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Two strains, designated JCM 36746 T and JCM 36749, were isolated from Bengal clock vine ( Thunbergia grandiflora ) and soil, respectively, in Okinawa, Japan. Analysis of the internal transcribed spacer (ITS) regions and D1/D2 domains of the large subunit rRNA gene sequences revealed identical sequences in both strains, indicating that they belong to the same species. Sequence analysis and physiological characterization identified these strains as representing a novel yeast species in the genus Yamadazyma . The sequence similarities of the concatenated ITS regions and D1/D2 domains indicated that JCM 36746 T and JCM 36749 formed a well-supported distinct from closely related species belonging to the Yamadazyma clade, including Candida dendronema , C. diddensiae , C. germanica , C. kanchanaburiensis , C. naeodendra , C. vaughaniae , Y. akitaensis , Y. koratensis , Y. nakazawae , Y. philogaea , Y. phyllophila , Y. siamensis , Y. ubonensis , and three undescribed species, comprising Candida aff. naeodendra / diddensiae Y151, Candida sp. GE19S08, and Yamadazyma sp. strain NYNU 22830. The sequences of the D1/D2 domains and ITS regions differed in nucleotide substitutions by 1.51% and 2.57% or greater, respectively, from those of the previously described and undescribed related species. In addition, the physiological characteristics of the novel species were distinct from those of the closely related described species. On the basis of these findings, we propose the name Yamadazyma thunbergiae sp. nov. to classify this species within the genus Yamadazyma . The holotype used is JCM 36746 T (ex-type strains CBS 18614 and NBRC 116657). The MycoBank accession number is MB 853823.

Genome-wide association studies have enabled the identification of important genetic factors in many trait studies. However, only a fraction of the heritability can be explained by known genetic factors, even in the most common diseases. Genetic loci combinations, or epistatic contributions expressed by combinations of single nucleotide polymorphisms (SNPs), have been argued to be one of the critical factors explaining some of the missing heritability, especially in oligogenic/polygenic diseases. Rheumatoid arthritis (RA) is a complex disease with more than 100 reported SNP associations, as well as various HLA haplotypes and amino acids; however, many associations between RA and inter-chromosomal SNP combinations are unknown. To discover novel associations of epistatic interactions with high odds ratios in RA, we applied the LAMPLINK method, a systematic enumerative procedure for identifying high-order SNP combinations, to a Japanese RA cohort (discovery cohort; 4024 patients with RA and 7731 controls). We validated the identified associations in a different Japanese cohort (validation cohort; 810 RA patients and 6303 controls). In this study, we identified 90 significant genetic associations in the discovery cohort. Among these, 74 (82.2%) associations were replicated in the validation cohort, and eight combinations were inter-chromosomal, all of which comprised rs7765379 or rs35265698 located in the HLA region. These two SNPs exhibited strong correlations with valine at amino acid position 11 in HLA-DRB1 (HLA-DRB1-11-Val). Finally, we discovered that rs9624 showed an association with RA through an epistatic interaction with HLA-DRB1-11-Val. Overall, LAMPLINK showed high reliability for identifying epistatic genetic contributions hidden in complex traits., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Background: Nocturnal blood pressure (BP) is associated with cardiovascular disease independently of awake BP. However, nocturnal BP measured using an ambulatory monitoring device has limited reproducibility because it is a single-day measurement. We investigated the association between sleep BP measured on multiple days using a timer-equipped home BP monitor and cardiovascular diseases in a general population., Methods: The study population comprised 5814 community residents. Participants were required to sleep with wrapping cuffs on their upper arm and BP was measured automatically at 0 : 00, 2 : 00, and 4 : 00. Actigraph was used to determine BP measured during sleep. Participants were also measured home morning and evening BP manually using the same device., Results: During the 7.3-year mean follow-up period, we observed 117 cases of cardiovascular diseases. The association between sleep BP (per 10 mmHg hazard ratio = 1.31, P  < 0.001) and cardiovascular events remained significant (hazard ratio = 1.22, P  = 0.036) even after adjusting for office BP and confounding factors, such as sleep-disordered breathing. Individuals with sleep-only hypertension ( n  = 1047; hazard ratio = 2.23, P  = 0.005) had a significant cardiovascular risk. Daytime-only hypertension ( n  = 264; hazard ratio = 3.57, P  = 0.001) and combined sleep and daytime hypertension ( n  = 1216; hazard ratio = 3.69, P  < 0.001) was associated with cardiovascular events to the same extent. Sleep BP dipping was not identified as a significant determinant of cardiovascular events., Conclusion: Sleep BP measured using a home BP monitor was independently associated with the incidence of cardiovascular disease in a general population., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Purpose: Atherosclerotic burden increases the risk of both extracranial internal carotid artery stenosis (ICS) and intracranial large artery disease (ICAD). However, the differences in risk profiles have not been thoroughly investigated., Methods: Participants were recruited from the Nagahama study cohort in Japan. Individuals over 60 years old who underwent 1.5-T head and neck magnetic resonance angiography (MRA) between July 2013 and February 2017 were included. ICAD was defined as WASID ≥ 50 %, and ICS was defined as NSCET ≥ 30 %. The prevalence and association of risk factors, including proatherogenic and proinflammatory factors, and the p.R4810K variant in the RNF213 gene, were investigated. Multivariable logistic regression analyses were performed., Results: A total of 3089 individuals participated in the study, with a mean age of 68.1 ± 5.3 years, and 36.0 % were males. Among them, 52 (1.7 %) had ICS, 119 (3.8 %) had ICAD, and 15 (0.49 %) had both conditions. Alopecia areata was an independent predictor for both ICS (Odds ratio [OR] 3.5; 95 % CI 1.3-8.3) and ICAD (OR 2.1; 95 % CI 1.0-3.9). Diabetes (OR 3.7; 95 % CI 2.0-7.0) and older age (OR 2.4; 95 % CI 1.2-4.5) were associated only with ICS, while the RNF213 variant was associated with only ICAD (OR 5.7; 95 % CI 1.6-16.0). ICS and ICAD were also independently associated with each other., Conclusions: In this MRA-based large scale study, alopecia areata, known as a systemic inflammatory disease, was shown to be a common risk factor for ICS and ICAD. While conventional atherosclerotic factors were associated with ICS, non-atherosclerotic factors appear to contribute to ICAD in Japan., Competing Interests: Declaration of competing interest We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Esotropia and exotropia in the entity of comitant strabismus are multifactorial diseases with both genetic and environmental backgrounds. Idiopathic superior oblique muscle palsy, as the predominant entity of non-comitant (paralytic) strabismus, also has a genetic background, as evidenced by varying degrees of muscle hypoplasia. A genome-wide association study (GWAS) was conducted of 711 Japanese patients with esotropia (n= 253), exotropia (n = 356), and idiopathic superior oblique muscle palsy (n = 102). The genotypes of single nucleotide polymorphisms (SNPs) were determined by Infinium Asian Screening Array. Three control cohorts from the Japanese population were used: two cohorts from BioBank Japan (BBJ) and the Nagahama Cohort. BBJ (180K) was genotyped by a different array, Illumina Infinium OmniExpressExome or HumanOmniExpress, while BBJ (ASA) and the Nagahama Cohort were genotyped by the same Asian array. After quality control of SNPs and individuals, common SNPs between the case cohort and the control cohort were chosen in the condition of genotyping by different arrays, while all SNPs genotyped by the same array were used for SNP imputation. The SNPs imputed with R-square values ≥ 0.3 were used to compare the case cohort of each entity or the combined entity with the control cohort. In comparison with BBJ (180K), the esotropia group and the exotropia group showed CDCA7 and HLA-F , respectively, as candidate genes at a significant level of p < 5 × 10 -8 , while the idiopathic superior oblique muscle palsy group showed DAB1 as a candidate gene which is involved in neuronal migration. DAB1 was also detected as a candidate in comparison with BBJ (ASA) and the Nagahama Cohort at a weak level of significance of p < 1 × 10 -6 . In comparison with BBJ (180K), RARB (retinoic acid receptor-β) was detected as a candidate at a significant level of p < 5 × 10 -8 in the combined group of esotropia, exotropia, and idiopathic superior oblique muscle palsy. In conclusion, a series of GWASs with three different control cohorts would be an effective method with which to search for candidate genes for multifactorial diseases such as strabismus.

