, tumor grade, nodal metastasis, lymphovascular invasion, human epidermal growth factor receptor 2 (her2) status, Her2-enriched and triple negative subtypes, and Ki67. Furthermore, an inverse significant correlation was found between Notch4 expression and both of age and estrogen receptor (ER). No statistical significant correlation was found between Notch4 expression and tumor histological subtypes, Tumor infiltrating lymphocytes (TILs), and fibrosis. Conclusion Notch4 overexpression has been implicated in breast cancer development, progression and emergence of aggressive biological phenotypes. (AU)
Introducción Empezando por su descubrimiento como pequeños surcos en las alas de la mosca, la vía de señalización del homólogo 4 del Notch del locus neurogénico (Notch4) se ha revelado como la única vía implicada en la multiplicación y diferenciación celular, y regulación de las células madre. Su activación aberrante causa una serie de cánceres, incluyendo el cáncer de mama. Objetivos El objetivo del presente estudio fue evaluar el nivel de expresión inmunohistoquímica de Notch4, así como su localización subcelular en el cáncer de mama invasivo. También se evaluaron la correlación entre la expresión de Notch4 y los parámetros clínico-patológicos y subtipos con base inmunohistoquímica de los casos estudiados. Métodos y materiales Se examinó la expresión inmunohistoquímica del receptor de Notch4 en 60 muestras de secciones parafinadas de cáncer de mama. También se incluyeron en el estudio células hiperplásicas de tejido de mama, adyacentes al carcinoma. Resultados Se produjo un incremento significativo del nivel de expresión de la proteína Notch4 en el cáncer de mama, en comparación con el tejido normal de la mama y las lesiones de mama hiperplásicas. De igual modo, se produjo una correlación estadísticamente significativa entre el nivel de expresión de Notch4 y el tamaño y el grado tumoral, el desarrollo de nódulos metastásicos, la invasión linfovascular, el estatus de Her2 (receptor 2 del factor de crecimiento epidérmico humano), los subtipos Her2 enriquecido y triple negativo, y Ki-67. Además, se encontró una correlación significativa inversa entre la expresión de Notch4 y la edad, y el receptor de estrógenos (ER). No se encontró correlación estadísticamente significativa entre la expresión de Notch4 y los subtipos histológicos del tumor, linfocitos infiltrantes tumorales (TIL) y fibrosis. Conclusión... (AU)
Subject(s)
Humans , Female , Adult , Middle Aged , Aged , Receptor, Notch4/analysis , Receptor, Notch4/chemistry , Immunohistochemistry , Breast Neoplasms , Cross-Sectional Studies , EgyptABSTRACT
Notch signaling is essential for multicellular life, regulating core functions such as cellular identity, differentiation, and fate. These processes require highly sensitive systems to avoid going awry, and one such regulatory mechanism is through Notch intracellular domain dimerization. Select Notch target genes contain sequence-paired sites (SPS); motifs in which two Notch transcriptional activation complexes can bind and interact through Notch's ankyrin domain, resulting in enhanced transcriptional activation. This mechanism has been mostly studied through Notch1, and to date, the abilities of the other Notch family members have been left unexplored. Through the utilization of minimalized, SPS-driven luciferase assays, we were able to test the functional capacity of Notch dimers. Here we show that the Notch 2 and 3 NICDs also exhibit dimerization-induced signaling, following the same stringent requirements as seen with Notch1. Furthermore, our data suggested that Notch4 may also exhibit dimerization-induced signaling, although the amino acids required for Notch4 NICD dimerization appear to be different than those required for Notch 1, 2, and 3 NICD dimerization. Interestingly, we identified a mechanical difference between canonical and cryptic SPSs, leading to differences in their dimerization-induced regulation. Finally, we profiled the Notch family members' SPS gap distance preferences and found that they all prefer a 16-nucleotide gap, with little room for variation. In summary, this work highlights the potent and highly specific nature of Notch dimerization and refines the scope of this regulatory function.
