Tohoku Medical Megabank Organization Research Articles

A principal component analysis of metabolome and cognitive decline among Japanese older adults: cross-sectional analysis using Tohoku Medical Megabank Cohort Study.

BackgroundDementia is the leading cause of disability and imposes a significant burden on society. Previous studies have suggested an association between metabolites and cognitive decline. Although the metabolite composition differs between Western and Asian populations, studies targeting Asian populations remain scarce.MethodsThis cross-sectional study used data from a cohort survey of community-dwelling older adults aged ≥ 60 years living in Miyagi, Japan, conducted by Tohoku Medical Megabank Organization between 2013 and 2016. Forty-three metabolite variables quantified using nuclear magnetic resonance spectroscopy were used as explanatory variables. Dependent variable was the presence of cognitive decline (≤ 23 points), assessed by the Mini-Mental State Examination. Principal component (PC) analysis was performed to reduce the dimensionality of metabolite variables, followed by logistic regression analysis to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for cognitive decline.ResultsA total of 2,940 participants were included (men: 49.0%, mean age: 67.6 years). Among them, 1.9% showed cognitive decline. The first 12 PC components (PC1-PC12) accounted for 71.7% of the total variance. Multivariate analysis showed that PC1, which mainly represented essential amino acids, was associated with lower odds of cognitive decline (OR = 0.89; 95% CI, 0.80-0.98). PC2, which mainly included ketone bodies, was associated with cognitive decline (OR = 1.29; 95% CI, 1.11-1.51). PC3, which included amino acids, was associated with lower odds of cognitive decline (OR = 0.81; 95% CI, 0.66-0.99).ConclusionAmino acids are protectively associated with cognitive decline, whereas ketone metabolites are associated with higher odds of cognitive decline.

The frequency and pathogenicity of BRCA1 and BRCA2 variants in the general Japanese population.

Hereditary breast and ovarian cancer syndrome (HBOC) resulting from pathogenic variants of BRCA1 or BRCA2 is the most common and well-documented hereditary tumor. Although founder variants have been identified in population-based surveys in various countries, the types of variants are not uniform across races and regions. Recently, the Tohoku Medical Megabank Organization (ToMMo) released whole-genome sequence data including approximately 54,000 individuals from the general population of the Tohoku area in Japan. We analyzed these data and comprehensively identified the prevalence of BRCA1/2 pathogenic and truncating variants. We believe that an accurate understanding of the unique distribution and characteristics of pathogenic BRCA1/2 variants in Japan through this analysis will enable better surveillance and intervention for HBOC patients, not only in Japan but also worldwide.

Genome‐wide association study of brain MRI and other phenotypes in the Tohoku Medical Megabank Organization

AbstractBackgroundThe Tohoku Medical Megabank Organization (ToMMo) is a large cohort study and biobank established in 2013 in the Miyagi Prefecture of Northern Japan following the Great East Japan Earthquake and Tsunami. ToMMo enrolled 150K individuals in a planned longitudinal study aiming to reveal numerous and diverse biological, psychological, and lifestyle characteristics associated with important diseases, and it collects and analyzes a rich set of biological data, including genomics, from participants to support innovative research on these diseases. Importantly, aging and Alzheimer’s disease are key areas of our research agenda, but little is known about common genetic variants that affect quantitative traits related to AD in Japanese people. MRI brain scans and cognitive screening on 12,164 cohort participants were collected at baseline (the TMM Brain‐MRI Study) since 2014 to 2019.MethodThe TMM Brain‐MRI study acquired multiple MRI sequences, including T1‐weighted imaging (T1WI). The ADNI Phantom was used, and each scan’s quality was checked. Following pre‐processing steps, Freesurfer (v7.2.0) was used with the Destrieux or Desikan‐Killiany atlas to parcellate multiple anatomical brain regions and derive cortical thickness data. We conducted a Genome‐Wide Association Study (GWAS) on all Brain‐MRI Study participants who were also genetically profiled with a Japanese‐oriented microarray (Japonica‐Array® v1, v2 and NEO) and WGS.ResultAlong with the other data types, the genotyping data for the TMM Brain‐MRI study participants represented etiological characteristics. The attached Figure shows the age distribution by decile for 7,630 male and female participants who were profiled with the Japonica‐Array® v2. The usable archived volumetric T1WI data demonstrated inverse correlations between brain volume and age, as well as very good agreement with correlations observed in previous clinical studies. We identified nominally genome‐wide significant loci (P < 5×10‐8) associated with imaging phenotypes in this sample consisted of Japanese adults as the discovery stage of the study.ConclusionThe ToMMo MRI and genetic data provide insights into the genetic architecture of the brain that are relevant to understanding brain aging and AD. Our results require some replication stages and meta‐analyses using samples of Japanese individuals in other studies.

