Publications by authors named "Fumihiko Matsuda"

317 Publications

Impacts of lipid-related metabolites, adiposity, and genetic background on blood eosinophil counts: the Nagahama study.

Sci Rep 2021 Jul 28;11(1):15373. Epub 2021 Jul 28.

Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Blood eosinophil count is a useful measure in asthma or COPD management. Recent epidemiological studies revealed that body mass index (BMI) is positively associated with eosinophil counts. However, few studies focused on the role of adiposity and fatty acid-related metabolites on eosinophil counts, including the effect of genetic polymorphism. In this community-based study involving 8265 participants (30-74 year old) from Nagahama city, we investigated the relationship between eosinophil counts and serum levels of fatty acid-related metabolites. The role of MDC1, a gene that is related to eosinophil counts in our previous study and encodes a protein that is thought to be involved in the repair of deoxyribonucleic acid damage, was also examined taking into account its interaction with adiposity. Serum levels of linoleic acid (LA) and β-hydroxybutyric acid (BHB) were negatively associated with eosinophil counts after adjustment with various confounders; however, there were positive interactions between serum LA and BMI and between serum BHB and BMI/body fat percentages in terms of eosinophil counts. In never-smokers, there was positive interaction for eosinophil counts between the CC genotype of MDC1 rs4713354 and BMI/body fat percentages. In conclusion, both serum LA and BHB have negative impacts on eosinophil counts, while adiposity shows robust positive effects on eosinophil counts, partly via genetic background in never-smokers.
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http://dx.doi.org/10.1038/s41598-021-94835-9DOI Listing
July 2021

Differential Contribution of the Medial and the Lateral Side of the Joint to Symptoms in Knee Osteoarthritis: A Radiographic and Laboratory Analysis in the Nagahama Study.

Cartilage 2021 Jul 14:19476035211025817. Epub 2021 Jul 14.

Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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.
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http://dx.doi.org/10.1177/19476035211025817DOI Listing
July 2021

Markers of cardiovascular disease risk in sleep-disordered breathing with or without comorbidities: the Nagahama Study.

J Clin Sleep Med 2021 Jun 21. Epub 2021 Jun 21.

Department of Respiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Study Objectives: Whether the association between sleep-disordered breathing (SDB) and cardiovascular disease (CVD) is independent of comorbid risk factors for CVD is controversial. The objective of this study is to elucidate whether the association between SDB severity and the surrogate markers of CVD evets differs in relation to the number of comorbidities.

Methods: This cross-sectional study included 7731 participants. Severity of SDB was determined by the oxygen desaturation index adjusted by actigraph-measured objective sleep time. Participants were stratified according to SDB severity and the number of comorbidities (hypertension, diabetes, dyslipidemia and obesity), and the associations between the maximum value of intima-media thickness of the common carotid artery (CCA-IMT-max), brachial-ankle pulse wave velocity (baPWV) and cardio-ankle vascular index (CAVI) were evaluated.

Results: Among participants with no risk factor, CCA-IMT-max increased according to SDB severity (n = 1022, <0.0001). Even after the matching of background, the median CCA-IMT-max value was 14% higher in moderate-severe SDB cases than those without SDB (n=45 in each group, =0.020). The difference was not significant for baPWV and CAVI. On the other hand, a significant difference in CCA-IMT-max was not found in those with multiple comorbidities. Consistently, multiple regression analysis revealed an independent association between CCA-IMT-max and moderate-severe SDB for all study participants (β: 0.0222 (95% confidence interval: 0.0039-0.0405), =0.017), but the association was not significant for stratified participants with multiple comorbidities.

Conclusions: SDB severity is associated with the CCA-IMT-max level, but the independent association becomes weaker for those with multiple comorbidities.
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http://dx.doi.org/10.5664/jcsm.9460DOI Listing
June 2021

Cutaneous T-cell-attracting chemokine as a novel biomarker for predicting prognosis of idiopathic pulmonary fibrosis: a prospective observational study.

Respir Res 2021 Jun 17;22(1):181. Epub 2021 Jun 17.

Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease that leads to respiratory failure and death. Although there is a greater understanding of the etiology of this disease, accurately predicting the disease course in individual patients is still not possible. This study aimed to evaluate serum cytokines/chemokines as potential biomarkers that can predict outcomes in IPF patients.

Methods: A multi-institutional prospective two-stage discovery and validation design using two independent cohorts was adopted. For the discovery analysis, serum samples from 100 IPF patients and 32 healthy controls were examined using an unbiased, multiplex immunoassay of 48 cytokines/chemokines. The serum cytokine/chemokine values were compared between IPF patients and controls; the association between multiplex measurements and survival time was evaluated in IPF patients. In the validation analysis, the cytokines/chemokines identified in the discovery analysis were examined in serum samples from another 81 IPF patients to verify the ability of these cytokines/chemokines to predict survival. Immunohistochemical assessment of IPF-derived lung samples was also performed to determine where this novel biomarker is expressed.

Results: In the discovery cohort, 18 cytokines/chemokines were significantly elevated in sera from IPF patients compared with those from controls. Interleukin-1 receptor alpha (IL-1Rα), interleukin-8 (IL-8), macrophage inflammatory protein 1 alpha (MIP-1α), and cutaneous T-cell-attracting chemokine (CTACK) were associated with survival: IL-1Rα, hazard ratio (HR) = 1.04 per 10 units, 95% confidence interval (95% CI) 1.01-1.07; IL-8, HR = 1.04, 95% CI 1.01-1.08; MIP-1α, HR = 1.19, 95% CI 1.00-1.36; and CTACK, HR = 1.12 per 100 units, 95% CI 1.02-1.21. A replication analysis was performed only for CTACK because others were previously reported to be potential biomarkers of interstitial lung diseases. In the validation cohort, CTACK was associated with survival: HR = 1.14 per 100 units, 95% CI 1.01-1.28. Immunohistochemistry revealed the expression of CTACK and CC chemokine receptor 10 (a ligand of CTACK) in airway and type II alveolar epithelial cells of IPF patients but not in those of controls.

Conclusions: CTACK is a novel prognostic biomarker of IPF. Trial registration None (because of no healthcare intervention).
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http://dx.doi.org/10.1186/s12931-021-01779-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218397PMC
June 2021

Population dynamics in the Japanese Archipelago since the Pleistocene revealed by the complete mitochondrial genome sequences.

Sci Rep 2021 Jun 13;11(1):12018. Epub 2021 Jun 13.

Department of Legal Medicine, Toho University School of Medicine, Tokyo, Japan.

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.
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http://dx.doi.org/10.1038/s41598-021-91357-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200360PMC
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Brachial-ankle pulse wave velocity and cardio-ankle vascular index are associated with future cardiovascular events in a general population: The Nagahama Study.

J Clin Hypertens (Greenwich) 2021 Jul 26;23(7):1390-1398. Epub 2021 May 26.

Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Faster pulse wave velocity (PWV) is known to be associated with the incidence of cardiovascular diseases (CVD). The aim of this study was to clarify the hypothesis that PWV may be associated with future CVD events even when its time-dependent changes were adjusted. We also investigated a prognostic significance of cardio-ankle vascular index, another index of arterial stiffness. Study participants included 8850 community residents. The repeated measures of the clinical parameters at 5.0 years after the baseline were available for 7249 of the participants. PWV was calculated using the arterial waveforms measured at the brachia and ankles (baPWV). The cardio-ankle vascular index was calculated by estimated pulse transit time from aortic valve to tibial artery. During the 8.53 years follow-up period, we observed 215 cases of CVD. The incidence rate increased linearly with baPWV quartiles (per 10 000 person-years: Q1, 2.7; Q2, 12.6; Q3, 22.5; Q4, 76.2), and the highest quartile was identified as an independent determinant of incident CVD by conventional Cox proportional hazard analysis adjusted for known risk factors [hazard ratio (HR), 4.00; p = .007]. Per unit HR of baPWV (HR, 1.15; p < .001) remained significant in the time-dependent Cox regression analysis including baPWV and other clinical values measured at 5-year after the baseline as time-varying variables (HR, 1.14; p < .001). The cardio-ankle vascular index was also associated with CVD with similar manner though the associations were less clear than that of baPWV. baPWV is a good risk marker for the incidence of CVD.
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http://dx.doi.org/10.1111/jch.14294DOI Listing
July 2021

Protocol for development and validation of a prediction model for 5-year risk of incident overactive bladder in the general population: the Nagahama study.

