How Healthy Lifestyle Habits Have Interacted with SARS-CoV-2 Infection and the Effectiveness of COVID-19 Vaccinations: Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

Introduction: To examine the interaction between lifestyle habits and the COVID-19 vaccinations for preventing SARS-CoV-2 infection, we analyzed 11,016 adult participants registered in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Methods: Lifestyle variables, including regular exercise, smoking and drinking habits, sleep status, body mass index, and daily breakfast consumption, were assessed from 2014 to 2019 using baseline questionnaires. Information on SARS-CoV-2 infection and the COVID-19 vaccination were also collected from March 2020 to May 2023. The study period was divided into two in the postvaccination phase: the first period (the beginning of the vaccination program) and the second period (the fourth shot onward). Results: In the Cox proportional-hazards model analysis, the five-time vaccinations group showed a significantly lower risk of SARS-CoV-2 infection adjusted age, sex, underlying health condition, and lifestyle variables (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.76-0.86). Logistic regression analysis revealed that a higher number of vaccinations was significantly associated with a low risk of SARS-CoV-2 infection regardless of lifestyle habits (three times in the first period: odds ratio [OR] 0.19, 95% CI 0.15-0.24; five times in the second period: OR 0.07, 95% CI 0.05-0.11 vs. none). Regarding lifestyle habits, the risk reduction in those who had sleep satisfaction (OR 0.12, 95% CI 0.08-0.18) was slightly larger than in those who had sleep dissatisfaction (OR 0.23, 95% CI 0.17-0.32) in the group with the highest number of vaccinations in the first period; however, this interaction was hardly confirmed in the second period when the number of infected cases significantly increased. Conclusions: Our findings indicated that a higher number of COVID-19 vaccinations was associated with reduced risk of SARS-CoV-2 infection; otherwise, we may need to understand the advantages and limitations of a healthy lifestyle for preventing infection depending on the situation with vaccinations and infection spreading.

Genetic Risk, Healthy Lifestyle Adherence, and Risk of Developing Diabetes in the Japanese Population.

AIM: This study examined the relationship between genetic risk, healthy lifestyle, and risk of developing diabetes. METHODS: This prospective cohort study included 11,014 diabetes-free individuals ≥ 20 years old from the Tohoku Medical Megabank Community-based cohort study. Lifestyle scores, including the body mass index, smoking, physical activity, and gamma-glutamyl transferase (marker of alcohol consumption), were assigned, and participants were categorized into ideal, intermediate, and poor lifestyles. A polygenic risk score (PRS) was constructed based on the type 2 diabetes loci from the BioBank Japan study. A multiple logistic regression model was used to estimate the association between genetic risk, healthy lifestyle, and diabetes incidence and to calculate the area under the receiver operating characteristic curve (AUROC). RESULT: Of the 11,014 adults included (67.8% women; mean age [standard deviation], 59.1 [11.3] years old), 297 (2.7%) developed diabetes during a mean 4.3 (0.8) years of follow-up. Genetic and lifestyle score is independently associated with the development of diabetes. Compared with the low genetic risk and ideal lifestyle groups, the odds ratio was 3.31 for the low genetic risk and poor lifestyle group. When the PRS was integrated into a model including the lifestyle and family history, the AUROC significantly improved to 0.719 (95% confidence interval [95% CI]: 0.692-0.747) compared to a model including only the lifestyle and family history (0.703 [95% CI, 0.674-0.732]). CONCLUSION: Our findings indicate that adherence to a healthy lifestyle is important for preventing diabetes, regardless of genetic risk. In addition, genetic risk might provide information beyond lifestyle and family history to stratify individuals at high risk of developing diabetes.

Activation of NOTCH signaling impedes cell proliferation and survival in acute megakaryoblastic leukemia.

The genetic lesions that drive acute megakaryoblastic leukemia (AMKL) have not been fully elucidated. To search for genetic alterations in AMKL, we performed targeted deep sequencing in 34 AMKL patient samples and 8 AMKL cell lines and detected frequent genetic mutations in the NOTCH pathway in addition to previously reported alterations in GATA-1 and the JAK-STAT pathway. Pharmacological and genetic NOTCH activation, but not inhibition, significantly suppressed AMKL cell proliferation in both in vitro and in vivo assays employing a patient-derived xenograft model. These results suggest that NOTCH inactivation underlies AMKL leukemogenesis. and NOTCH activation holds the potential for therapeutic application in AMKL.

Bag1 protein loss sensitizes mouse embryonic fibroblasts to glutathione depletion.