Association Between Olfactory Test Data with Multiple Levels of Odor Intensity and Suspected Cognitive Impairment: A Cross-Sectional Study.

Olfactory function decline has recently been reported to be associated with a risk of cognitive impairment. Few population-based studies have included younger adults when examining the association between olfactory test data with multiple odor intensities and suspected cognitive impairment. We investigated the association between high-resolution olfactory test data with fewer odors and suspected cognitive impairments. We also examined the differences between older and younger adults in this association. The Japanese version of the Montreal Cognitive Assessment (MoCA-J) was administered to 1,450 participants, with three odor-intensity-level olfactometry using six different odors. Logistic regressions to discriminate suspected cognitive impairment were conducted to examine the association, adjusted for age, sex, education duration, and smoking history. Data were collected from the Program by Tohoku University Tohoku Medical Megabank Organization, with an additional olfactory test conducted between 2019 and 2021. We generally observed that the lower the limit of distinguishable odor intensity was, the higher the MoCA-J score was. The combination of spearmint and stuffy socks contributed most to the distinction between suspected and unsuspected cognitive impairment. Furthermore, the association was significant in women aged 60-74 years (adjusted odds ratio 0.881, 95% confidence interval [0.790, 0.983], p = 0.024). The results indicate an association between the limit of distinguishable odor intensity and cognitive function. The olfactory test with multiple odor intensity levels using fewer odors may be applicable for the early detection of mild cognitive impairment, especially in older women aged 60-74 years.

Prevalence, Associated Factors, and Inter-Eye Differences of Refractive Errors in a Population-Based Japanese Cohort: The Tohoku Medical Megabank Eye Study

ABSTRACT Purpose To investigate the prevalence, associated factors, and inter-eye differences of myopia and astigmatism in an adult Japanese population-based cohort. Methods A total of 4282 participants from the Tohoku Medical Megabank Organization Eye Study (ToMMo Eye Study) underwent comprehensive ocular examinations as well as extensive physiological tests and a lifestyle questionnaire. The spherical equivalent (SE) and cylinder power were obtained as refractive parameters. The age- and gender-stratified prevalences of high myopia (SE < −5D), myopia (SE < −0.5D), hyperopia (SE > 0.5D), astigmatism (cylinder power < −0.5D), and anisometropia (SE difference >1D) were calculated. Multivariable analyses were performed to identify associated factors for refractive error (RE). Distribution and associated factors of the inter-eye difference in RE were also investigated. Results The age-adjusted prevalence of high myopia, myopia, hyperopia, astigmatism, and anisometropia was 15.9%, 63.5%, 14.7%, 51.1%, and 14.7%, respectively. Both myopia and high myopia were more prevalent in the younger age group, while astigmatism was more prevalent in the older age group. Age, education, blood pressure, intraocular pressure, and corneal thickness are significantly associated with myopic refraction. Age, gender, intraocular pressure, and corneal thickness are correlated with astigmatism. Older age was associated with against-the-rule astigmatism. Older age, myopia, and longer education showed a significant correlation with large inter-eye differences in SERE. Conclusions This study demonstrated the high prevalence of myopia in young Japanese, which may be caused by a generational shift. This study also confirmed the influence of age and education on both the prevalence and inter-eye differences of RE.

Weight-for-age z-scores of Japanese children using the World Health Organization Child Growth Standards.

Weight-for-age z-scores of Japanese children using the World Health Organization Child Growth Standards.