BMC Urol 2021 May 13;21(1):78. Epub 2021 May 13.

Department of Urology, Faculty of Medicine, Kyoto University Graduate School of Medicine, 54 Shogoinkawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: An accurate prediction model could identify high-risk subjects of incident Overactive bladder (OAB) among the general population and enable early prevention which may save on the related medical costs. However, no efficient model has been developed for predicting incident OAB. In this study, we will develop a model for predicting the onset of OAB at 5-year in the general population setting.

Methods: Data will be obtained from the Nagahama Cohort Project, a longitudinal, general population cohort study. The baseline characteristics were measured between Nov 28, 2008 and Nov 28, 2010, and follow-up was performed every 5 years. From the total of 9,764 participants (male: 3,208, female: 6,556) at baseline, we will exclude participants who could not attend the follow-up assessment and those who were defined as having OAB at baseline. The outcome will be incident OAB defined using the Overactive Bladder Symptom Score (OABSS) at follow-up assessment. Baseline questionnaires (demographic, health behavior, comorbidities and OABSS) and blood test data will be included as predictors. We will develop a logistic regression model utilizing shrinkage methods (LASSO penalization method). Model performance will be evaluated by discrimination and calibration. Net benefit will be evaluated by decision curve analysis. We will perform an internal validation and a temporal validation of the model. We will develop a web-based application to visualize the prediction model and facilitate its use in clinical practice.

Discussion: This will be the first study to develop a model to predict the incidence of OAB.
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http://dx.doi.org/10.1186/s12894-021-00848-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120704PMC
May 2021

Clinical Characteristics, Differential Diagnosis and Genetic Analysis of Concentric Retinitis Pigmentosa.

Life (Basel) 2021 Mar 22;11(3). Epub 2021 Mar 22.

Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.

Concentric retinitis pigmentosa (RP), in which retinal degeneration is limited in the periphery, is rare and little information exists to date on the subject. Herein, we describe the clinical and genetic characteristics of this atypical form of RP. We retrospectively reviewed our database and identified 14 patients with concentric RP. Additionally, 14 patients with age-matched typical RP were also included. Patients with concentric RP had better visual acuity (logarithm of minimum angle of resolution -0.04 vs. 0.32, = 0.047) and preserved ellipsoid zones (7630 µm vs. 2646 µm, < 0.001) compared to typical RP. The electroretinogram showed subnormal but recordable responses in patients with concentric RP. Genetic testing was done in nine patients with concentric RP and revealed causative mutations in the gene in one patient and the gene in one patient. Two patients had myotonic dystrophy and the diagnosis was revised as myotonic dystrophy-associated retinopathy. Concentric RP is a rare, atypical form of RP with better visual function. There is some overlap in the causative genes in concentric and typical RP. Myotonic dystrophy-associated retinopathy is an important differential diagnosis.
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http://dx.doi.org/10.3390/life11030260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004166PMC
March 2021

Age-related changes in gait speeds and asymmetry during circular gait and straight-line gait in older individuals aged 60-79 years.

Geriatr Gerontol Int 2021 May 29;21(5):404-410. Epub 2021 Mar 29.

Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Aim: The present study aimed to investigate the age-related changes in gait speeds and asymmetry during circular and straight-line gaits among older adults aged 60-79 years.

