Association of mitochondrial DNA haplogroup and hearing impairment with aging in Japanese general population of the Iwaki Health Promotion Project

Age-related hearing loss (ARHL) is a complex multifactorial disorder. Studies in animals, including mitochondria-mutator mice, and in human suggest that oxidative stress and mitochondrial disturbance play an important role in the pathoetiology of ARHL. Mitochondrial DNA (mtDNA) haplogroups are populations with genetically similar traits, and they have been reported to affect the mitochondrial function of oxidative phosphorylation. To gain further insights into the relationships between mitochondrial haplotypes and the susceptibility to cochlear aging, in this study, we aimed to elucidate how the differences in mtDNA haplogroups may affect ARHL development in Japanese general population. We focused on early onset ARHL, as the same mtDNA haplogroup can show either a negative or positive effect on systemic co-morbidities of ARHL that appear later in life. A total of 1167 participants of the Iwaki Health Promotion Project were surveyed in 2014, and 12 major haplotype groups (D4a, D4b, D5, G1, G2, M7a, M7b, A, B4, B5, N9, and F) were selected for the analysis. A total of 698 subjects aged 30 to 65 years were included in the statistical analysis, and the hearing loss group consisted of 112 males (40.3%) and 111 females (26.4%). Multiple logistic regression analysis showed that the male subjects belonging to haplogroup A had a significantly increased risk of hearing loss, whereas the female subjects belonging to haplogroup N9 had a significantly decreased risk of hearing loss. These results suggested that the mtDNA haplogroup may be an indicator for future risk of morbidity associated with ARHL.

A Comparative Study of Site-Specific Distribution of Aging-Related Tau Astrogliopathy and Its Risk Factors Between Alzheimer Disease and Cognitive Healthy Brains: The Hisayama Study

Knowledge of aging-related tau astrogliopathy (ARTAG) in healthy elderly individuals remains incomplete and studies to date have not focused on the olfactory nerve, which is a vulnerable site of various neurodegenerative disease pathologies. We performed a semiquantitative evaluation of ARTAG in 110 autopsies in the Japanese general population (Hisayama study). Our analysis focused on Alzheimer disease (AD) and cognitive healthy cases (HC), including primary age-related tauopathy. Among the various diseased and nondiseased brains, ARTAG was frequently observed in the amygdala. The ARTAG of HC was exclusively limited to the amygdala whereas gray matter ARTAG in AD cases was prominent in the putamen and middle frontal gyrus following the amygdala. ARTAG of the olfactory nerve mainly consists of subpial pathology that was milder in the amygdala. A logistic regression analysis revealed that age at death and neurofibrillary tangle Braak stage significantly affected the ARTAG of HC. In AD, age at death and male gender had significant effects on ARTAG. In addition, the Thal phase significantly affected the presence of white matter ARTAG. In conclusion, our research revealed differences in the distribution of ARTAG and affected variables across AD and HC individuals.

Declines in health literacy and health-related quality of life during the COVID-19 pandemic: a longitudinal study of the Japanese general population

Background During the coronavirus disease 2019 (COVID-19) pandemic, the importance of health literacy (HL) was addressed by public health researchers. We longitudinally examined the changes in general HL and health-related quality of life (HRQOL) between immediately before the COVID-19 outbreak and 1 year later, and how general HL before the outbreak was related to changes in HRQOL in the Japanese general population. Methods Among the Japanese residents aged 20–79 years who participated in our previous study in 2017, 826 were followed-up via self-administered questionnaires in January 2020 and February 2021, for the purposes of this study. The HRQOL was measured using the SF-8, a short version of the SF-36 Health Survey, and general HL was measured using the short form of the European Health Literacy Survey Questionnaire (HL-SF12) in the 2020 and 2021 surveys. Results The physical and mental dimensions of HRQOL as well as general HL declined significantly from immediately before the COVID-19 outbreak to 1 year later (p = .010, p < .001 and p < .001, respectively). The decline in HRQOL, especially the mental dimension, was more significant among women. A lower economic status was also related to a greater decline in HRQOL (p = .026 for the physical dimension and p = .012 for the mental dimension). Higher general HL before the COVID-19 outbreak was associated with a lesser decline in HRQOL in both the physical and mental dimensions (p = .040 and p < .001, respectively) after controlling for possible confounding variables such as gender and economic status. Conclusions Healthcare support is crucial for vulnerable populations during and after the pandemic. General HL may be important for attenuating the decline in HRQOL, by enabling effective use of health information and adaptive behaviors toward health threats. Further studies are needed to better understand the association between HL and HRQOL.