Cross-sectional relationships between nocturia and sleep problems have been well evaluated but the risk association for each incidence is scarcely reported. This analysis included 8076 participants of the Nagahama study in Japan (median age 57, 31.0% male) and associations between nocturia and self-reported, sleep-related problems (poor sleep) were evaluated cross-sectionally. Causal effects on each new-onset case were analyzed longitudinally after 5 years. Three models were applied: univariable analysis, adjustment for basic variables (i.e., demographic and lifestyle variables) and full adjustment for basic and clinical variables. The overall prevalences of poor sleep and nocturia were 18.6% and 15.5%, while poor sleep was positively associated with nocturia (OR = 1.85, p < 0.001) and vice versa (OR = 1.90, p < 0.001). Among 6579 good sleep participants, 18.5% developed poor sleep. Baseline nocturia was positively associated with this incident poor sleep (OR = 1.49, p < 0.001, full adjustment). Among 6824 non-nocturia participants, the nocturia incidence was 11.3%. Baseline poor sleep was positively associated with this incident nocturia (OR = 1.26, p = 0.026); such associations were significant only in women (OR = 1.44, p = 0.004) and under-50-year-old groups (OR = 2.82, p < 0.001), after full adjustment. Nocturia and poor sleep associate with each other. Baseline nocturia can induce new-onset poor sleep while baseline poor sleep may induce new-onset nocturia only in women., (© 2023. The Author(s).)

Type 1 diabetes incidence has increased worldwide, although the long-term trends on pediatric type 1 diabetes in Japan remain elusive. To investigate the incidence and secular trend of pediatric type 1 diabetes from 1999 to 2021, including the coronavirus disease 2019 (COVID-19) pandemic years, in Oita Prefecture, Japan. We investigated the number of newly diagnosed patients with type 1 diabetes aged < 15 years from 1999 to 2021. We surveyed hospital databases in Oita Prefecture in Japan. The type 1 diabetes incidence in children aged < 15 years increased annually by 5.3% among all children, especially in boys aged 10-14 years by 8.1%, over the past 23 years. The average incidence rate of 3.9/100,000/year was nearly consistent with the previous reports on Asian countries. No significant change was found in the increasing incidence trend of type 1 diabetes before and during the COVID-19 pandemic. The incidence of pediatric type 1 diabetes has significantly increased over the past 23 years in Oita Prefecture, Japan, which is consistent with the worldwide trend., (© 2023. The Author(s).)

Two strains were isolated from flowers and insects in Japan, namely NBRC 115686 T and NBRC 115687, respectively. Based on sequence analysis of the D1/D2 domain of the 26S large subunit (LSU) rRNA gene and the internal transcribed spacer (ITS) region and physiological characteristics, these strains were found to represent a novel yeast species of the genus Wickerhamiella . Considering pairwise sequence similarity, NBRC 115686 T and NBRC 115687 differ from the type strain of the most closely related species, Wickerhamiella galacta NRRL Y-17645 T , by 65-66 nucleotide substitutions with 12 gaps (11.65-11.83 %) in the D1/D2 domain of the LSU rRNA gene. The novel species differ from the closely related Wickerhamiella species in some physiological characteristics. For example, compared with Wickerhamiella galacta JCM 8257 T , NBRC 115686 T and NBRC 115687 assimilated d-galactose, and could grow at 35 and 37 °C. Hence, the name Wickerhamiella bidentis sp. nov. is proposed to accommodate this species in the genus Wickerhamiella . The holotype is NBRC 115686 T (ex-type strain JCM 35540=CBS 18008).

Inherited genetic variation is associated with 6-mercaptopurine (6-MP) dose reduction and frequent toxicities induced by 6-MP. However, the tolerable dose for 6-MP is not fully predicted by the known variation in NUDT15 and TPMT among Asian children with acute lymphoblastic leukaemia (ALL). We performed a genome-wide association study (GWAS) related to 6-MP dose among Japanese children with ALL. This GWAS comprised 224 patients previously enrolled in Tokyo Children's Cancer Study Group clinical studies with replication attempted in 55 patients. Genome-wide single nucleotide polymorphism (SNP) genotypes were evaluated for association with average 6-MP dose during the initial 168 days of maintenance therapy. Possible associations were observed across five gene-coding regions, among which only variants at 13q14.2 were significant and replicated genome-wide (rs116855232, NUDT15, β = -10.99, p = 3.7 × 10 -13 ). Notable findings were observed for variants in AFF3 (rs75364948, p = 2.05 × 10 -6 ) and CHST11 (rs1148407, p = 2.09 × 10 -6 ), but were not replicated possibly due to small numbers. A previously reported candidate SNP in MTHFR was associated with higher average 6-MP dose (rs1801133, p = 0.045), and FOLH1 (rs12574928) was associated in an evaluation of candidate regions (p adjust  = 0.013). This study provides strong evidence that rs116855232 in NUDT15 is the genetic factor predominantly associated with 6-MP tolerable dose in children in Japan., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

The use of antimicrobial agents in food-producing animals may lead to the emergence and spread of antimicrobial resistance in bacteria of animal origin. However, there is a paucity of data on the quantity of antimicrobials use on dairy farms in Japan. This study describes antimicrobial use on dairy farms from 1 January 2014 to 31 December 2016 in five administrative districts (central, eastern, western, southern and northern) of Chiba Prefecture. The use of antimicrobial agents in dairy cattle over these three years was evaluated in terms of the antimicrobial treatment incidence (ATI; theoretical number of animals per 1,000 animal-days subjected to antimicrobial treatment) using data collected from a total of 442 dairy farms in that prefecture. Our results revealed that the average ATI on these farms for these years ranged from 38.7 to 39.4 with no significant difference between years and that the average ATI for these administrative districts varied between 32.9 and 43.2 with a significant variation between some of the districts. Approximately 84% of antimicrobials were administered intramammarily, 13-14% by injection and 1-2% orally. Scenario analyses were performed to assess the effect of changes in some of the defined daily dose (DDDjp) values used to calculate the ATI. Our results revealed that the calculated ATI is considerably affected by the changes in the long-acting factor used for assigning the DDDjp values of intramammary products for dry cows and the way in which DDD values are assigned for combination products.

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge 1-5 . Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target., (© 2022. The Author(s).)

Objective: An association between the Moyamoya disease susceptible gene ring finger protein 213 (RNF213) variant and ischemic stroke and coronary artery disease has been suggested in case-control studies. We aimed to investigate the possible association between the RNF213 variant and the incidence of cardiovascular disease in a general population., Methods: The study participants consisted of 9153 Japanese community residents without history of cardiovascular disease. The clinical parameters employed in this analysis were observed at baseline between 2008 and 2010. The RNF213 p.R4859K variant was determined by TaqMan probe assay and then confirmed by Sanger sequencing., Results: During 8.52 years follow-up period, we observed 214 incident cases of cardiovascular diseases (99 total stroke cases, 119 major adverse cardiac event cases, including 4 cases of both). The incidence rate was higher for the variant allele carriers (120 cases; incidence rate, 71.0 per 10 000 person-years) than for the homozygotes of the wild-type allele (26.9), and the group differences achieved statistical significance (P = 0.009). Although the RNF213 variant was also associated with systolic blood pressure (dominant model: coefficient of 8.19 mmHg; P < 0.001), the Cox regression analysis adjusted for major covariates including systolic blood pressure identified the RNF213 variant as an independent determinant for cardiovascular disease (hazard ratio of 3.41, P = 0.002) and major adverse cardiac event (hazard ratio of 3.80, P = 0.010) but not with total stroke (P = 0.102)., Conclusion: The Moyamoya disease susceptible RNF213 variant was associated with blood pressure and the incidence of cardiovascular disease in a Japanese general population., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This cross-sectional study aimed to explore the differences of the medial and lateral sides of the knee joint and precise radiographic abnormalities in contribution to the knee pain and clinical outcomes., Design: Participants 60 years or older who underwent radiographic evaluation were included. Knee radiography was assessed using grading systems of the Osteoarthritis Research Society International (OARSI) atlas. The Japanese Knee Osteoarthritis Measure (JKOM) was evaluated as clinical outcomes. Serum high-sensitivity C-reactive protein (hsCRP) was used to evaluate systemic inflammation. We divided the participants into normal, medial-, lateral-, and medial & lateral-OA types and compared their JKOM using an analysis of covariance. Furthermore, we analyzed the relationship between the knee pain and stiffness of JKOM and the grading of each radiographic feature using a multiple regression model., Results: Lateral- and medial & lateral-OA groups had a significantly worse symptoms in the total and the pain score, especially in movement subscales, in JKOM score. Lateral-OA groups had higher hsCRP than medial-OA group. Multivariate analysis showed that medial joint space narrowing (JSN), and lateral femoral and tibial osteophytes significantly affected knee pain (adjusted odds ratios: 1.73, 1.28, and 1.55, respectively). The radiographic changes are associated with pain more in JSN in the medial side and osteophytes in the lateral side., Conclusion: Lateral- and medial & lateral-OA groups showed worth symptom. In addition, medial JSN and lateral osteophytes have potent effects on the knee pain.

