Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

Metabolically healthy obesity and risks of cardiovascular disease and all-cause mortality, a matched cohort study: the Shizuoka study.

BACKGROUND: Metabolically healthy obesity is not always a benign condition. It is associated with an increased incidence of cardiovascular disease and all-cause mortality. We investigated the prognostic significance of metabolically healthy obesity by comparing clinical profile-matched metabolically healthy obesity and non-obesity groups. METHODS: We analyzed a health insurance dataset with annual health checkup data from Japan. The analyzed data included 168,699 individuals aged <65 years. Obesity was defined as ≥25 kg/m2 body mass index. Metabolically healthy was defined as ≤1 metabolic risk factor (high blood pressure, low high-density lipoprotein cholesterol, high low-density lipoprotein cholesterol, or high hemoglobin A1c). Incidence rates of stroke, myocardial infarction, and all-cause mortality identified from the insurance data were compared between metabolically healthy obesity and non-obesity groups (n = 8644 each) using a log-rank test. RESULTS: The stroke (obesity: 9.2 per 10,000 person-years; non-obesity: 10.5; log-rank test p = 0.595), myocardial infarction (obesity: 3.7; non-obesity: 3.1; p = 0.613), and all-cause mortality (obesity: 26.6; non-obesity: 23.2; p = 0.304) incidence rates did not differ significantly between the metabolically healthy obesity and non-obesity groups, even when the abdominal obesity was considered in the analysis. The lack of association was also observed in the comparison between the metabolically unhealthy obesity and non-obesity groups (n = 10,965 each). The population with metabolically healthy obesity reported negligibly worse metabolic profiles than the population with non-obesity at the 5.6-year follow-up. CONCLUSION: Obesity, when accompanied by a healthy metabolic profile, did not increase the risk of cardiovascular outcomes and all-cause mortality.

One-leg standing time is a simple measure for loss of skeletal muscle mass and fat deposition in muscle: the J-SHIPP study.

BACKGROUNDS: One-leg standing time (OLST) has been frequently used physical performance measure; however, what muscular characteristics OLST represents remains uncertain. AIM: This cross-sectional study aimed to investigate the association between OLST and muscle characteristics to clarify the possibility of using OLST as a physical performance measure. METHODS: Study participants comprised 1144 older adults aged 65 years or older. Computed tomography images provided mid-thigh skeletal muscle cross-sectional area and mean attenuation value. OLST was measured for a maximum of 60 s. Static postural instability was assessed using a posturography. RESULTS: A frequency of OLST < 20 s was increased by quartiles of muscle cross-sectional area (Q1: 33.6, Q2: 12.8, Q3: 13.6, Q4: 11.9%, P < 0.001) and mean attenuation value (Q1: 32.3, Q2: 21.7, Q3: 14.3, Q4: 7.7%, P < 0.001). Results of the multinomial regression analysis indicated that muscle cross-sectional area and mean attenuation value were independently associated with an OLST of less than 20 s. The crude odds ratio of OLST less than 20 s for the lowest quartiles of both cross-sectional area and mean attenuation value was 4.19 (95% CI: 3.01 - 5.84). The cross-sectional area of muscles with greater fat deposition was inversely associated with OLST, while that with smaller fat deposition showed a positive association with OLST, indicating why mean attenuation value and cross-sectional area were independently associated with OLST. No clear relationship was observed with static postural instability. CONCLUSION: OLST was a simply measurable quantifiable physical measure representing the loss of muscle mass and quality in older adults.

Common and distinct risk profiles of asymptomatic extra- and intracranial atherosclerosis in the Nagahama cohort.

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.

[Utilization of the standard questionnaire in specific health checkups].

Objectives　Interviewing people about their health behaviour in specific health checkups (SHCs) is thought to promote awareness of and help improve such behaviour. The standard questionnaire (SQ) for SHCs consists of 22 items presented in the guidelines of the Ministry of Health, Labour, and Welfare. However, using items other than those necessary for stratification for specific health guidance (SHG) is optional. We believe that clarifying the actual utilization of SQ items could contribute to improving the procedure used for the fourth SHCs and SHG, which will be initiated in 2024.　This study seeks to clarify the actual utilization of the SQ for (1) conducting SHCs, (2) planning, implementing, and evaluating SHG and health programs aimed at preventing lifestyle-related diseases, and (3) planning, implementing, and evaluating the data health plan.Methods　We enrolled 3,179 people from 1,741 departments in charge of national health insurance, 47 Japan Health Insurance Association branches, and 1,391 health insurance societies across all municipalities in Japan. One participant among the study participants was the main person in charge of SHCs and SHG at each facility. We conducted a self-reported survey on the implementation of SHCs and SHG in February 2022. This study was approved by the ethics review board of the institution to which the first author belongs.Results　A total of 1,221 (38.4%) were received. The proportions of valid responses from national health insurance departments, Japan Health Insurance Association branches, and health insurance societies were 816 (46.9%), 47 (100%), and 358 (25.7%), respectively. Over 96% of responders used the group SHCs method, and over 93% of those adopting the individual SHCs method used each of the 22 SQ items. However, 187 (18.2%) responders found it difficult to use the item "If you had the opportunity to receive health guidance for lifestyle improvement, would you take it?" The reason was that the on-request SHG system was misunderstood. Additionally, only approximately 50% of respondents used the SQ to develop, implement, and evaluate their health program.Conclusion　We believe there will be no problem in implementing the SQ even if using all its component items is required. However, the aforementioned item needs to be revised. Methods to encourage health insurers and their supporters to use the SQ for health-related data collection and health program planning should be devised.