Bcl2-associated athanogene-1 protein (Bag1) acts as a co-chaperone of heat shock protein 70 and heat shock cognate 70 and regulates multiple cellular processes, including cell proliferation, apoptosis, environmental stress response, and drug resistance. Since Bag1 knockout mice exhibited fetal lethality, the in vivo function of Bag1 remains unclear. In this study, we established a mouse line expressing Bag1 gene missing exon 5, which corresponds to an encoding region for the interface of heat shock protein 70/heat shock cognate 70. Despite mice carrying homoalleles of the Bag1 mutant (Bag1Δex5) expressing undetectable levels of Bag1, Bag1Δex5 homozygous mice developed without abnormalities. Bag1Δex5 protein was found to be highly unstable in cells and in vitro. We found that the growth of mouse embryonic fibroblasts derived from Bag1Δex5-homo mice was attenuated by doxorubicin and a glutathione (GSH) synthesis inhibitor, buthionine sulfoximine. In response to buthionine sulfoximine, Bag1Δex5-mouse embryonic fibroblasts exhibited a higher dropping rate of GSH relative to the oxidized glutathione level. In addition, Bag1 might mitigate cellular hydrogen peroxide levels. Taken together, our results demonstrate that the loss of Bag1 did not affect mouse development and that Bag1 is involved in intracellular GSH homeostasis, namely redox homeostasis.

PNPO-PLP axis senses prolonged hypoxia in macrophages by regulating lysosomal activity.

Oxygen is critical for all metazoan organisms on the earth and impacts various biological processes in physiological and pathological conditions. While oxygen-sensing systems inducing acute hypoxic responses, including the hypoxia-inducible factor pathway, have been identified, those operating in prolonged hypoxia remain to be elucidated. Here we show that pyridoxine 5'-phosphate oxidase (PNPO), which catalyses bioactivation of vitamin B6, serves as an oxygen sensor and regulates lysosomal activity in macrophages. Decreased PNPO activity under prolonged hypoxia reduced an active form of vitamin B6, pyridoxal 5'-phosphate (PLP), and inhibited lysosomal acidification, which in macrophages led to iron dysregulation, TET2 protein loss and delayed resolution of the inflammatory response. Among PLP-dependent metabolism, supersulfide synthesis was suppressed in prolonged hypoxia, resulting in the lysosomal inhibition and consequent proinflammatory phenotypes of macrophages. The PNPO-PLP axis creates a distinct layer of oxygen sensing that gradually shuts down PLP-dependent metabolism in response to prolonged oxygen deprivation.

Differential squamous cell fates elicited by NRF2 gain of function versus KEAP1 loss of function.

Clinical evidence has revealed that high-level activation of NRF2 caused by somatic mutations in NRF2 (NFE2L2) is frequently detected in esophageal squamous cell carcinoma (ESCC), whereas that caused by somatic mutations in KEAP1, a negative regulator of NRF2, is not. Here, we aspire to generate a mouse model of NRF2-activated ESCC using the cancer-derived NRF2L30F mutation and cancer driver mutant TRP53R172H. Concomitant expression of NRF2L30F and TRP53R172H results in formation of NRF2-activated ESCC-like lesions. In contrast, while squamous-cell-specific deletion of KEAP1 induces similar NRF2 hyperactivation, the loss of KEAP1 combined with expression of TRP53R172H does not elicit the formation of ESCC-like lesions. Instead, KEAP1-deleted cells disappear from the esophageal epithelium over time. These findings demonstrate that, while cellular NRF2 levels are similarly induced, NRF2 gain of function and KEAP1 loss of function elicits distinct fates of squamous cells. The NRF2L30F mutant mouse model developed here will be instrumental in elucidating the mechanistic basis leading to NRF2-activated ESCC.

The Health History of First-Degree Relatives' Dyslipidemia Can Affect Preferences and Intentions following the Return of Genomic Results for Monogenic Familial Hypercholesterolemia.

Genetic testing is key in modern healthcare, particularly for monogenic disorders such as familial hypercholesterolemia. This Tohoku Medical Megabank Project study explored the impact of first-degree relatives' dyslipidemia history on individual responses to familial hypercholesterolemia genomic results. Involving 214 participants and using Japan's 3.5KJPN genome reference panel, the study assessed preferences and intentions regarding familial hypercholesterolemia genetic testing results. The data revealed a significant inclination among participants with a family history of dyslipidemia to share their genetic test results, with more than 80% of participants intending to share positive results with their partners and children and 98.1% acknowledging the usefulness of positive results for personal health management. The study underscores the importance of family health history in genetic-testing perceptions, highlighting the need for family-centered approaches in genetic counseling and healthcare. Notable study limitations include the regional scope and reliance on questionnaire data. The study results emphasize the association between family health history and genetic-testing attitudes and decisions.

Strain-dependent modifiers exacerbate familial leukemia caused by GATA1-deficiency.