Background: The Japanese Orthopaedic Association (JOA) proposed the concept of locomotive syndrome (LS) in 2007 for detecting high-risk individuals with mobility limitation. In 2020, the JOA revised the clinical decision limits and introduced LS stage 3, which carried the highest-risk for LS compared to the conventional stages, 1 and 2. The purpose of this study was to characterize the prevalence, comorbidities, and physical characteristics in each LS stage, as per the LS criteria 2020., Methods: We analyzed 2077 participants (64.9% women; mean age, 68.3 ± 5.4 years) from the Nagahama Study aged ≥60 years. Participants were classified into 4 groups, non-LS and LS stages 1, 2, and 3, based on a 25-question Geriatric Locomotive Function Scale. The prevalence of comorbidities (sarcopenia, osteoporosis, diabetes mellitus, low back pain [LBP], and knee pain) were investigated. Physical characteristics were measured based on the physical performance tests including gait speed, five-times chair-stand, single-leg stand, and short physical performance battery; muscle strength tests including grip, knee extension, hip flexion, and abduction; and body-composition analysis including muscle quantity and quality. Differences in the prevalence of comorbidities between LS stages were tested using the chi-square test. The general linear model was performed for univariate and multivariate analyses with post-hoc test to compare the differences in physical characteristics among the LS stages., Results: The prevalence of LS increased with age, and the mean prevalence of LS stages 1, 2, and 3 were 24.4, 5.5, and 6.5%, respectively. The prevalence of comorbidities, including sarcopenia, osteoporosis, LBP, and knee pain, increased with worsening LS stage. Physical performance tests were significantly different between LS stages 2 and 3; and muscle strength differed significantly between LS stages 1 and 2. Additionally, in terms of body composition analysis, muscle quality but not muscle quantity showed significant differences among all the LS stages., Conclusions: Our findings suggest that muscle strengthening and dynamic training, including balance training in LS stage 1 and 2, respectively, were needed for preventing the LS progression. Individuals with LS stage 3 should perform dynamic training and muscle strengthening exercises while receiving treatment for comorbidities., (© 2021. The Author(s).)

Purpose: To survey the prevalence and clinical and genetic characteristics of pachydrusen in eyes with central serous chorioretinopathy (CSC) and those of Japanese individuals in the general population., Design: Prospective, observational cohort study., Participants: One thousand thirty-seven Japanese patients were included in this study. Three hundred seven patients (614 eyes) had treatment-naïve CSC without choroidal neovascularization in either eye, whereas 730 individuals (1640 eyes) were Japanese individuals from the general population without explicit ocular diseases., Methods: Pachydrusen were detected using color fundus photography, and subfoveal choroidal thickness was measured using OCT. Genotypic distributions of 3 single nucleotide polymorphisms, ARMS2 A69S, CFH I62V, and CFH Y402H, were evaluated., Main Outcome Measures: Prevalence of pachydrusen and association with choroidal thickness., Results: The prevalence of pachydrusen was significantly higher among CSC patients than among the general population group (40.1% vs. 15.6%; P < 0.001). Individuals with pachydrusen in either group were significantly older than those without pachydrusen (CSC patients: 62.1 years vs. 48.8 years [P < 0.001]; general individuals: 70.3 years vs. 51.9 years [P < 0.001]). No significant difference was found in subfoveal choroidal thickness between those with and without pachydrusen (CSC patients: 370 μm vs. 375 μm; [P = 0.574]; general population: 297 μm vs. 303 μm [P = 0.521]). However, after adjusting for age, gender, and refractive error, subfoveal choroidal thickness was notably thicker in individuals with pachydrusen than that in individuals without pachydrusen in both groups (P = 0.003 and P = 0.013, respectively). No significant difference was found in genotype distributions between CSC patients with pachydrusen and those without it; whereas, the T allele frequency of ARMS2 A69S was higher in general population individuals with pachydrusen than that in general population individuals without pachydrusen (42.2% vs. 33.9%; P < 0.001; OR, 1.86, adjusted for age, gender, and choroidal thickness)., Conclusions: Pachydrusen was observed more frequently in CSC patients compared with individuals from the general population. In both groups, pachydrusen was associated with a thicker choroid, suggesting that pachydrusen should be considered as a significant sign of pachychoroid., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Circulating levels of inflammatory proteins have to be prognostic markers of all-cause mortality. α1-Antitrypsin (AAT) is a major inflammatory plasma protein, but its association with all-cause mortality is unclear. We aimed to evaluate the prognostic significance of AAT levels for all-cause mortality. Study participants comprised 9682 community residents (53.5 ± 13.3 years old). During the 9.8-year follow-up period, 313 participants died from any cause. The mortality rate increased linearly with AAT quintiles (Q1, 18.2; Q2, 24.7; Q3, 23.8; Q4, 31.9; Q5, 64.6 per 10,000 person-years). There were significant correlations between AAT and high-sensitivity C-reactive protein (hsCRP) levels (correlation coefficient, 0.331; P < 0.001). However, the Cox model analysis, when adjusted for possible covariates including hsCRP, identified the fifth AAT quintile as a risk factor for all-cause death (hazard ratio, 2.12 [95% confidence interval, 1.41-3.18]; P < 0.001). An analysis of participants older than 50 years (hazard ratio, 1.98, P < 0.001) yielded similar results. The hazard ratio increased proportionately in combination with high AAT and high hsCRP levels, and the highest hazard ratio reached 4.51 (95% confidence interval, 3.14-6.54, P < 0.001). High AAT levels were determined to be an independent risk factor for mortality in the general population., (© 2021. The Author(s).)

The Japanese Archipelago is widely covered with acidic soil made of volcanic ash, an environment which is detrimental to the preservation of ancient biomolecules. More than 10,000 Palaeolithic and Neolithic sites have been discovered nationwide, but few skeletal remains exist and preservation of DNA is poor. Despite these challenging circumstances, we succeeded in obtaining a complete mitogenome (mitochondrial genome) sequence from Palaeolithic human remains. We also obtained those of Neolithic (the hunting-gathering Jomon and the farming Yayoi cultures) remains, and over 2,000 present-day Japanese. The Palaeolithic mitogenome sequence was not found to be a direct ancestor of any of Jomon, Yayoi, and present-day Japanese people. However, it was an ancestral type of haplogroup M, a basal group of the haplogroup M. Therefore, our results indicate continuity in the maternal gene pool from the Palaeolithic to present-day Japanese. We also found that a vast increase of population size happened and has continued since the Yayoi period, characterized with paddy rice farming. It means that the cultural transition, i.e. rice agriculture, had significant impact on the demographic history of Japanese population.