Pathological variants in genes associated with disorders of sex development and central causes of hypogonadism in a whole-genome reference panel of 8380 Japanese individuals

Disorders of sex development (DSD) comprises a congenital condition in which chromosomal, gonadal, or anatomical sex development is atypical. In this study, we screened for pathogenic variants in 32 genes associated with DSDs and central causes of hypogonadism (CHG) in a whole-genome reference panel including 8380 Japanese individuals constructed by Tohoku Medical Megabank Organization. Candidate pathogenic (P) or likely pathogenic (LP) variants were extracted from the ClinVar, InterVar, and Human Gene Mutation databases. Ninety-one candidate pathological variants were found in 25 genes; 28 novel candidate variants were identified. Nearly 1 in 40 (either ClinVar or InterVar P or LP) to 157 (both ClinVar and InterVar P or LP) individuals were found to be carriers of recessive DSD and CHG alleles. In these data, genes implicated in gonadal dysfunction did not show loss-of-function variants, with a relatively high tendency of intolerance for haploinsufficiency based on pLI and Episcore, both of which can be used for estimating haploinsufficiency. We report the types and frequencies of causative variants for DSD and CHG in the general Japanese population. This study furthers our understanding of the genetic causes and helps to refine genetic counseling of DSD and CHG.

Association between high-sensitivity cardiac troponin T levels and incident stroke in the elderly Japanese population: Results from the Tohoku Medical Megabank Community-based Cohort Study

Elevated levels of circulating high-sensitivity cardiac troponin T (hs-cTnT) are associated with cardiovascular disease. This study aimed to examine whether hs-cTnT levels are associated with incident stroke in the elderly population.The Iwate Tohoku Medical Megabank Organization pooled participant data for a community-based cohort study (n = 15,063, 69.6 ± 3.4 years), with a mean follow-up period of 5.23 years for all-cause death and incident stroke. The follow-up revealed 316 incident strokes, including atherothrombotic (n = 98), cardioembolic (n = 54), lacunar (n = 63), hemorrhagic (n = 101), and 178 all-cause deaths. Participants were classified into quartiles according to hs-cTnT levels (Q1 ≦ 4 ng/L, Q2: 5–6 ng/L, Q3: 7–9 ng/L, and Q4 > 9 ng/L). After adjusting for sex, age, smoking, drinking, systolic blood pressure, estimated glomerular filtration rate, N-terminal pro-brain natriuretic peptide, hemoglobin A1c, and lipid profile, a Cox proportional hazard model showed that higher hs-cTnT levels were associated with ischemic stroke (Q1 vs. Q4, hazard ratio [HR] = 2.24, 95 % confidence interval [CI] = 1.12–4.51, p = 0.023). The incident of total stroke was not associated with hs-cTnT levels (Q1 vs. Q4, HR 1.39, 95 % CI = 0.89–1.74, p = 0.145). Numerical differences were highest regarding incident lacunar stroke subtypes; however, this association was not statistically significant.Higher hs-cTnT concentrations were associated with ischemic stroke in the elderly Japanese population.

Further survey of genetic variants of flavin-containing monooxygenase 3 (FMO3) in Japanese subjects found in an updated database of genome resources and identified by phenotyping for trimethylaminuria

The number of single-nucleotide substitutions of human flavin-containing monooxygenase 3 (FMO3) recorded in mega-databases is increasing. Moreover, phenotype–gene analyses have revealed impaired FMO3 variants associated with the metabolic disorder trimethylaminuria. In this study, four novel amino-acid substituted FMO3 variants, namely p.(Gly191Asp), p.(Glu414Gln), p.(Phe510Ser), and p.(Val530CysfsTer1), were identified in the whole-genome sequences in the Japanese population reference panel (8.3K JPN) of the Tohoku Medical Megabank Organization. Additionally, four variants, namely p.(Ile369Thr), p.(Phe463Val), p.(Arg500Gln), and p.(Ala526Thr) FMO3, were found in the 8.3K JPN database but were already recorded in the National Center for Biotechnology Information database. Novel FMO3 variants p.[(Met1Leu)] and p.[(Trp231Ter)] were also identified in phenotype–gene analyses of 290 unrelated subjects with self-reported malodor. Among the eight recombinant FMO3 variants tested (except for p.[(Met1Leu)] and p.[(Trp231Ter)]), Arg500Gln and Gly191Asp FMO3, respectively, had lower and much lower capacities for trimethylamine and/or benzydamine N-oxygenation activities than wild-type FMO3. Because another FMO3 mutation p.[(Gly191Cys)] with diminished recombinant protein activity was previously detected in two independent probands, Gly191 would appear to be important for FMO3 catalytic function. Analysis of whole-genome sequence data and trimethylaminuria phenotypes revealed missense FMO3 variants that severely impaired FMO3-mediated N-oxygenations in Japanese subjects that could be susceptible to low drug clearances.