Effect of endothelial nitric oxide synthase gene polymorphism on cardiovascular death and nonfatal myocardial infarction in Japanese general population

Introduction Single nucleotide polymorphisms (SNP) of endothelial nitric oxide synthase (NOS3) have been reported to be associated with diabetes mellitus and myocardial infarction. However, few reports have prospectively investigated the effects of NOS3 SNP on cardiovascular death and nonfatal myocardial infarction. Purpose The purpose of this study was to investigate the impact of NOS3 SNP on cardiovascular death and the development of nonfatal myocardial infarction. Methods This prospective cohort study included 2,752 subjects (aged ≥40) who participated in a community based health checkup. We genotyped two SNPs within NOS3 (rs1808593, rs1799983). All subjects were prospectively followed during the median follow-up period of 15.4 years with the end point of cardiovascular death and nonfatal myocardial infarction. Results The homozygous G-allele (GG), heterozygous (GT), and homozygous T-allele (TT) carriers of rs1808593 were identified in 60 (2%), 706 (26%), and 1,986 (72%) subjects, respectively. Kaplan-Meier analysis demonstrated that homozygous G-allele carriers of rs1808593 had the greater risk than those without. Multivariate Cox proportional hazard regression analysis revealed that the homozygous G allele of rs1808593 was associated with cardiovascular death and the development of nonfatal myocardial infarction after adjusting for confounding risk factors. Conclusions NOS3 gene polymorphism could be a genetic risk factor for cardiovascular death and nonfatal myocardial infarction in the Japanese general population. FUNDunding Acknowledgement Type of funding sources: None. Figure 1

291Serum albumin levels reversed the impact of higher resting heart rate on cardiovascular mortality

Background Higher resting heart rate (RHR) has been proved as a risk factor for all-cause and cardiovascular disease (CVD) mortality. However, few studies discussed its synergy with other markers on mortality prediction. Our study focused on whether the impact of RHR on CVD mortality is affected by serum albumin (SA) in Japanese general population. Methods We followed 8,307 participants without history of CVD from a Japanese general population. We divided participants according to quartiles of RHR [Q1(&lt;62), Q2(62-68), Q3(69-76), and Q4(&gt;76)], then we used Cox proportional hazard model adjusting for age, gender, BMI, blood glucose, blood pressure, anti-hypertensive treatment, total cholesterol, smoking and alcohol drinking status for estimating CVD mortality. Furthermore, we stratified the participants according to median value of SA (4.4 mg/dL) to conduct subgroup analysis. Results During a 29-year follow-up, 1,030 deaths due to CVD were detected. Compared to Q1 group, hazard ratios [95% confidence interval] in each RHR group for CVD mortality was Q2: 0.87 [0.74-1.04], Q3: 1.01 [0.85-1.20], Q4: 0.98 [0.83-1.16]. In lower SA group, Q2: 0.90[0.72-1.13], Q3: 0.99 [0.80-1.25], Q4: 1.27 [1.03-1.58], meanwhile in higher SA group, Q2: 0.83 [0.63-1.09], Q3: 0.99 [0.77-1.29], Q4: 0.65 [0.49-0.85]. Conclusions Higher RHR was associated with increased risk for CVD mortality in individuals with lower SA, meanwhile the reversed relationship shown in those with higher SA. Key messages The impact of RHR on CVD mortality might be influenced by SA in a Japanese general population.