Purpose: Japan has been known as a super-aged society, and ageing is a well-known risk factor for blinding eye diseases. However, epidemiological studies in ophthalmology are still scarce in Japan, and the sizes of the cohorts are relatively small. "Ganka-Ekigaku Network" (GEN, an acronym for the epidemiological network in ophthalmology in Japanese) is established to develop a capacity to boost each epidemiological study and enrich a potential inter-study collaboration to identify risk factors of visual impairment in aged society., Methods: We reviewed cohort studies in Japan with the inclusion criteria as: (1) at least n = 1000 at baseline, (2) multiple modalities of ophthalmic data, and (3) diagnosis reviewed by ophthalmologist(s), and (4) ophthalmologists are involved in the investigators group. As of January 2020, GEN includes 4 individual Japanese epidemiological studies namely, Hisayama study, Yamagata Study (Funagata), Tsuruoka Metabolomics Cohort study, and the Nagahama Prospective Genome Cohort for Comprehensive Human Bioscience., Results: GEN includes approximately 25,000 Japanese participants. The baseline surveys started from 1998 to 2012, and since then the data has been prospectively collected approximately every 5 years. A variety of ophthalmic measurements and other factors have been collected in each study in GEN: ophthalmic measurements (fundus photography, optical coherence tomography, etc.), systemic conditions (laboratory data, etc.), and others (DNA, etc.)., Conclusion: GEN is an open platform for observational ophthalmic epidemiological studies to share standardized methodologies. While each study in GEN pursues specific and original research questions, standardization of the methods will enable us to conduct reliable meta-analysis/pooled data analyses.

Purpose: To evaluate the association between daily coffee consumption and intraocular pressure (IOP) in healthy persons without glaucoma and the association between daily coffee consumption and history of glaucoma., Design: Cross-sectional study., Participants: A total of 9850 individuals participated in the first follow-up of the Nagahama Prospective Cohort for Comprehensive Human Bioscience (the Nagahama Study) conducted between 2013 and 2016., Methods: All participants underwent a standardized ophthalmic examination. Self-reporting questionnaires were completed by all participants. First, the association between habitual coffee consumption and IOP among nonglaucoma individuals was evaluated by a multivariate linear regression analysis, adjusting for possible confounders. Second, the association between habitual coffee consumption and history of glaucoma also was evaluated using a multivariate logistic regression analysis., Main Outcome Measures: The association between habitual coffee consumption and IOP among nonglaucoma individuals., Results: Of 9850 participants, 9418 did not have history of glaucoma. Among these participants, the mean ± standard deviation IOP of both eyes was 14.7 ± 2.9 mmHg. The multivariate regression analysis revealed that habitual coffee consumption was associated significantly with IOP (P < 0.001): the higher the consumption of coffee, the lower the IOP of an individual. The IOP of the group who consumed coffee most frequently (3 times daily or more) was 0.4 mmHg lower (95% confidence interval, 0.2-0.5 mmHg lower) than that of the group that consumed coffee least frequently (less than once daily). However, the logistic regression analysis showed that habitual coffee consumption was not associated significantly with history of glaucoma (P = 0.53)., Conclusions: Frequent coffee consumption was associated with a slightly lower IOP in people without glaucoma but was not associated with a decreased risk of glaucoma developing. Additional experimental studies are needed to examine the effects of coffee on IOP and glaucoma risk., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe the distribution of ocular biometry and refraction in Japanese adults., Design: Cross-sectional analysis of a prospective cohort study., Participants: A total of 9850 individuals participated in the first follow-up of the Nagahama Prospective Cohort for Comprehensive Human Bioscience (the Nagahama Study) conducted between 2013 and 2016. Participants were between 34 and 80 years of age., Methods: All participants underwent axial length (AL; in millimeters), anterior chamber depth (ACD; in millimeters), corneal diameter (white to white; in millimeters), and central corneal thickness (CCT; in micrometers) measurement (IOL Master; Carl Zeiss Meditec, Dublin, CA) and refraction (spherical equivalent [SE]; in diopters [D]) and corneal curvature (CC; in millimeters) measurement (ARK-530A; Nidek, Aichi, Japan). Distribution of these ocular biometric parameters and prevalence of myopia, high myopia, and extreme myopia were summarized., Main Outcome Measures: Distribution of ocular biometry and refraction., Results: After standardization to the national population of 2015, estimates of mean AL and SE were 24.21 mm and -1.44 D, respectively. Estimates of mean CC, corneal diameter, CCT, and ACD were 7.69 mm, 12.01 mm, 543.96 μm, and 3.21 mm, respectively. After standardization of age and gender, the prevalence of myopia (SE, ≤-0.5 D) and high myopia (SE, ≤-6.0 D) were 49.97% and 7.89%, respectively. Approximately 70% of the younger participants (34-59 years of age) showed myopia, whereas high myopia was observed in approximately 10%. Although the number of individuals with myopia or high myopia was higher in the younger age groups, the prevalence of more extreme phenotypes remained stable across all ages, especially in women. Axial length of more than 30 mm was observed only in older women (n = 5 [0.05%])., Conclusions: We showed detailed distributions of various ocular biometry and refraction parameters using a large general Japanese cohort. Prevalences of myopia and high myopia from 2013 through 2016 were higher than those in earlier studies, which reflects recent environmental change. However, constant prevalence of extreme myopia across all ages suggests high genetic predisposition of the extreme phenotype., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

HTLV-1-associated myelopathy (HAM/TSP) is a chronic and progressive inflammatory disease of the central nervous system. The aim of our study was to identify genetic determinants related to the onset of HAM/TSP in the Japanese population. We conducted a genome-wide association study comprising 753 HAM/TSP patients and 899 asymptomatic HTLV-1 carriers. We also performed comprehensive genotyping of HLA-A , -B , -C , -DPB1 , -DQB1 , and -DRB1 genes using next-generation sequencing technology for 651 HAM/TSP patients and 804 carriers. A strong association was observed in HLA class I ( P = 1.54 × 10 -9 ) and class II ( P = 1.21 × 10 -8 ) loci with HAM/TSP. Association analysis using HLA genotyping results showed that HLA-C * 07:02 ( P = 2.61 × 10 -5 ), HLA-B * 07:02 ( P = 4.97 × 10 -10 ), HLA-DRB1 * 01:01 ( P = 1.15 × 10 -9 ) and HLA-DQB1 * 05:01 ( P = 2.30 × 10 -9 ) were associated with disease risk, while HLA-B * 40:06 ( P = 3.03 × 10 -5 ), HLA-DRB1 * 15:01 ( P = 1.06 × 10 -5 ) and HLA-DQB1 * 06:02 ( P = 1.78 × 10 -6 ) worked protectively. Logistic regression analysis identified amino acid position 7 in the G-BETA domain of HLA-DRB1 as strongly associated with HAM/TSP ( P = 9.52 × 10 -10 ); individuals homozygous for leucine had an associated increased risk of HAM/TSP (odds ratio, 9.57), and proline was protective (odds ratio, 0.65). Both associations were independent of the known risk associated with proviral load. DRB1-GB-7-Leu was not significantly associated with proviral load. We have identified DRB1-GB-7-Leu as a genetic risk factor for HAM/TSP development independent of proviral load. This suggests that the amino acid residue may serve as a specific marker to identify the risk of HAM/TSP even without knowledge of proviral load. In light of its allele frequency worldwide, this biomarker will likely prove useful in HTLV-1 endemic areas across the globe., Competing Interests: Competing interest statement: S.K. and F.M. are board members of GenoConcierge Kyoto Inc. S.K., M. Shimizu, and F.M. have patents pending for HLA typing software, primer sets for PCR amplification of HLA genes and its experimental protocol, and a risk marker of DRB1-GB-7 for HAM/TSP development., (Copyright © 2021 the Author(s). Published by PNAS.)

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10 -12 ). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10 -12 ), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10 -7 ). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.