[Optimal search conditions for identification of patients with chronic myeloid leukemia from Japanese National Health Insurance data].

This study investigated which conditions could be used to identify patients with chronic myeloid leukemia (CML) from a National Health Insurance claims dataset. During April 2012 and September 2018, 1,789,462 employees were enrolled in the dataset for Shizuoka Prefecture residents. The number of patients with the ICD-10 code for CML was 761. Among them, 246 who had been prescribed a tyrosine kinase inhibitor were considered as having true CML. The positive predictive value was calculated as 32.3% when CML was identified by ICD-10 code alone. Combination of ICD-10 code with prescribed drugs was required to accurately identify patients with CML from the insurance database.

Additive association of blood pressure and short stature with stroke incidence in 450,000 Japanese adults: the Shizuoka study.

Short stature was suggested to be a risk factor for cardiovascular events. Because short stature increases central blood pressure, this study aimed to investigate a longitudinal association between short stature, blood pressure, and incidence of cardiovascular disease by the analysis of insurance-based real-world dataset. We analyzed data from 463,844 adults aged 40 or older with a mean age of 66.7 enrolled in National Health Insurance, excluding individuals who experienced a stroke or myocardial infarction, or required long-term care. Data from annual health checkups were used to obtain baseline clinical information. Comorbidities and incidences of stroke and myocardial infarction were obtained from the insurance data. During a 5.5-year follow-up period, we observed 11,027 cases of stroke. Adults of a short stature exhibited a higher incidence rate in both men (≤155 cm: 99.7, >175 cm: 24.4) and women (≤140 cm: 85.9, >160 cm: 13.7). Although those in the short stature group had higher blood pressure, and often took antihypertensive drugs, the inverse association between height and stroke incidence was independent of these factors (hazard ratio for 5 cm shorter in height; men: 1.06 [1.03-1.09], women: 1.11 [1.06-1.13]). Short stature and blood pressure showed additive association with stoke incidence (log-rank p < 0.001). No significant association was observed with myocardial infarction (men: 1.01 [0.95-1.06], women: 1.06 [0.98-1.14]). In a longitudinal analysis of a large general Japanese population, short stature was linked to an increased risk of stroke in both genders in any blood pressure range.

Interaction effect between low birthweight and resistin gene rs1862513 variant on insulin resistance and type 2 diabetes mellitus in adulthood: Toon Genome Study.

AIMS/INTRODUCTION: Gene-environment interactions are considered to critically influence type 2 diabetes mellitus development; however, the underlying mechanisms and specific interactions remain unclear. Given the increasing prevalence of low birthweight (LBW) influenced by the intrauterine environment, we sought to investigate genetic factors related to type 2 diabetes development in individuals with LBW. MATERIALS AND METHODS: The interaction between 20 reported type 2 diabetes susceptibility genes and the development of type 2 diabetes in LBW (<2,500 g) individuals in a population-based Japanese cohort (n = 1,021) was examined by logistic regression and stratified analyses. RESULTS: Logistic regression analyses showed that only the G/G genotype at the rs1862513 locus of the resistin gene (RETN), an established initiator of insulin resistance, was closely related to the prevalence of type 2 diabetes in individuals with LBW. Age, sex and current body mass index-adjusted stratified analyses showed a significant interaction effect of LBW and the RETN G/G genotype on fasting insulin, homeostatic model assessment 2-insulin resistance, Matsuda index and the prevalence of type 2 diabetes (all P-values for interaction <0.05). The adjusted odds ratio for type 2 diabetes in the LBW + G/G genotype group was 7.33 (95% confidence interval 2.43-22.11; P = 0.002) compared with the non-LBW + non-G/G genotype group. Similar results were obtained after excluding the influence of malnutrition due to World War II. CONCLUSIONS: Simultaneous assessment of LBW and the RETN G/G genotype can more accurately predict the risk of future type 2 diabetes than assessing each of these factors alone, and provide management strategies, including early lifestyle intervention in LBW population.

Transcriptomic Analysis Reveals Sixteen Potential Genes Associated with the Successful Differentiation of Antibody-Secreting Cells through the Utilization of Unfolded Protein Response Mechanisms in Robust Responders to the Influenza Vaccine.

