Overview and Update of Population Genetic Screening of Actionable Genes in the United States

Background: With the advancement in the knowledge of genetics and the emergence of evidence-based recommendations, genomic/genetic screening of adult-onset genetic conditions in healthy adults has gained attention in the past decade. Population genetic screening provides the opportunity to identify high-risk individuals within the general population regardless of medical indications. To date, no central database exists for population genetic screening programs. Research programs offer screening for actionable genetic conditions by referencing some guides provided by professional organizations, which were not intended for population screening application. This study aims to identify existing programs and create a patient-friendly educational resource about the existing programs that are actively enrolling participants. Methods: The list of programs was first obtained using Foss et al. (2022), followed by a review of CDC’s State Public Health Genomics Program Map and online searches of each state. The website was created on Wix, a cloud-based development platform. The Flesch–Kincaid readability test was used to assess website readability. Results: In addition to the All of Us Research Program, the study identified a total of 17 population genetic screening programs in the United States. Many programs are clustered either in the western states or the eastern states, leaving a gap in the middle and northern west states. This was also true for the enrollment sites for the All of Us Program. The website, a patient-friendly educational resource, included overviews of genetics, population genetic screening, common population screening conditions, and existing population genetic screening programs. The website scored 8.2nd-grade reading level. Conclusion: This study is one of the first efforts in identifying a comprehensive list of population genetic screening programs across the United States. The educational resource developed provides novel information to the public, which will continue to grow in importance as more opportunities for the public to participate in population genetic screening programs become available. Public Health Significance: This study contributes to public health by addressing one of the 10 essential services of public health: linking people to appropriate health services. Creating a patient-friendly tool that helps identify the programs can help initiate patients to participate in population screening programs

Investigating the Association Between Lynch Syndrome and the Prevalence of Autoimmune Disorders

Background: Lynch syndrome is caused by germline pathogenic variants in one of the mismatch repair (MMR) genes. It contributes to a significant portion of MMR deficient tumors, which are more susceptible to immune checkpoint inhibitors compared to MMR proficient tumors. MMR deficiency leads to high levels of microsatellite instability as insertion/deletion mutations are accumulated in microsatellites, leading to neoantigen production, which triggers immune responses. T-cell responses towards these neoantigens have been observed in the peripheral blood of individuals with Lynch syndrome without tumor development. These data suggest that having a germline MMR mutation may elicit an immune response, raising the question of whether patients with Lynch syndrome may be at a higher risk of developing autoimmune disorders. Methods: The study included 312 patients diagnosed with Lynch syndrome who are enrolled in the UPMC Hereditary Colorectal and Associated Tumor Registry. A retrospective chart review investigated the presence of 30 autoimmune disorders in these patients. The prevalence of each autoimmune disorder was compared to that of the general population. Chi-square tests were performed on demographic/cancer data and two-sided exact binomial tests were used to assess the significance of prevalence data. Results: Out of 312 patients, 35 individuals were identified to have autoimmune disorders, including 10 out of 30 autoimmune conditions assessed. Most of the identified autoimmune disorders did not show significant differences in their prevalence compared to the general population. The prevalence of inflammatory bowel disease (IBD), however, was 1.92% in this study compared to 0.48% in the general population (p=0.004237). Conclusion: This study suggests that patients with Lynch syndrome may have higher rates of IBD, but do not seem to have significantly higher frequencies of other autoimmune disorders. Future studies should involve larger sample sizes to conduct further statistical analyses on the cancer risks in patients with Lynch syndrome with autoimmune disorders and explore potential mechanisms of an IBD overrepresentation in patients with Lynch syndrome. Public Health Significance: Our investigation may contribute to the scientific community by providing knowledge that is yet to be explored and will potentially inform care and management for patients with Lynch syndrome and their providers

Inhibition of microbiota-dependent TMAO production attenuates chronic kidney disease in mice

Abstract Patients with chronic kidney disease (CKD) have elevated circulating levels of trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes and associated with cardiovascular diseases. High circulating levels of TMAO and its dietary precursor, choline, predict increased risk for development of CKD in apparently healthy subjects, and studies in mice fed TMAO or choline suggest that TMAO can contribute to kidney impairment and renal fibrosis. Here we examined the interactions between TMAO, kidney disease, and cardiovascular disease in mouse models. We observed that while female hyperlipidemic apoE KO mice fed a 0.2% adenine diet for 14 weeks developed CKD with elevated plasma levels of TMAO, provision of a non-lethal inhibitor of gut microbial trimethylamine (TMA) production, iodomethylcholine (IMC), significantly reduced multiple markers of renal injury (plasma creatinine, cystatin C, FGF23, and TMAO), reduced histopathologic evidence of fibrosis, and markedly attenuated development of microalbuminuria. In addition, while the adenine-induced CKD model significantly increased heart weight, a surrogate marker for myocardial hypertrophy, this was largely prevented by IMC supplementation. Surprisingly, adenine feeding did not increase atherosclerosis and significantly decreased the expression of inflammatory genes in the aorta compared to the control groups, effects unrelated to TMAO levels. Our data demonstrate that inhibition of TMAO production attenuated CKD development and cardiac hypertrophy in mice, suggesting that TMAO reduction may be a novel strategy in treating CKD and its cardiovascular disease complications

Inhibition of microbiota-dependent TMAO production attenuates chronic kidney disease in mice.

Patients with chronic kidney disease (CKD) have elevated circulating levels of trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes and associated with cardiovascular diseases. High circulating levels of TMAO and its dietary precursor, choline, predict increased risk for development of CKD in apparently healthy subjects, and studies in mice fed TMAO or choline suggest that TMAO can contribute to kidney impairment and renal fibrosis. Here we examined the interactions between TMAO, kidney disease, and cardiovascular disease in mouse models. We observed that while female hyperlipidemic apoE KO mice fed a 0.2% adenine diet for 14 weeks developed CKD with elevated plasma levels of TMAO, provision of a non-lethal inhibitor of gut microbial trimethylamine (TMA) production, iodomethylcholine (IMC), significantly reduced multiple markers of renal injury (plasma creatinine, cystatin C, FGF23, and TMAO), reduced histopathologic evidence of fibrosis, and markedly attenuated development of microalbuminuria. In addition, while the adenine-induced CKD model significantly increased heart weight, a surrogate marker for myocardial hypertrophy, this was largely prevented by IMC supplementation. Surprisingly, adenine feeding did not increase atherosclerosis and significantly decreased the expression of inflammatory genes in the aorta compared to the control groups, effects unrelated to TMAO levels. Our data demonstrate that inhibition of TMAO production attenuated CKD development and cardiac hypertrophy in mice, suggesting that TMAO reduction may be a novel strategy in treating CKD and its cardiovascular disease complications

Genome Sequences of Cluster K Mycobacteriophages Deby, LaterM, LilPharaoh, Paola, SgtBeansprout, and Sulley

Mycobacteriophages Deby, LaterM, LilPharaoh, Paola, SgtBeansprout, and Sulley were isolated from soil using Mycobacterium smegmatis mc2155. Genomic analysis indicated that they belong to subclusters K1 and K5. Their genomic architectures are typical of cluster K mycobacteriophages, with most variability occurring on the right end of the genome sequence