Genome-wide Association Study of Axial Length in Population-based Cohorts in Japan: The Tohoku Medical Megabank Organization Eye Study.

PurposeTo elucidate the differences in ocular biometric parameters by generation and gender and to identify axial length (AL)-associated genetic variants in Japanese individuals, we analyzed Tohoku Medical Megabank Organization (ToMMo) Eye Study data.DesignWe designed the ToMMo Eye Study, examined AL variations, and conducted genome-wide association studies (GWASs).ParticipantsIn total, 33 483 participants aged > 18 years who were recruited into the community-based cohort (CommCohort) and the birth and three-generation cohort (BirThree Cohort) of the ToMMo Eye Study were examined.MethodsEach participant was screened with an interview, ophthalmic examinations, and a microarray analysis. The GWASs were performed in 22 379 participants in the CommCohort (discovery stage) and 11 104 participants in the BirThree Cohort (replication stage). We evaluated the associations of single nucleotide polymorphisms (SNPs) with AL using a genome-wide significance threshold (5 × 10-8) in each stage of the study and in the subsequent meta-analysis.Main Outcome MeasuresWe identified the association of SNPs with AL and distributions of AL in right and left eyes and individuals of different sexes and ages.ResultsIn the discovery stage, the mean AL of the right eye (23.99 mm) was significantly greater than that of the left eye (23.95 mm). This difference was reproducible across sexes and ages. The GWASs revealed 703 and 215 AL-associated SNPs with genome-wide significance in the discovery and validation stages, respectively, and many of the SNPs in the discovery stage were replicated in the validation stage. Validated SNPs and their associated loci were meta-analyzed for statistical significance (P < 5 × 10-8). This study identified 1478 SNPs spread over 31 loci. Of the 31 loci, 5 are known AL loci, 15 are known refractive-error loci, 4 are known corneal-curvature loci, and 7 loci are newly identified loci that are not known to be associated with AL. Of note, some of them shared functional relationships with previously identified loci.ConclusionsOur large-scale GWASs exploiting ToMMo Eye Study data identified 31 loci linked to variations in AL, 7 of which are newly reported in this article. The results revealed genetic heterogeneity and similarity in SNPs related to ethnic variations in AL.

Association between Plasma Xanthine Oxidoreductase Activity and the Renal Function in a General Japanese Population: The Tohoku Medical Megabank Community-Based Cohort Study

Introduction: Xanthine oxidoreductase (XOR) has been identified as a critical source of reactive oxygen species in various pathophysiological conditions, including hypertension, endothelial dysfunction, and atherosclerosis. This study investigated the association between XOR and renal function in a general Japanese population. Methods: The Iwate Tohoku Medical Megabank Organization pooled individual participant data from a community-based cohort study in Iwate prefecture. Chronic kidney disease (CKD) was estimated using the estimated glomerular filtration rate of cystatin C (eGFRcys). Individuals with a history of hyperuricemia or severe renal dysfunction (eGFRcys <15 mL/min/1.73 m² or undergoing dialysis) were excluded from the study. We performed a multinominal multivariate logistic analysis adjusted for age, blood pressure, uric acid, glycated hemoglobin A1c, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol to associate XOR activity and renal function. Results: The present study included 4,248 participants (male/female: 1,373/2,875, age: 62.9 ± 11.7 years). When participants were divided according to XOR quartiles, blood pressure, body mass index, uric acid, low-density lipoprotein cholesterol, and glycated hemoglobin A1c were highest in the highest XOR quartile (all p < 0.001). The XOR activity was significantly higher in the subgroup with CKD stage G3 and G4 (G1 vs. G2 vs. G3-G4: 44.8 ± 40.5 vs. 52.0 ± 42.9 vs. 54.1 ± 43.9 pmol/h/mL, p = 0.02). The higher XOR activity was significantly associated with an increase of CKD stage: the odd ratios (95% confidence intervals) per 1 pmol/h/mL increase in XOR activity with CKD stage G1 as a reference were 1.37 (1.13–1.73) in G2 and 1.51 (1.30–1.84) in G3-G4. Conclusion: The present study concluded that high XOR activity was associated with the severity of CKD in a general Japanese population, suggesting that upregulated XOR activity may be involved in advanced renal dysfunction.