Background: Chronic sputum production in the general population is historically associated with clinical indices including male sex and smoking history. However, its relationship with gastroesophageal reflux disease (GERD), which may prove an underlying factor in sputum production, is unclear. We aimed to clarify factors associated with sputum production in the general population in cross-sectional and longitudinal manners., Methods: In the Nagahama study, a community-based cohort study, 9804 subjects were recruited between 2008 and 2010 (baseline assessment), 8293 of whom were followed from 2013 to 2015 (follow-up assessment). This study contained a self-completed questionnaire which included medical history, assessment of sputum production, and a frequency scale for symptoms of GERD. A Frequency Scale for Symptoms of Gastroesophageal Reflux Disease score of ≥ 8 was defined as GERD. In addition to the frequency of sputum production at each assessment, frequency of persistent sputum production defined as sputum production at both assessments was examined., Results: Frequency of sputum production was 32.0% at baseline and 34.5% at follow-up. Multivariable analysis demonstrated that sputum production at baseline was significantly associated with GERD [odds ratio (OR), 1.92; 95% confidence interval (CI) 1.73-2.13] and post-nasal drip (PND) (OR, 2.40; 95% CI 2.15-2.68), independent of other known factors such as older age, male sex and smoking history. These associations between sputum production and GERD or PND were also observed at follow-up. In longitudinal analysis, 19.4% had persistent sputum production and 12.3% had transient sputum production, i.e., at baseline only. Multivariable analysis for risk of persistence of sputum production revealed that persistent sputum production was associated with GERD and PND, in addition to the known risk factors listed above. The proportion of subjects with GERD at both assessments was highest among subjects with persistent sputum production., Conclusions: Cross-sectional and longitudinal analysis demonstrated an association in the general population between sputum production and GERD, as well as PND, independent of known risk factors. The presence of GERD should be assessed in patients complaining of sputum production.

Purpose: To identify novel susceptibility loci for high myopia., Design: Genome-wide association study (GWAS) followed by replication and meta-analysis., Participants: A total of 14 096 samples from East and Southeast Asian populations (2549 patients with high myopia and 11 547 healthy controls)., Methods: We performed a GWAS in 3269 Japanese individuals (1668 with high myopia and 1601 control participants), followed by replication analysis in a total of 10 827 additional samples (881 with high myopia and 9946 control participants) from Japan, Singapore, and Taiwan. To confirm the biological role of the identified loci in the pathogenesis of high myopia, we performed functional annotation and Gene Ontology (GO) analyses., Main Outcome Measures: We evaluated the association of single nucleotide polymorphisms with high myopia and GO terms enriched among genes identified in the current study., Results: We identified 9 loci with genome-wide significance (P < 5.0 × 10 -8 ). Three loci were previously reported myopia-related loci (ZC3H11B on 1q41, GJD2 on 15q14, and RASGRF1 on 15q25.1), and the other 6 were novel (HIVEP3 on 1p34.2, NFASC/CNTN2 on 1q32.1, CNTN4/CNTN6 on 3p26.3, FRMD4B on 3p14.1, LINC02418 on 12q24.33, and AKAP13 on 15q25.3). The GO analysis revealed a significant role of the nervous system related to synaptic signaling, neuronal development, and Ras/Rho signaling in the pathogenesis of high myopia., Conclusions: The current study identified 6 novel loci associated with high myopia and demonstrated an important role of the nervous system in the disease pathogenesis. Our findings give new insight into the genetic factors underlying myopia, including high myopia, by connecting previous findings and allowing for a clarified interpretation of the cause and pathophysiologic features of myopia at the molecular level., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Next-generation sequencing (NGS) has greatly advanced the studies of causative genes and variants of inherited diseases. While it is sometimes challenging to determine the pathogenicity of identified variants in NGS, the American College of Medical Genetics and Genomics established the guidelines to help the interpretation. However, as to the genetic screenings for patients with retinitis pigmentosa (RP) in Japan, none of the previous studies utilized the guidelines. Considering that EYS is the major causative gene of RP in Japan, we conducted stepwise genetic screening of 220 Japanese patients with RP utilizing the guidelines. Step 1-4 comprised the following, in order: Sanger sequencing for two major EYS founder mutations; targeted sequencing of all coding regions of EYS; whole genome sequencing; Sanger sequencing for Alu element insertion in RP1, a recently determined founder mutation for RP. Among the detected variants, 2, 19, 173, and 1 variant(s) were considered pathogenic and 8, 41, 44, and 5 patients were genetically solved in step 1, 2, 3, and 4, respectively. Totally, 44.5% (98/220) of the patients were genetically solved, and 50 (51.0%) were EYS-associated and 5 (5.1%) were Alu element-associated. Among the unsolved 122 patients, 22 had at least one possible pathogenic variant.

Purpose: Nocturia has been reported as a risk factor for mortality. However, evidence is limited and has a high risk of bias. We evaluated the association between nocturia and mortality using longitudinal data from the general Japanese population., Materials and Methods: Data were obtained from the Nagahama Cohort Project, a longitudinal, general population cohort study. Nocturia was measured using the International Prostate Symptom Score. Mortality data were obtained from the Basic Resident Register in Nagahama City. We used Cox proportional hazard models and time-varying covariates at baseline and 5-year followup to analyze the association between nocturia and mortality., Results: We analyzed 9,762 participants (median age 56.8 years, male 32.8%). The prevalence rates of nocturnal voiding at 0, 1, 2 and 3 or more times were 44.3%, 39.1%, 11.7% and 4.9%, respectively. A total of 263 participants died. Followup assessment was performed 3,224 (SD 537) days after baseline. According to multivariable Cox proportional hazard regressions, mortality increased dose dependently with the nocturnal voiding frequency as HR 1.46 for 1 time (95% CI 1.02-2.09), HR 1.85 for 2 times (95% CI 1.23-2.77) and HR 2.06 (95% CI 1.28-3.32) for 3 or more times in comparison with 0 times (p for trend=0.00084). In the time varying Cox proportional hazard regression the association was still significant (p for trend=0.0017)., Conclusions: According to this longitudinal study with a low incidence of missing data and high representation of the general population, nocturia is associated with mortality.

To elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study of 168,228 individuals of Japanese ancestry (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,781 CAD cases and 2,636 controls. We detected eight new susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a trans-ancestry meta-analysis and discovered 35 additional new loci. Using the meta-analysis results, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European genome-wide association studies. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improve the clinical characterization of CAD genetics and suggest the utility of trans-ancestry meta-analysis for PRS derivation in non-European populations.

Characteristics of high frequency (HF) component based on heart rate variability (HRV) in a large general population remain unclear, particularly on the relationship with daily physical activity. We aimed to characterize the distribution of HF component and examine the association with daily physical activity among community residents. We performed spectral analysis of HRV from 10-second ECG recordings among 9135 residents aged 30 to 74 years in Nagahama City, Japan. HF components were log-transformed to consider the distribution. Simple correlations between HF and age were determined. Age-adjusted mean values of HF component were calculated for each questionnaire item related to daily physical activity. Multiple regression analysis was performed to examine the effect of daily physical activity on HF component value. Mean values of logarithmically-transformed HF component (lnHF) were higher in women than in men (p < 0.001). lnHF was inversely associated with age (r = -0.40, -0.49 for men, women, respectively). Adjusted mean lnHF for physically active people was significantly higher than that in inactive people (p < 0.001). HF components from 10-second ECG recordings were moderately and negatively correlated with age in both sexes, and positively correlated with daily physical activity in the general adult population. Maintaining the level of daily physical activity, especially to exercise regularly could keep the parasympathetic function high.

Purpose: Although the association between nocturia and depressive symptoms has been demonstrated, the causal direction remains unclear. We investigated the directional association between nocturia and depressive symptoms using longitudinal data from the general population., Materials and Methods: This longitudinal analysis was conducted as part of the Nagahama Cohort Project, a population based cohort study, with baseline and 5-year followup investigations. Nocturnal voiding frequency and mental health were measured with self-report questionnaires, the International Prostate Symptom Score and the 5-item Mental Health Inventory. Logistic regression analyses and a cross-lagged panel analysis were performed to analyze the bidirectional association between nocturia and depressive symptoms., Results: With 9,764 participants at baseline, data from 8,285 were used in this analysis. Median age at baseline was 57.3 years and the proportion of men was 32.0%. New onset depressive symptoms and nocturia were observed among 369 and 793 participants, respectively. In adjusted logistic regression analyses we observed a clear dose-relationship between baseline nocturnal voiding frequency and new onset depressive symptoms (p for trend <0.001) and a weak association between baseline 5-item Mental Health Inventory and new onset nocturia (p for trend=0.0087). In a cross-lagged panel analysis the path coefficient from nocturnal voiding frequency to 5-item Mental Health Inventory (β=-0.06, p <0.001) was stronger than that from 5-item Mental Health Inventory to nocturnal voiding frequency (β=-0.02, p=0.047)., Conclusions: This longitudinal study demonstrated a bidirectional association between nocturia and depressive symptoms. The cross-lagged path coefficient suggested that nocturia could more likely be a cause than a result of depressive symptoms.

