Integrative Analysis to Identify Common Genetic Markers of Metabolic Syndrome, Dementia, and Diabetes.

BACKGROUND Emerging data have established links between systemic metabolic dysfunction, such as diabetes and metabolic syndrome (MetS), with neurocognitive impairment, including dementia. The common gene signature and the associated signaling pathways of MetS, diabetes, and dementia have not been widely studied. MATERIAL AND METHODS We exploited the translational bioinformatics approach to choose the common gene signatures for both dementia and MetS. For this we employed "DisGeNET discovery platform". RESULTS Gene mining analysis revealed that a total of 173 genes (86 genes common to all three diseases) which comprised a proportion of 43% of the total genes associated with dementia. The gene enrichment analysis showed that these genes were involved in dysregulation in the neurological system (23.2%) and the central nervous system (20.8%) phenotype processes. The network analysis revealed APOE, APP, PARK2, CEPBP, PARP1, MT-CO2, CXCR4, IGFIR, CCR5, and PIK3CD as important nodes with significant interacting partners. The meta-regression analysis showed modest association of APOE with dementia and metabolic complications. The directionality of effects of the variants on Alzheimer disease is generally consistent with previous observations and did not differ by race/ethnicity (p>0.05), although our study had low power for this test. CONCLUSIONS Our novel approach showed APOE as a common gene signature with a link to dementia, MetS, and diabetes. Future gene association studies should focus on the association of gene polymorphisms with multiple disease models to identify novel putative drug targets.

Clinical and dermoscopic variation of basal cell carcinoma according to age of onset and anatomic location: a multicenter, retrospective study.

Basal cell carcinoma (BCC) is rare in young individuals and reported to possess different pathogenetic, clinical and histological features from late-onset BCC. However, the dermoscopic variability of BCC according to age of onset has not been investigated. Anatomic location was revealed to be associated with dermoscopic variation of BCC in Western population, but whether it applies to Asian population remains unknown. We evaluated the clinical and dermoscopic features of 448 BCCs and compared each feature by age of onset (age < 50/ > 50 years) and anatomic location. Early-onset BCCs occurred more frequently on non-sun-exposed sites (OR 3.28, P = 0.001) and were less pigmented than late-onset BCCs (P = 0.003). Blue-gray globules (OR 1.74, P = 0.037) and no vessels (OR 2.04, P = 0.021) were independently associated with early-onset BCCs, whereas arborizing telangiectasia (OR 0.30, P < 0.001), large blue-gray ovoid nests (OR 0.38, P < 0.001) and ulceration (OR 0.33, P < 0.001) were less common in early-onset BCCs. Scalp BCCs were significantly more pigmented than BCCs located elsewhere (P = 0.022). Superficial subtype (OR 5.90, P < 0.001), spoke-wheel areas (OR 4.78, P = 0.034), superficial erosions (OR 4.69, P = 0.003) and polymorph vessels (OR 6.86, P = 0.001) were independently associated with trunk BCCs, whereas nodular subtype (OR 5.48, P < 0.001) and arborizing telangiectasias (OR 3.64, P < 0.001) with BCCs on face and neck. Our findings suggest that age of onset and anatomic location are independent factors affecting the dermoscopic appearance of BCC.

The Polygenic Map of Keloid Fibroblasts Reveals Fibrosis-Associated Gene Alterations in Inflammation and Immune Responses.

Due to many inconsistencies in differentially expressed genes (DEGs) related to genomic expression changes during keloid formation and a lack of satisfactory prevention and treatment methods for this disease, the critical biomarkers related to inflammation and the immune response affecting keloid formation should be systematically clarified. Normal skin/keloid scar tissue-derived fibroblast genome expression data sets were obtained from the Gene Expression Omnibus (GEO) and ArrayExpress databases. Hub genes have a high degree of connectivity and gene function aggregation in the integration network. The hub DEGs were screened by gene-related protein-protein interactions (PPIs), and their biological processes and signaling pathways were annotated to identify critical biomarkers. Finally, eighty-one hub DEGs were selected for further analysis, and some noteworthy signaling pathways and genes were found to be closely related to keloid fibrosis. For example, IL17RA is involved in IL-17 signal transduction, TIMP2 and MMP14 activate extracellular matrix metalloproteinases, and TNC, ITGB2, and ITGA4 interact with cell surface integrins. Furthermore, changes in local immune cell activity in keloid tissue were detected by DEG expression, immune cell infiltration, and mass CyTOF analyses. The results showed that CD4+ T cells, CD8+ T cells and NK cells were abnormal in keloid tissue compared with normal skin tissue. These findings not only support the key roles of fibrosis-related pathways, immune cells and critical genes in the pathogenesis of keloids but also expand our understanding of targets that may be useful for the treatment of fibrotic diseases.

Association between rs1800629 polymorphism in tumor necrosis factor-α gene and dilated cardiomyopathy susceptibility: Evidence from case-control studies.

OBJECTIVE: Several published studies have investigated the association between the -308G/A (rs1800629) polymorphism in the tumor necrosis factor-α (TNF-α) gene and the risk of dilated cardiomyopathy (DCM). However, the TNF-α gene polymorphism has a controversial role in the pathogenesis of DCM among different populations. In the present study, a meta-analysis was performed to resolve this inconsistency. METHODS: Potentially eligible papers reporting an association between the TNF-α rs1800629 polymorphism and DCM susceptibility were searched in 4 databases including PubMed, EMBASE, Chinese Biomedical Database (CBM), and the Cochrane Library up to April 1, 2018. The odds ratio (OR) with its 95% confidence interval (CI) was used to estimate the strength of the associations. Subgroup analysis based on the ethnicity, studies with or without ischemic and valvular DCM was conducted. Publication bias detection was conducted using Begg test. RESULTS: Nine papers detailing case-control studies were included, reporting a total of 1339 DCM cases and 1677 healthy controls. The meta-analysis results indicated that TNF-α rs1800629 was associated with increased DCM susceptibility in the populations studied under the heterozygous model (AG vs GG: OR = 1.91, 95% CI = 1.05-3.50, P = .035) and dominant model (AG + AA vs GG: OR = 1.87, 95% CI = 1.01-3.45, P = .046). In the subgroup analysis for ethnicity, rs1800629 polymorphism was significantly associated with the susceptibility of DCM for Asians under the 5 models (A vs G: OR = 2.87, 95% CI = 1.56-5.30, P = .001; AA vs GG: OR = 3.95, 95% CI = 1.13-13.82, P = 0.031; AG vs GG: OR = 3.8, 95% CI = 1.57-9.19, P = .003; AA vs GG + AG: OR = 2.51, 95% CI = 1.41-4.49, P = .002; AG + AA vs GG: OR = 3.77, 95% CI = 1.54-9.20, P = .004). CONCLUSION: There may be a moderate association between TNF-α rs1800629 polymorphism and DCM susceptibility in the whole populations studied; however, TNF-α rs1800629 polymorphism was significantly associated with the susceptibility of DCM for Asians, which indicates that such associations may be different between ethnicities.