Spousal similarities in cardiometabolic risk factors: A cross-sectional comparison between Dutch and Japanese data from two large biobank studies

Background and aimsFew studies have examined and compared spousal concordance in different populations. This study aimed to quantify and compare spousal similarities in cardiometabolic risk factors and diseases between Dutch and Japanese populations. MethodsThis cross-sectional study included 28,265 Dutch Lifelines Cohort Study spouse pairs (2006–2013) and 5,391 Japanese Tohoku Medical Megabank Organization (ToMMo) Cohort Study pairs (2013–2016). Spousal similarities in cardiometabolic risk factors were evaluated using Pearson's correlation or logistic regression analyses adjusted for spousal age. ResultsThe husbands' and wives’ average ages in the Lifelines and ToMMo cohorts were 50.0 and 47.7 years and 63.2 and 60.4 years, respectively. Significant spousal similarities occurred with all cardiometabolic risk factors and diseases of interest in both cohorts. The age-adjusted correlation coefficients ranged from 0.032 to 0.263, with the strongest correlations observed in anthropometric traits. Spousal odds ratios [95% confidence interval] for the Lifelines vs. ToMMo cohort ranged from 1.45 (1.36–1.55) vs. 1.20 (1.05–1.38) for hypertension to 6.86 (6.30–7.48) vs. 4.60 (3.52–6.02) for current smoking. An increasing trend in spousal concordance with age was observed for sufficient physical activity in both cohorts. For current smoking, those aged 20–39 years showed the strongest concordance between pairs in both cohorts. The Dutch pairs showed stronger similarities in anthropometric traits and lifestyle habits (smoking and drinking) than their Japanese counterparts. ConclusionsSpouses showed similarities in several cardiometabolic risk factors among Dutch and Japanese populations, with regional and cultural influences on spousal similarities.

Plasma Xanthine Oxidoreductase Activity Is Associated with a High Risk of Cardiovascular Disease in a General Japanese Population.

The purpose of this study was to investigate the association between xanthine oxidoreductase (XOR) activity and a high risk of cardiovascular disease (CVD) in a general Japanese population. The Iwate Tohoku Medical Megabank Organization pooled individual participant data from a general population-based cohort study in Iwate prefecture. The cardiovascular risk was calculated using the Framingham Risk Score (FRS). A total of 1605 of the 1631 participants (98.4%) had detectable XOR activity. Multiple regression analysis demonstrated that XOR activity was independently associated with body mass index (β = 0.26, p < 0.001), diabetes (β = 0.09, p < 0.001), dyslipidemia (β = 0.08, p = 0.001), and uric acid (β = 0.13, p < 0.001). Multivariate analysis showed that the highest quartile of XOR activity was associated with a high risk for CVD (FRS ≥ 15) after adjustment for baseline characteristics (OR 2.93, 95% CI 1.16–7.40). The area under the receiver operating characteristic curves of the FRS with XOR activity was 0.81 (p = 0.008). XOR activity is associated with a high risk for CVD, suggesting that high XOR activity may indicate cardiovascular risk in a general Japanese population.

Oral Microbiome Analysis in Prospective Genome Cohort Studies of the Tohoku Medical Megabank Project.