Although alkaline phosphatase (ALP) activity is relatively low in carriers of recessive type hypophosphatasia (HPP), most are asymptomatic and therefore do not undergo medical evaluations. We analyzed the association of ALP-encoding ALPL variants with serum ALP and bone traits in the general Japanese population. Study participants (n = 9671) were from the Nagahama Study, which was a longitudinal cohort study of an apparently healthy general Japanese population. ALPL variants were analyzed by whole-genome sequencing or TaqMan probe assays using DNA extracted from peripheral blood samples. The speed of sound in calcaneal bone was assessed by quantitative ultrasound (QUS) and used as surrogate measures of bone mineral density. We identified 13 ALPL variants. Minor allele frequencies of three variants were higher than expected. Variant c.529G > A has been reported as a possible pathogenic variant for adult type HPP. Variants c.979C > T and c.1559delT are reported as pathogenic variants for perinatal severe HPP or infantile HPP. The allele frequencies of c.529G > A, c.979C > T, and c.1559delT were 0.0107, 0.0040, and 0.0014, respectively. Serum ALP activity was significantly lower and differed among the three variants (P < 0.001), as well as between individuals with and without any of the three variants (P < 0.001). Serum ALP activity was inversely associated with QUS values, although no direct association was observed between the ALPL variants and QUS values. An association between serum ALP activity and QUS was confirmed; however, we failed to detect an association between ALPL variants and bone traits in the general Japanese population.

Accumulation of advanced glycation end products (AGEs) has been linked with cognitive decline as a risk factor based on the analysis in small populations. We investigated the association between skin autofluorescence of AGEs and global cognitive function in a Japanese older (≥60 years) population (n = 4,041). The AGEs quartiles were inversely associated with the Revised Hasegawa's Dementia Scale score (Q1: reference, Q2: β= -0.011, p = 0.537, Q3: β= -0.043, p = 0.016, Q4: β= -0.064, p < 0.001) independent of major risk factors. Accumulation of AGEs was associated with lower cognitive performance in older adults.

Background: Obesity affects the pathogenesis of various chronic diseases, including asthma. Research on correlations between obesity/BMI and eosinophilic inflammation in asthma has yielded contradictory results, which could be partly ascribed to the absence of epidemiological data on the correlations. We aimed to elucidate the correlations between blood eosinophil count, its genetic backgrounds, and BMI in the general population., Methods: This community-based Nagahama study in Japan enrolled 9789 inhabitants. We conducted self-reporting questionnaires, lung function tests, and blood tests in the baseline and 5-year follow-up studies. A genome-wide association study (GWAS) was performed in 4650 subjects at the baseline and in 4206 of these at the follow-up to determine single-nucleotide polymorphisms for elevated blood eosinophil counts. We assessed the correlations between BMI and eosinophil counts using a multifaceted approach, including the cluster analysis., Results: Eosinophil counts positively correlated with BMI, observed upon the interchange of an explanatory variable, except for subjects with the highest quartile of eosinophils (≥200/μL), in whom BMI negatively correlated with eosinophil counts. GWAS and human leukocyte antigen (HLA) imputation identified rs4713354 variant (MDC1 on chromosome 6p21) for elevated eosinophil counts, independent of BMI and IgE. Rs4713354 was accumulated in a cluster characterized by elevated eosinophil counts (mean, 498 ± 178/μL) but normal BMI., Conclusions: Epidemiologically, there may be a positive association between blood eosinophil counts and BMI in general, but there was a negative correlation in the population with high eosinophil counts. Factors other than BMI, particularly genetic backgrounds, may contribute to elevated eosinophil counts in such populations., (Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Objective: Recent attention has been focused on sedentary behavior (SB) affecting health outcomes, but the characteristics of indicators reflecting SB remain to be identified. This cross-sectional study aims to identify the characteristics of indicators of SB, focusing on the examination of correlations, reliability, and validity of sedentary variables assessed by the smartphone app., Method: Objectively measured data of SB of eligible 46 Japanese workers obtained from smartphones were used. We assessed the characteristics of current indicators being used with a 10-minute or 30-minute thresholds, in addition to the conventional indicators of total sedentary time, mean sedentary bout duration, and total number of sedentary bouts. They were evaluated from three perspectives: (a) association among the indicators, (b) reliability of the indicators, and (c) criterion validity., Results: Total sedentary time under 10 minutes (U10) and U30 had negative associations with Total sedentary time (r = -.47 and -.21 respectively). The correlation between Mean sedentary bout duration and Total number of sedentary bouts was -.84, whereas between Mean sedentary bout duration 10, 30 and Total number of sedentary bouts were -.54 and -.21, respectively. The intraclass correlation coefficients of almost all indicators were around .80. Mean sedentary bout duration, Mean sedentary bout duration 10, Total number of sedentary bouts, Total sedentary time 30, U30 and U10 have significant differences between three BMI groups., Conclusion: This study comprehensively revealed the rationale of advantage in the current indicator being used with a 10-minute or 30-minute threshold, rather than the conventional total amount of SB., (© 2019 The Authors. Journal of Occupational Health published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society for Occupational Health.)

Recent reports have identified differences in the mutational spectra across human populations. Although some of these reports have been replicated in other cohorts, most have been reported only in the 1000 Genomes Project (1kGP) data. While investigating an intriguing putative population stratification within the Japanese population, we identified a previously unreported batch effect leading to spurious mutation calls in the 1kGP data and to the apparent population stratification. Because the 1kGP data are used extensively, we find that the batch effects also lead to incorrect imputation by leading imputation servers and a small number of suspicious GWAS associations. Lower quality data from the early phases of the 1kGP thus continue to contaminate modern studies in hidden ways. It may be time to retire or upgrade such legacy sequencing data., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Nocturia is a risk factor for poor quality of life and increased mortality. This study was aimed to clarifying dietary habits, eating behaviors, and sleep characteristics associated with nocturia to identify modifiable lifestyle factors for nocturia., Methods: This cross-sectional study included 5683 community residents (64.5 ± 7.7 years old). The frequency of nocturnal urination was recorded for 1 week using a sleep diary. The frequency of food intake, unfavorable eating behaviors, and sleep characteristics that may have influence on salt intake and wasting were obtained using a structured questionnaire., Results: The frequency of nocturnal urination was increased with age (β = .312, P < .001). Other basic factors associated with the frequency were the male sex (β = .090), hypertension (β = .038), sleep apnea (β = .030), B-type natriuretic peptide level (β = .089), and spot urine sodium excretion (β = -.058). Dietary factors independently associated with nocturnal urination frequency were coffee (≥1 time/day: β = -.059, P < .001) and green vegetable consumption (≥1 time/week: β = -.042, P = .001), whereas habitual intake of dairy products, miso soup, and alcohol were not associated with urination frequency. Later bedtime was inversely associated with nocturnal urination frequency independent of sleep duration (before 23:00: β = -.096; before 24:00: β = -.225; after midnight: β = -.240; all P < .001)., Conclusion: Coffee and green vegetable consumption and later bedtime but not sleep duration are lifestyle factors associated with nocturnal urination frequency., (© 2019 Wiley Periodicals, Inc.)