The seasonal influenza vaccine remains one of the vital recommended infection control measures for the elderly with chronic illnesses. We investigated the immunogenicity of a single dose of influenza vaccine in 123 seronegative participants and classified them into four distinct groups, determined by the promptness of vaccine response, the longevity of humoral immunity, and the likelihood of exhibiting cross-reactivity. Subsequently, we used transcriptional profiling and differential gene expression analysis to identify potential genes directly associated with the robust response to the vaccine. The group of exemplary vaccine responders differentially expressed 16 genes, namely: MZB1, MYDGF, TXNDC5, TXNDC11, HSP90B1, FKBP11, PDIA5, PRDX4, CD38, SDC1, TNFRSF17, TNFRSF13B, PAX5, POU2AF1, IRF4, and XBP1. Our findings point out a list of expressed proteins that are related to B cell proliferation, unfolded protein response, and cellular haemostasis, as well as a linkage of these expressions to the survival of long-lived plasma cells.

Sleep blood pressure measured using a home blood pressure monitor was independently associated with cardiovascular disease incidence: the Nagahama study.

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.

Usefulness of the serum creatinine/cystatin C ratio as a blood biomarker for sarcopenia components among age groups in community-dwelling older people: The SONIC study.

AIM: The serum creatinine/cystatin C ratio (CCR) or sarcopenia index is considered a useful marker of muscle mass. However, its usefulness in late-stage older adults remains unclear. We aimed to determine the usefulness of CCR as an indicator of sarcopenia in community-dwelling Japanese adults aged >75 years. METHODS: Our study recruited participants aged 70, 80, and 90 ± 1 years during the baseline years, and included a 3-year follow-up in the Septuagenarians, Octogenarians, Nonagenarians, Investigation with Centenarians study. From 2015 to 2018, 955 participants were eligible: 367 in their 70s, 304 in their 80s, and 284 in their 90s. The diagnostic components of sarcopenia, including "low muscle mass, plus low muscle strength, and/or low physical performance," were evaluated using the bioelectrical impedance analysis-measured skeletal muscle mass index (SMI), handgrip strength, and short physical performance battery (SPPB) score, respectively, in accordance with the Asia Working Group for Sarcopenia 2019 criteria. Separate analyses were performed between each component and CCR, adjusting for sex, body mass index, and other blood biomarkers in each group. RESULTS: The relationship between CCR and sarcopenia components was significant for handgrip strength (ß = 0.21, 0.13, 0.19, and P < 0.0001, =0.0088, <0.0001, for the 70s, 80s, and 90s age groups, respectively); however, it was limited for SMI (ß = 0.14; P = 0.0022, only for the 90s) and not significant for the SPPB score. CONCLUSION: CCR is a limited indicator of sarcopenia in late-stage older adults. Although its association with muscle strength was significant, its relationship with muscle mass and physical performance was less pronounced. Geriatr Gerontol Int 2024; 24: 529-536.

Associations between Nocturnal Hypoxemia and Retinal Nerve Fiber Layer Thinning: The Nagahama Study.

Rationale: There have been meta-analyses that showed reduced retinal nerve fiber layer (RNFL) thickness, which is a surrogate marker of glaucoma, in patients with obstructive sleep apnea (OSA). However, the sample sizes in these reports were small (<300), and the mechanism of RNFL thinning in patients with OSA was not revealed.Objectives: To investigate the relationship of RNFL thickness with nocturnal hypoxemia or hypoxemic burden in a large-scale study.Methods: In this epidemiological study, 8,309 community residents were enrolled. The actigraphy-modified 3% oxygen desaturation index (acti-ODI3%) and cumulative percentage of sleep time with oxygen saturation <90% (acti-CT90) modified by objective sleep duration using actigraphy were measured. The hypoxemic burden is shown as acti-CT90. Circumpapillary RNFL thickness was determined using optical coherence tomography.Results: Multivariable logistic analysis models revealed that an increase in acti-CT90 was significantly associated with mean RNFL thinning after adjusting for several factors in participants without glaucoma diagnosed or treated previously (ß = -0.037; P = 0.009). There were significant differences in mean RNFL thickness among participants stratified according to acti-CT90 (>1.5 vs. ⩽1.5; P = 0.04). Although acti-ODI3% was significantly associated with acti-CT90 (ß = 0.72; P < 0.0001), acti-ODI3% was not significantly associated with mean RNFL thickness in the multivariable logistic analysis (ß = -0.011; P = 0.48). In addition, acti-CT90 was significantly associated with mean RNFL thickness both in the elderly (⩾60 yr; ß = -0.058; P = 0.002) and nonelderly (<60 yr; ß = -0.054; P = 0.007).Conclusions: Acti-CT90, but not acti-ODI3%, was associated with mean RNFL thinning in participants irrespective of age in the elderly or nonelderly. Further prospective studies are required to investigate whether the prevention of hypoxic burden, which was shown as acti-CT90 in this study, is favorable for RNFL thinning.

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

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