Transcriptional profiling of HERV-K(HML-2) in amyotrophic lateral sclerosis and potential implications for expression of HML-2 proteins

Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. About 90% of ALS cases are without a known genetic cause. The human endogenous retrovirus multi-copy HERV-K(HML-2) group was recently reported to potentially contribute to neurodegeneration and disease pathogenesis in ALS because of transcriptional upregulation and toxic effects of HML-2 Envelope (Env) protein. Env and other proteins are encoded by some transcriptionally active HML-2 loci. However, more detailed information is required regarding which HML-2 loci are transcribed in ALS, which of their proteins are expressed, and differences between the disease and non-disease states. Methods For brain and spinal cord tissue samples from ALS patients and controls, we identified transcribed HML-2 loci by generating and mapping HML-2-specific cDNA sequences. We predicted expression of HML-2 env gene-derived proteins based on the observed cDNA sequences. Furthermore, we determined overall HML-2 transcript levels by RT-qPCR and investigated presence of HML-2 Env protein in ALS and control tissue samples by Western blotting. Results We identified 24 different transcribed HML-2 loci. Some of those loci are transcribed at relatively high levels. However, significant differences in HML-2 loci transcriptional activities were not seen when comparing ALS and controls. Likewise, overall HML-2 transcript levels, as determined by RT-qPCR, were not significantly different between ALS and controls. Indeed, we were unable to detect full-length HML-2 Env protein in ALS and control tissue samples despite reasonable sensitivity. Rather our analyses suggest that a number of HML-2 protein variants other than full-length Env may potentially be expressed in ALS patients. Conclusions Our results expand and refine recent publications on HERV-K(HML-2) and ALS. Some of our results are in conflict with recent findings and call for further specific analyses. Our profiling of HML-2 transcription in ALS opens up the possibility that HML-2 proteins other than canonical full-length Env may have to be considered when studying the role of HML-2 in ALS disease

Association of premature atherosclerotic cardiovascular disease with higher risk of cancer: A behavioral risk factor surveillance system study

Aim: The aim of this study was to investigate a possible association between atherosclerotic cardiovascular disease (ASCVD) and risk of cancer in young adults.Methods: We utilized data from the Behavioral Risk Factor Surveillance System, a nationally representative US telephone-based survey to identify participants in the age group of 18-55 years who reported a history of ASCVD. These patients were defined as having premature ASCVD. Weighted multivariable logistic regression models were used to study the association between premature ASCVD and cancer including various cancer subtypes.Results: Between 2016 and 2019, we identified 28 522 (3.3%) participants with a history of premature ASCVD. Compared with patients without premature ASCVD, individuals with premature ASCVD were more likely to be Black adults, have lower income, lower levels of education, reside in states without Medicaid expansion, have hypertension, diabetes mellitus, chronic kidney disease, obesity, and had delays in seeking medical care. Individuals with premature ASCVD were more likely to have been diagnosed with any form of cancer (13.7% vs 3.9%), and this association remained consistent in multivariable models (odds ratio, 95% confidence interval: 2.08 [1.72-2.50], P \u3c 0.01); this association was significant for head and neck (21.08[4.86-91.43], P \u3c 0.01), genitourinary (18.64 [3.69-94.24], P \u3c 0.01), and breast cancer (3.96 [1.51-10.35], P \u3c 0.01). Furthermore, this association was consistent when results were stratified based on gender and race, and in sensitivity analysis using propensity score matching.Conclusion: Premature ASCVD is associated with a higher risk of cancer. These data have important implications for the design of strategies to prevent ASCVD and cancer in young adults