Aims/introduction: Hyperglycemia is a risk factor for sarcopenia when comparing individuals with and without diabetes. However, no studies have investigated whether the findings could be extrapolated to patients with diabetes with relatively higher glycemic levels. Here, we aimed to clarify whether glycemic control was associated with sarcopenia in patients with type 2 diabetes., Materials and Methods: Study participants consisted of patients with type 2 diabetes (n = 746, the average age was 69.9 years) and an older general population (n = 2,067, the average age was 68.2 years). Sarcopenia was defined as weak grip strength or slow usual gait speed and low skeletal mass index., Results: Among patients with type 2 diabetes, 52 were diagnosed as having sarcopenia. The frequency of sarcopenia increased linearly with glycated hemoglobin (HbA1c) level, particularly in lean individuals (HbA1c <6.5%, 7.0%, ≥6.5% and <7.0%: 18.5%; HbA1c ≥7.0% and <8.0%: 20.3%; HbA1c ≥8.0%: 26.7%). The linear association was independent of major covariates, including anthropometric factors and duration of diabetes (HbA1c <6.5%: reference; ≥6.5% and <7.0%: odds ratio [OR] 4.38, P = 0.030; HbA1c ≥7.0% and <8.0%: 4.29, P = 0.024; HbA1c ≥8.0%: 7.82, P = 0.003). HbA1c level was specifically associated with low skeletal mass index (HbA1c ≥8.0%: OR 5.42, P < 0.001) rather than weak grip strength (OR 1.89, P = 0.058) or slow gait speed (OR 1.13, P = 0.672). No significant association was observed in the general population with a better glycemic profile., Conclusions: Poor glycemic control in patients with diabetes was associated with low muscle mass., (© 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aim: Nocturia is a common phenomenon in older individuals, and is associated with poor quality of life. Nocturia is a multifactorial disorder, wherein the frailty of skeletal muscles, particularly muscle weakness in the lower trunk and hip regions, might be a risk factor in women. We analyzed a dataset of the general Japanese population to clarify the hypothesis., Methods: Study participants included 1207 older women (mean age 67.4 ± 5.2 years). The frequency of nocturnal urination was assessed using a sleep diary for 1 week, and associations with lower muscle strength, skeletal muscle index, sarcopenia and physical performance (one-leg standing time and Timed Up and Go test) were investigated., Results: The frequency of nocturnal urination more than one voiding per night was 28.1%; this frequency was inversely associated with hip abduction strength quartiles (Q1: 37.0, Q2: 30.5, Q3: 25.1 and Q4: 19.9%, P < 0.001). When a sleep diary-based nocturnal urination frequency >1.5 times/night (corresponding to a ≥2 times/night frequency obtained by questionnaire) was considered as nocturia, logistic regression analysis adjusted for major covariates identified hip abduction strength as an independent inverse determinant of nocturia (odds ratio 0.75, 95% CI 0.52-0.90, P = 0.002). In contrast, no significant association was observed with knee extension (P = 0.322) and hip flexion (P = 0.603) strengths. Physical performance, skeletal muscle index and sarcopenia did not show significant associations with nocturia., Conclusions: Weak hip abduction strength might be a factor associated with nocturnal urination frequency in older women. Geriatr Gerontol Int 2019; 19: 1010-1016., (© 2019 Japan Geriatrics Society.)

There are more than 300 research groups for rare diseases in Japan. Although various clinical and genomic information of patients are being collected by the groups, the information is managed individually by each research group and the current practices for managing and sharing research data are not very efficient. Since "rare diseases" are literally rare, the understanding of the underlying disease mechanisms are incomplete and collecting a sufficient number of patients for clinical trials is difficult. Therefore, there is a need to collect and integrate the data and construct a data integration platform for rare disease research. Funded by the Japan Agency for Medical Research and Development, a national research and development project to establish a standard platform and supporting organization for rare disease registries in Japan is currently under way. In this article, we report the background, purpose, process, results, current status, and future plans of this project.

Although recent genome-wide association studies (GWASs) have identified genetic variants associated with Helicobacter pylori (HP)-induced gastric cancer, few studies have examined the genetic traits associated with the risk of HP-induced gastric precancerous conditions. This study aimed to elucidate genetic variants associated with these conditions using a genome-wide approach. Data from four sites of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study were used in the discovery phase (Stage I); two datasets from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center 2 (HERPACC2) study were used in the replication phases (Stages II and III) and SKAT (SNP-set Kernel Association Test) and single variant-based GWASs were conducted for the risks of gastric atrophy (GA) and severe GA defined by serum pepsinogen (PG) levels, and PG1 and PG1/2 ratios. In the gene-based SKAT in Stage I, prostate stem cell antigen (PSCA) was significantly associated with the risks of GA and severe GA, and serum PG1/2 level by linear kernel [false discovery rate (FDR) = 0.011, 0.230 and 7.2 × 10-7, respectively]. The single variant-based GWAS revealed that nine PSCA single nucleotide polymorphisms (SNPs) fulfilled the genome-wide significance level (P < 5 × 10-8) for the risks of both GA and severe GA in the combined study, although most of these associations did not reach genome-wide significance in the discovery or validation cohort on their own. GWAS for serum PG1 levels and PG1/2 ratios revealed that the PSCA rs2920283 SNP had a striking P-value of 4.31 × 10-27 for PG1/2 ratios. The present GWAS revealed the genetic locus of PSCA as the most significant locus for the risk of HP-induced GA, which confirmed the recently reported association in Europeans., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

To assess the use of plasma free amino acids (PFAAs) as biomarkers for metabolic disorders, it is essential to identify genetic factors that influence PFAA concentrations. PFAA concentrations were absolutely quantified by liquid chromatography-mass spectrometry using plasma samples from 1338 Japanese individuals, and genome-wide quantitative trait locus (QTL) analysis was performed for the concentrations of 21 PFAAs. We next conducted a conditional QTL analysis using the concentration of each PFAA adjusted by the other 20 PFAAs as covariates to elucidate genetic determinants that influence PFAA concentrations. We identified eight genes that showed a significant association with PFAA concentrations, of which two, SLC7A2 and PKD1L2, were identified. SLC7A2 was associated with the plasma levels of arginine and ornithine, and PKD1L2 with the level of glycine. The significant associations of these two genes were revealed in the conditional QTL analysis, but a significant association between serine and the CPS1 gene disappeared when glycine was used as a covariate. We demonstrated that conditional QTL analysis is useful for determining the metabolic pathways predominantly used for PFAA metabolism. Our findings will help elucidate the physiological roles of genetic components that control the metabolism of amino acids.

Background: Orthostatic hypertension was associated with worse cardiovascular outcomes, although the factors responsible for an orthostatic rise in blood pressure (BP) are uncertain. We investigated a possible relationship between a stooping posture and orthostatic BP change., Methods: Study participants consisted of 1,992 older individuals. Orthostatic BP change was calculated by systolic BP measured at sitting position, and again 1 and 3 minutes after standing up. Spinal alignment and curvature was assessed by guiding the SpinalMouse device on the surface of the skin along the spine., Results: Mean lumbar lordosis at standing position was 13.4° ± 12.4°. The degree of lumbar lordosis was significantly smaller in orthostatic hypertensive individuals (systolic BP change, ≥+20 mm Hg: 3.3° ± 15.6°, ≥+10 mm Hg: 10.4° ± 14.3°) than in individuals who were orthostatic normotensive (14.2° ± 11.9°). Multiple linear regression analysis identified lumbar lordosis (β = -0.171, P < 0.001) and thoracic kyphosis (β = 0.062, P = 0.007), but not sacral inclination (β = 0.033, P = 0.303), as independent determinants for orthostatic BP change. As waist circumference was another independent determinant, the frequency of orthostatic hypertensive individuals was linearly increased with the combination of abdominal obesity and small degree of lumbar lordosis (control: 9.9%, abdominal obesity: 17.4%, small degree of lordosis: 19.4%, both: 24.1%, P < 0.001). Participants who sustained orthostatic hypertension for 3 minutes after standing up had the smallest degree of lumbar lordosis (5.2° ± 16.4°)., Conclusion: Stooped posture was an overlooked determinant for orthostatic increases in BP.

Purpose: Although several genetic factors may play a role in leisure-time exercise behavior, there is currently no evidence of a significant genomewide association, and candidate gene replication studies have produced inconsistent results., Methods: We conducted a two-stage genomewide association study and candidate single-nucleotide polymorphisms (SNP) association study on leisure-time exercise behavior using 13,980 discovery samples from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study, and 2036 replication samples from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center-2 study. Leisure-time physical activity was measured using a self-administered questionnaire that inquired about the type, frequency and duration of exercise. Participants with ≥4 MET·h·wk of leisure-time physical activity were defined as exhibiting leisure-time exercise behavior. Association testing using mixed linear regression models was performed on the discovery and replication samples, after which the results were combined in a meta-analysis. In addition, we tested six candidate genetic variants derived from previous genomewide association study., Results: We found that one novel SNP (rs10252228) located in the intergenic region between NPSR1 and DPY19L1 was significantly associated with leisure-time exercise behavior in discovery samples. This association was also significant in replication samples (combined P value by meta-analysis = 2.2 × 10). Several SNP linked with rs10252228 were significantly associated with gene expression of DPY19L1 and DP19L2P1 in skeletal muscle, heart, whole blood, and the nervous system. Among the candidate SNP, rs12612420 in DNAPTP6 demonstrated nominal significance in discovery samples but not in replication samples., Conclusions: We identified a novel genetic variant associated with regular leisure-time exercise behavior. Further functional studies are required to validate the role of these variants in exercise behavior.