GATA1 plays a critical role in differentiation, proliferation, and apoptosis during erythropoiesis. We developed a Gata1 knock-down allele (Gata1.05) that results in GATA1 expression at 5% of endogenous level. In female mice heterozygous for both the Gata1.05 and wild-type alleles, we observed a predisposition to erythroblastic leukemia three to six months after birth. Since no male Gata1.05 progeny survive gestation, we originally maintained heterozygous females in a mixed genetic background of C57BL/6J and DBA/2 strains. Around 30% of these mice reproducibly develop leukemia, but the other subset did not develop leukemia, even though they harbor a high number of preleukemic erythroblasts. These observations prompted us to hypothesize that there may be potential influence of genetic determinants on the progression of Gata1.05-driven hematopoietic precursors to full-blown leukemia. In an initial examination of Gata1.05/X mice backcrossed into C3H/He, BALB/c, DBA/2, C57BL/6J and 129X1/SvJ strains, we discerned that the backgrounds of C57BL/6J and 129X1/SvJ significantly expedited leukemia onset in Gata1.05/X mice. Conversely, backgrounds of C3H/He, BALB/c and DBA/2 did not substantially modify the effect of the Gata1 mutation. This indicates the existence of genetic modifiers that accentuate Gata1.05 leukemogenesis. Subsequent cohort studies evaluated Gata1.05/X mice within mix backgrounds of BALB/c:129X1/SvJ and BALB/c:C57BL/6J. In these settings, Gata1.05-driven leukemia manifested in autosomal dominant patterns within the 129X1/SvJ background and in autosomal recessive patterns within C57BL/6J background. To the best of our knowledge, this study provides the inaugural evidence of genetic modifiers that can reshape the outcome based on leukemia-associated gene signatures.

The abundance of the short GATA1 isoform affects megakaryocyte differentiation and leukemic predisposition in mice.

Transcription factor GATA1 controls the delicate balance between proliferation, differentiation and apoptosis in both the erythroid and megakaryocytic lineages. In addition to full-length GATA1, there is an GATA1 isoform, GATA1s, that lacks the amino-terminal transactivation domain. Somatic GATA1 mutations that lead to the exclusive production of GATA1s appear to be necessary and sufficient for the development of a preleukemic condition called transient myeloproliferative disorder (TMD) in Down syndrome newborns. Subsequent clonal evolution among latent TMD blasts leads to the development of acute megakaryoblastic leukemia (AMKL). We originally established transgenic mice that express only GATA1s, which exhibit hyperproliferation of immature megakaryocytes, thus mimicking human TMD; however, these mice never developed AMKL. Here, we report that transgenic mice expressing moderate levels of GATA1s, i.e., roughly comparable levels to endogenous GATA1, were prone to develop AMKL in young adults. However, when GATA1s is expressed at levels significantly exceeding that of endogenous GATA1, the development of leukemia was restrained in a dose dependent manner. If the transgenic increase of GATA1s in progenitors remains small, GATA1s supports the terminal maturation of megakaryocyte progenitors insufficiently, and consequently the progenitors persisted, leading to an increased probability for acquisition of additional genetic modifications. In contrast, more abundant GATA1s expression compensates for this maturation block, enabling megakaryocytic progenitors to fully differentiate. This study provides evidence for the clinical observation that the abundance of GATA1s correlates well with the progression to AMKL in Down syndrome.

Dietary melatonin and liver cancer incidence in Japan: From the Takayama study.

There is some biological plausibility that exogenous melatonin plays a role in preventing liver carcinogenesis. There has been little research on the association between melatonin intake in a normal diet and health outcomes. We evaluated the association between dietary melatonin intake and the incidence of liver cancer in a population-based prospective study in Japan. This study included 30,824 residents of Takayama city who were 35 years of age or older in 1992 and had participated in the Takayama study, Japan. Dietary intake was assessed using a validated food frequency questionnaire at the baseline. Melatonin content in foods was measured by liquid chromatography-tandem mass spectrometry. Cancer incidence was confirmed through regional population-based cancer registries in Gifu. Liver cancer was defined as code C22 according to the International Classification of Diseases and Related Health Problems, 10th Revision. Hazard ratios for liver cancer were estimated for the tertile groups of melatonin intake using a Cox proportional hazards model. During the mean follow-up period of 13.6 years, 189 individuals developed liver cancer. Compared with subjects in the lowest tertile of melatonin intake, those in the middle and highest tertiles had decreased risks of liver cancer, with a significant linear trend after multivariate adjustments (hazard ratios: 0.64 and 0.65, respectively, trend p = 0.023). There was no significant interaction by sex (interaction p = 0.54). This initial finding, which needs to be confirmed by further studies, suggests that consuming melatonin-containing foods might play a role in the prevention of liver cancer.

Genetic architecture of alcohol consumption identified by a genotype-stratified GWAS and impact on esophageal cancer risk in Japanese people.

An East Asian-specific variant on aldehyde dehydrogenase 2 (ALDH2 rs671, G>A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide association study meta-analysis of alcohol consumption in 175,672 Japanese individuals to explore gene-gene interactions with rs671 behind drinking behavior. The analysis identified three genome-wide significant loci (GCKR, KLB, and ADH1B) in wild-type homozygotes and six (GCKR, ADH1B, ALDH1B1, ALDH1A1, ALDH2, and GOT2) in heterozygotes, with five showing genome-wide significant interaction with rs671. Genetic correlation analyses revealed ancestry-specific genetic architecture in heterozygotes. Of the discovered loci, four (GCKR, ADH1B, ALDH1A1, and ALDH2) were suggested to interact with rs671 in the risk of esophageal cancer, a representative alcohol-related disease. Our results identify the genotype-specific genetic architecture of alcohol consumption and reveal its potential impact on alcohol-related disease risk.