A baseline oral microbiome study of the Tohoku Medical Megabank Organization (TMM) was planned to characterize the profile of the oral microbiome in the Japanese population. The study also aimed to clarify risk factors for multifactorial diseases by integrated analysis of the oral microbiome and host genome/omics information. From 2013 to 2016, we collected three types of oral biospecimens, saliva, supragingival plaque, and tongue swab, from a total of 25,101 participants who had a dental examination in TMM. In this study, we used two independent cohorts; the Community-Based Cohort and Birth and Three-Generation Cohort as discovery and validation cohorts, respectively, and we selected participants examined by a single dentist. We found through the 16S ribosomal RNA gene sequencing analysis of 834 participants of the Community-Based Cohort Study that there are differences in the microbial composition and community structure between saliva and plaque. The species diversities in both saliva and plaque were increased in correlation with the severity of periodontal disease. These results were nicely reproduced in the analysis of 455 participants of the Birth and Three-Generation Cohort Study. In addition, strong positive and negative associations of microbial taxa in both plaque and saliva with periodontitis-associated biofilm formation were detected by co-occurrence network analysis. The classes Actinobacteria and Bacilli, including oral health-associated bacterial species, showed a positive correlation in saliva. These results revealed differences in microbial composition and community structure between saliva and plaque and a correlation between microbial species and the severity of periodontal disease. We expect that the large database of the oral microbiome in the TMM biobank will help in the discovery of novel targets for the treatment and prevention of oral diseases, as well as for the discovery of therapeutic and/or preventive targets of systemic diseases.

Combining MRI and genetic data in the Tohoku Medical Megabank Organization cohort study for innovative Alzheimer’s disease research

AbstractBackgroundThe Tohoku Medical Megabank Organization (ToMMo) is a prospective genome cohort study and biobank established in 2012 in Northern Japan’s Miyagi Prefecture following the Great East Japan Earthquake and Tsunami. ToMMo has enrolled 120,000 healthy male and female adults aged over 20, plus 30,000 children in a longitudinal study designed to identify diverse biological, psychological, and lifestyle characteristics associated with mainly common diseases and support additional innovative research. Baseline information includes brain MRI, genetic data, physiological measurements, several cognitive and psychological screening tests, and health/lifestyle assessments. Alzheimer’s disease (AD) is a key research focus; goals include using MRI, genomic and other data in combination to identify predictive biomarkers. This communication reports initial progress.MethodMRI: MP‐RAGE, PCASL, FLAIR and DTI sequences were performed. Following quality checks and pre‐processing, Freesurfer (2.1.0) was used with the Destrieux or Desikan‐Killiany atlas to parcellate multiple anatomical brain regions and derive cortical thickness data. The digitized data were archived; raw data was preserved. Genetics: whole genome sequencing (WGS) and/or DNA array data were obtained for participants; apolipoprotein E (APOE) genotype was identified. Blood, urine, stool, saliva and dental plaque samples were collected and stored for biomarker identification and other studies.ResultUsable MRI data exist for &gt;12,000 participants (4,000 for FLAIR); approximately half the scans are of participants aged ≥50 (see Table). The quality exclusion rate was &lt;5%. WGS and DNA array data have so far been prepared for 800 participants who had MRI scans; APOE genotype information exists for all participants with MRI scans. The MRI and genetic data, plus demographic, cognitive screening and relevant health data are currently being readied for use in combination to identify valuable biomarkers, e.g., those predicting incipient cognitive impairment in preclinical AD. The frequency of major known AD risk alleles in the ToMMo sample will also be determined and compared to that in external GWAS studies.ConclusionToMMo’s MRI, WGS/DNA array, biospecimen repository and other data represent a powerful resource for AD research. Specifically, the combination of MRI and genetic data will support unique disease progression analyses and investigations to elucidate AD pathophysiology.

Genome-wide association study identifies new loci for albuminuria in the Japanese population

BackgroundUrinary albumin excretion (UAE) is a risk factor for cardiovascular diseases, metabolic syndrome, chronic kidney disease, etc. Only a few genome-wide association studies (GWAS) for UAE have been conducted in the European population, but not in the Asian population. Here we conducted GWAS and identified several candidate genes harboring single nucleotide polymorphisms (SNPs) responsible for UAE in the Japanese population.MethodsWe conducted GWAS for UAE in 7805 individuals of Asian ancestry from health-survey data collected by Tohoku Medical Megabank Organization (ToMMo) and Iwate Tohoku Medical Megabank Organization (IMM). The SNP genotype data were obtained with a SNP microarray. After imputation using a haplotype panel consisting of 2000 genome sequencing, 4,962,728 SNP markers were used for the GWAS.ResultsEighteen SNPs at 14 loci (GRM7, EXOC1/NMU, LPA, STEAP1B/RAPGEF5, SEMA3D, PRKAG2, TRIQK, SERTM1, TPT1-AS1, OR5AU1, TSHR, FMN1/RYR3, COPRS, and BRD1) were associated with UAE in the Japanese individuals. A locus with particularly strong associations was observed on TSHR, chromosome 14 [rs116622332 (p = 3.99 × 10−10)].ConclusionIn this study, we successfully identified UAE-associated variant loci in the Japanese population. Further study is required to confirm this association.