695Gene and environmental factors for liver fibrosis among Japanese general population with NAFLD

Background A part of nonalcoholic fatty liver disease (NAFLD) develops nonalcoholic steatohepatitis (NASH), liver cirrhosis and hepatocellular carcinoma. Metabolic syndrome is involved in their development, and hepatic fibrosis plays an important role in their pathogenesis. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene encode proteins on hepatic lipid metabolism regulation, and PNPLA3 gene polymorphism is associated with the development and progression of NAFLD. To investigate the gene and environmental factors, and their interaction for liver fibrosis, we conducted a prospective study among Japanese general population with NAFLD. Methods The subjects were 295 general residents who participated as a part of the Japan Multi-Institutional Collaborative Cohort (J-MICC) study in Kagoshima, Japan, and were followed for 5 years. NAFLD was defined as fatty liver using abdominal ultrasonography. PNPLA3 C/G polymorphism (rs738409) was analysed using TaqMan PCR. Hepatic fibrosis was defined using FIB 4 index (≥1.3). Logistic regression model was used to estimate the odds ratios (ORs) after adjusted for confounding factors. Results Mean age was 55.1 years and liver fibrosis was observed at 73.2% among NAFLD subjects. No environmental factors were associated with liver fibrosis, and PNPLA3 GG genotype was not associated with liver fibrosis, too. However, the ORs of CC & CG, and GG genotypes for dyslipidemia was respectively 0.45 (0.19-1.04) and 11.9 (1.81-78.4), and their interaction was significant (p = 0.01). Conclusions The interaction between PNPLA3 GG gene polymorphism and dyslipidemia for liver fibrosis was observed. Key messages Genetic susceptibility with dyslipidemia may be involved in liver fibrosis of NAFLD.

Distinct Regulation of U-ACE2 and P-ACE2 (Urinary and Plasma Angiotensin-Converting Enzyme 2) in a Japanese General Population

Severe acute respiratory syndrome coronavirus 2 in coronavirus disease 2019 invades the host through ACE (angiotensin-converting enzyme) 2 as the host cellular receptor for a viral spike protein. ACE2 converts angiotensin II to angiotensin-(1–7) and cleaved ACE2 is detectable in urine and plasma. However, regulation of U-ACE2 (urinary ACE2) and P-ACE2 (plasma ACE2) and their alterations by renin-angiotensin-aldosterone system inhibitors remain unclear. We simultaneously investigated U-ACE2 and P-ACE2 in 605 Japanese participants (male/female: 280/325, mean age: 65±15 years) in the Tanno-Sobetsu cohort study in 2017. Males had significantly lower U-ACE2 and higher P-ACE2 than did females. There was no significant correlation between U-ACE2 and P-ACE2. P-ACE2 was significantly lower in subjects treated with renin-angiotensin-aldosterone system inhibitors than in those not treated with renin-angiotensin-aldosterone system inhibitors, but there was no significant difference in U-ACE2 between the groups. Multivariable regression analyses showed that female sex, high levels of systolic blood pressure, hemoglobin A1c, and urinary albumin-to-creatinine ratio, and low uric acid level were independent predictors of high U-ACE2 level and that high levels of γ-glutamyl transpeptidase, estimated glomerular filtration rate, and uric acid were independent predictors of high P-ACE2 level. In conclusion, U-ACE2 and P-ACE2 are distinctly regulated and the use of renin-angiotensin-aldosterone system inhibitors is not an independent predictor of their levels in a Japanese general population. U-ACE2 is associated with high blood pressure, high glucose level, and microalbuminuria, and low urate level, whereas P-ACE2 is associated with liver dysfunction, high glomerular filtration rate, and high urate level.