Background: The aim of this study is to clarify associations between orthostatic blood pressure (BP) change, as well as possible physiological factors, and day-to-day home BP variability, a promising risk factor for cardiovascular outcomes., Methods: Study participants were 6,465 community residents (age 58.3 years). Home BP was measured every morning and evening for 7 days. Orthostatic BP was calculated as the maximum difference between BP measured while sitting and remeasured after 1 and 3 minutes standing., Results: Frequency of individuals who showed orthostatic BP decline was as follows: systolic BP (SBP) change ≥-20 mm Hg: 2.6%, ≥-10 mm Hg: 14.1%. These subgroups showed larger home SBP variability (average real variability: 11.3 ± 5.3, 8.7 ± 3.9 mm Hg) when compared with orthostatic normotensives (7.6 ± 3.7 mm Hg) (all P < 0.001). Multiple linear regression analysis adjusted for major covariates, including seated BP, identified orthostatic BP drop as an independent determinant for morning BP variability (≥-20 mm Hg: β = 0.037, P = 0.003; ≥-10 mm Hg: β = 0.026, P = 0.036) but not for evening BP variability. Carotid hypertrophy was significantly associated with home BP variability (morning: β = 0.052, P = 0.001; evening: β = 0.065, P < 0.001) and showed a U-shaped association with orthostatic BP change. Plasma B-type natriuretic peptide level, a previously suggested factor for BP variability, did not show significant association with morning and evening BP variability., Conclusion: Orthostatic BP decline was significantly associated with morning BP variability. Large artery atherosclerosis was a common risk factor.

Objective: Abnormalities in circadian blood pressure (BP) variation, particularly increase in nocturnal BP, have been reported to be risk factors for cardiovascular disease, although the factors associated with BP abnormalities are not fully understood. This study aimed to clarify possible associations of sleep characteristics, including sleep fragmentation, sleep disordered breathing, and nocturia, with sleep BP by simultaneous multiday measurements., Methods: A cross-sectional study evaluated 5959 community participants having home-measured data on nocturnal BP change (sleep BP - awaking BP), sleep characteristics, and sleep disordered breathing. Sleep characteristics including the fragmentation index were assessed using wrist-wearable actigraphy, whereas sleep disordered breathing was assessed by 3% oxygen desaturation index obtained using a finger-type monitor. The number of nocturnal urinations was recorded in a sleep diary., Results: Mean nocturnal SBP change was -8.5 ± 7.9%. A 3% oxygen desaturation index was associated with the BP change independently of the basic covariates (β = 0.051, P = 0.001), although the association became insignificant (P = 0.196) after adjusting the fragmentation index (β = 0.105, P < 0.001). The association of the fragmentation index was also insignificant (P = 0.153) after adjusting measurement season (middle season: β = 0.163, P < 0.001; summer season: β = 0.249, P < 0.001). In contrast, the frequency of urination showed strong and independent association (β = 0.140, P < 0.001), with smaller nocturnal BP drop in participants with frequent urination., Conclusion: Subjective sleep estimates and frequent nocturnal urination may represent a potential risk for circadian BP abnormalities.

Purpose: To analyse the disc-fovea angle (DFA) by age group and to compare sex differences in each age group in a large cohort population., Methods: This community-based cross-sectional cohort study included 9682 eyes of 9682 volunteers (aged 30-75 years). We measured the DFA, which is the angle between a horizontal line and a line connecting the fovea with the centroid of an optic disc on fundus photographs of the right eye. We manually marked the fovea and surrounded the optic disc. The centroid of an optic disc and the DFA was automatically calculated using originally developed software. We compared the DFA between age groups in 10-year increments and investigated sex differences of DFA in each age group., Results: Overall mean DFA was 6.32 ± 3.53°. The DFA of older subjects was significantly larger than that of younger subjects (p < 0.001). The DFA of women was larger than that of men in their 60s and 70s (p < 0.001 for both), but not in subjects in their 30s, 40s and 50s., Conclusion: Larger DFA in women than in men in their 60s and 70s suggests the possibility that age-related excyclo-shift occurs more easily in postmenopausal women compared to men of the same age., (© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Genome-wide association studies (GWASs) have identified many single nucleotide polymorphisms (SNPs) that are significantly associated with pancreatic cancer susceptibility. We sought to replicate the associations of 61 GWAS-identified SNPs at 42 loci with pancreatic cancer in Japanese and to develop a risk model for the identification of individuals at high risk for pancreatic cancer development in the general Japanese population. The model was based on data including directly determined or imputed SNP genotypes for 664 pancreatic cancer case and 664 age- and sex-matched control subjects. Stepwise logistic regression uncovered five GWAS-identified SNPs at five loci that also showed significant associations in our case-control cohort. These five SNPs were included in the risk model and also applied to calculation of the polygenic risk score (PRS). The area under the curve determined with the leave-one-out cross-validation method was 0.63 (95% confidence interval, 0.60-0.66) or 0.61 (0.58-0.64) for versions of the model that did or did not include cigarette smoking and family history of pancreatic cancer in addition to the five SNPs, respectively. Individuals in the lowest and highest quintiles for the PRS had odds ratios of 0.62 (0.42-0.91) and 1.98 (1.42-2.76), respectively, for pancreatic cancer development compared with those in the middle quintile. We have thus developed a risk model for pancreatic cancer that showed moderately good discriminatory ability with regard to differentiation of pancreatic cancer patients from control individuals. Our findings suggest the potential utility of a risk model that incorporates replicated GWAS-identified SNPs and established demographic or environmental factors for the identification of individuals at increased risk for pancreatic cancer development., Competing Interests: The authors have declared that no competing interests exist.

Imported dengue into naive areas is a recognized but unquantified threat. Differentiating imported and autochthonous cases remains problematic. A threshold approach applied to Japan identified several aberrant incidences of dengue. Despite these alerts, no epidemics occurred other than 1 in Yoyogi Park in Tokyo, which was probably an unusual event.

Background: Genotype imputation from single-nucleotide polymorphism (SNP) genotype data using a haplotype reference panel consisting of thousands of unrelated individuals from populations of interest can help to identify strongly associated variants in genome-wide association studies. The Tohoku Medical Megabank (TMM) project was established to support the development of precision medicine, together with the whole-genome sequencing of 1070 human genomes from individuals in the Miyagi region (Northeast Japan) and the construction of the 1070 Japanese genome reference panel (1KJPN). Here, we investigated the performance of 1KJPN for genotype imputation of Japanese samples not included in the TMM project and compared it with other population reference panels., Results: We found that the 1KJPN population was more similar to other Japanese populations, Nagahama (south-central Japan) and Aki (Shikoku Island), than to East Asian populations in the 1000 Genomes Project other than JPT, suggesting that the large-scale collection (more than 1000) of Japanese genomes from the Miyagi region covered many of the genetic variations of Japanese in mainland Japan. Moreover, 1KJPN outperformed the phase 3 reference panel of the 1000 Genomes Project (1KGPp3) for Japanese samples, and IKJPN showed similar imputation rates for the TMM and other Japanese samples for SNPs with minor allele frequencies (MAFs) higher than 1%., Conclusions: 1KJPN covered most of the variants found in the samples from areas of the Japanese mainland outside the Miyagi region, implying 1KJPN is representative of the Japanese population's genomes. 1KJPN and successive reference panels are useful genome reference panels for the mainland Japanese population. Importantly, the addition of whole genome sequences not included in the 1KJPN panel improved imputation efficiencies for SNPs with MAFs under 1% for samples from most regions of the Japanese archipelago.