The Value of a Cystatin C-based Estimated Glomerular Filtration Rate for Cardiovascular Assessment in a General Japanese Population: Results From the Iwate Tohoku Medical Megabank Project.

BackgroundEpidemiological studies have shown that high circulating cystatin C is associated with a risk of cardiovascular disease (CVD) independent of creatinine-based renal function measurements. The present study investigated the comparison between the cystatin C-based estimated glomerular filtration rate (GFRcys) and creatinine-based GFR (GFRcr) to determine whether these measurements are associated with CV biomarkers and elevated CVD risk in a general Japanese population.MethodsThe Iwate Tohoku Medical Megabank Organization pooled individual participant data from a general population-based cohort study in Iwate prefecture (n = 29,375). Chronic kidney disease (CKD) was estimated using the GFRcys, GFRcr and the urine albumin-to-creatinine ratio (UACR).ResultsThe prevalence of CKD in the participants was found to be higher based on the GFRcr than the GFRcys. Multiple variable analyses after adjusting for baseline characteristics showed that high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were associated with the GFRcys. The area under the receiver operating characteristic (AUROC) curve for identifying individuals with a high Suita score was higher for the GFRcys (AUROC = 0.68) than it was for the GFRcr (AUROC = 0.64, P < 0.001). The GFRcys provided reclassification improvement for the CVD risk prediction model by the GFRcr (net reclassification improvement = 0.341; integrated discrimination improvement = 0.018, respectively, P < 0.001).ConclusionsThe GFRcys is more closely associated with CV biomarkers, including hs-cTnT and NT-proBNP levels, and a high Suita score than the GFRcr, and it provides additional value in the assessment of CVD risk using GFRcr.

Abstract P539: The Association Between Social Isolation and Metabolic Syndrome in Japanese Adults: The Tohoku Medical Megabank Project

Metabolic syndrome (MetS) and its components are well established as risk factors for cardiovascular disease (CVD). On the other hand, it has also been reported that social isolation is associated with an increased risk of CVD. However, the relationship between social isolation and MetS and its components is not clear. Thus, the purpose of this study is to investigate the association between social isolation and the number of MetS components in Japanese adults. Participants were 28,917 individuals (male/female = 10,226/18,691, age = 59.9±11.6 years) from the Iwate area of the Tohoku Medical Megabank Organization Community-based cohort study (TMM CommCohort study). They had no history of coronary heart disease or stroke. Social isolation was assessed using the Lubben Social Network Scale-6 (LSNS-6). The participants were classified into two groups, the social isolation group and the non-isolation group, based on a cutoff point of 11/12 on the LSNS-6. An assessment of MetS used the criteria defined by the Japanese societies’ committee. The multivariate-adjusted odds ratios (95% confidence intervals) [AORs (95% CIs)] of the social isolation group versus the non-isolation group were calculated using ordered logistic analyses and compared to the number of MetS components. We used gender, age, education, current smoker, current alcohol drinker, total physical activity, current job status, and depression as covariates. AORs (95% CIs) of social isolation against non-isolation were 1.02 (0.95-1.09) for one component of MetS, 1.09 (1.01-1.19) for two components of MetS, and 1.16 (1.06-1.28) for three or more components of MetS, when compared to 0 component of MetS. In conclusion, Japanese adults who experience social isolation might have a greater number of MetS components.

Design and Progress of Oral Health Examinations in the Tohoku Medical Megabank Project.

In order to assess the long-term impact of the Great East Japan Earthquake on the oral health of disaster victims and to evaluate gene-environmental interactions in the development of major oral diseases and oral-systemic associations, the oral part of two large-scale genome cohort studies by the Tohoku Medical Megabank Organization (ToMMo), including the Community-based cohort (CommCohort) study and the Birth and Three-Generation cohort (BirThree) study, have been conducted. The study population comprised 32,185 subjects, including 16,886 participants in the CommCohort study and 15,299 participants in the BirThree cohort study, recruited from 2013 to 2017. The oral studies consist of a questionnaire regarding oral hygiene behavior, clinical examinations by dentists, and oral plaque and saliva sampling for microbiome analyses, which were carried out at seven community support centers in Miyagi prefecture. The median age of all participants was 55.0 years, and 66.1% of participants were women. Almost all participants reported that they brushed their teeth more than once a day. The median number of present teeth was 27.0, and the decayed, missing and filled tooth number was 16.0, with a significant difference according to age and sex. The median periodontal pocket and clinical attachment level was 2.48 mm and 4.00 mm, respectively. Periodontal parameters increased significantly according to age, except for the accumulation of dental calculus. The oral part of these extensive cross-sectional studies provides a unique and important platform for future studies on oral health and diseases that elicit through interactions with systemic diseases, lifestyles, life events and genetic backgrounds, and contributes to researches clarifying the long-term effects of disasters on oral health.

Association of Germline Variants of TCF3 and PAX5 with Pediatric Acute Lymphoblastic Leukemia Development

Background: The development of B-lymphocyte is controlled by the coordinated action of transcription factors networks, such as IKZF1, TCF3, EBF1 or PAX5. It is increasingly recognized that germline variants of those genes which disrupt their function are responsible for inborn errors of humoral immunity. Meanwhile, it is well understood genetic alterations of those molecules are frequently altered in B-lineage acute lymphoblastic leukemia (ALL) and are associated with leukemogenesis. However, those involvements are usually attributed to somatic mutation. Germline variations may also trigger cancer development in some cases. For instance, genome-wide association studies (GWAS) have identified B-cell precursor (BCP-) ALL susceptibility variants within IKZF1. Furthermore, germline variants of IKZF1, TCF3, and PAX5 are reported to be associated with B-ALL development. Therefore, we hypothesize that attenuated function due to germline variation in those genes may predispose to ALL development in Japanese population to some extent. Method: Saliva DNA from 583 pediatric ALL patients in remission registered in Tokyo Children's Cancer Study Group (TCCSG) were analyzed in this study. Targeted sequencing for exons and exon-intron boundaries of IKZF1, TCF3, and PAX5 was performed using next-generation sequencer. Frequency of the detected variant alleles was compared to data from the Exome Aggregation Consortium (ExAC) East Asian Cohort (n=4327), Tohoku Medical Megabank Organization (ToMMo) cohort (n=3554), and the Human Genetic Variation Database (HGVD) cohort (n=1208) by chi-square test or Fisher's exact test. Results: In total, 113 variants (28 nonsynonymous, 19 synonymous, 56 intronic, 8 untranslated regions, and 2 deletions) were detected. We could not detect any nonsynonymous variations, insertion or deletion in IKZF1. On the other hand, we detected 8 rare variations in TCF3 and 7 of them are found to be deleterious by in silico analysis. Among them, 1 variant, TCF3 p.S514L, was significantly more common in ALL patients (0.26% in patients vs 0% in ExAC, 0.01% in ToMMO and 0% in HGVD, p=0.0017, 0.0115 and 0.0343 respectively). In PAX5, we found 6 rare variations and 3 of them are found to be deleterious by in silico analysis, However, we could not identify a statistically significant difference in frequency among these variants between TCCSG and normal cohorts. On the other hand, a patient who harbored heterozygous PAX5 p.V26G, which had been reported as a somatic mutation in B-ALL, was diagnosed with primary antibody deficiency after treatment of B-ALL. He is receiving immunoglobulin replacement therapy without relapse of ALL for 15 years. Discussion: Our study implied TCF3 p.S514L is associated with ALL development. Besides, we identified a case of heterozygous PAX5 p.V26G variant who exhibited antibody deficiency and B-ALL. These findings suggest those rare variants impair the normal B-cell development and may predispose to ALL development. GWAS is effective in evaluating common genetic variants. However, it is hard to identify the genes involved Mendelian inheritance or functionally defective rare variants associated with disease susceptibility. Although it is rare, our study suggests that rare variants of genes involved in B cell development could be associated with ALL susceptibility and immunodeficiency, and we revealed the frequency of functionally defective rare variants in Japanese childhood ALL cohort. Disclosures No relevant conflicts of interest to declare.