Methods: The study included 391 community-dwelling older adults aged >60 years, who participated in the Nagahama cohort study. They were assigned to four age groups: 60-64 years (early 60s), 65-69 years (late 60s), 70-74 years (early 70s) and 75-79 years (late 70s). For the circular gait test, the time required to walk twice around a 1-m diameter circle for right and left rotations were measured. The average time of the two trials was measured as the circular gait time, and the side-to-side difference in the circular gait times was calculated as an asymmetry index. Walking speed, asymmetry of step length, and asymmetry of stance duration time during straight-line gait at comfortable and maximal walking pace were measured.

Results: Circular gait time in older women in the late 70s group was significantly slower than that in other age groups; however, no age-related change was observed in older men. Maximal gait speeds in the early and late 70s groups were significantly slower than those in the early 60s group.

Conclusions: Age-related decline in circular gait speed was observed in older women aged ≥75 years, but not in older men. Maximal straight-line gait speed decreased significantly in both genders after the age of 70 years. Geriatr Gerontol Int 2021; 21: 404-410.
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http://dx.doi.org/10.1111/ggi.14150DOI Listing
May 2021

Genome wide association study of HTLV-1-associated myelopathy/tropical spastic paraparesis in the Japanese population.

Proc Natl Acad Sci U S A 2021 Mar;118(11)

Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Sakyo-ku, 606-8507 Kyoto, Japan;

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 , , , , , and genes using next-generation sequencing technology for 651 HAM/TSP patients and 804 carriers. A strong association was observed in class I ( = 1.54 × 10) and class II ( = 1.21 × 10) loci with HAM/TSP. Association analysis using genotyping results showed that * ( = 2.61 × 10), * ( = 4.97 × 10), * ( = 1.15 × 10) and * ( = 2.30 × 10) were associated with disease risk, while * ( = 3.03 × 10), * ( = 1.06 × 10) and * ( = 1.78 × 10) worked protectively. Logistic regression analysis identified amino acid position 7 in the G-BETA domain of HLA-DRB1 as strongly associated with HAM/TSP ( = 9.52 × 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.
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http://dx.doi.org/10.1073/pnas.2004199118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980450PMC
March 2021

Coexistence of low back pain and lumbar kyphosis is associated with increased functional disability in knee osteoarthritis: the Nagahama Study.

Arthritis Care Res (Hoboken) 2021 Feb 19. Epub 2021 Feb 19.

Kyoto University, Department of Physical Therapy, Human Health Sciences, Graduate School of Medicine, Kyoto, Japan.

Objective: To examine the association of low back pain (LBP) and lumbar kyphosis with functional disabilities and knee symptoms in patients with knee osteoarthritis (OA).

Methods: We analyzed 586 participants (80.1% female; age, 68.8 ± 5.2 years) from the Nagahama Study who were aged ≥60 years and had radiographically confirmed knee OA. The Knee Scoring System (KSS) was used to assess functional disabilities and knee symptoms. LBP was defined as the presence of any persistent back pain for more than 3 months. Lumbar kyphosis was determined by skin-surface methods using a computer-aided electronic device called the Spinal Mouse. Multiple linear regression analysis was used for assessing the association of LBP and lumbar kyphosis with the KSS scores. Subgroup analyses based on sex were also performed.

Results: LBP and lumbar kyphosis were independently associated with a lower KSS function score after adjustment for covariates (mean difference [95%CI, confidence interval] = -4.96 [-7.56 to -2.36] points for LBP alone, -4.47 [-8.51 to -0.43] points for lumbar kyphosis alone, and -13.86 [-18.86 to -8.86] points for the coexistence of LBP and lumbar kyphosis, respectively). The coexistence of LBP and lumbar kyphosis in women was associated with a lower KSS symptom score (mean difference [95%CI] = -4.49 [-6.42 to -2.55] points).

Conclusion: These findings suggest that both LBP and lumbar kyphosis are useful clinical signals indicating functional disability and knee symptoms in patients with knee OA.
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http://dx.doi.org/10.1002/acr.24580DOI Listing
February 2021

Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.

Nat Commun 2021 02 15;12(1):1032. Epub 2021 Feb 15.

Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.

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). 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), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10). 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.
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http://dx.doi.org/10.1038/s41467-021-21011-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884840PMC
February 2021

Relationship between Intraocular Pressure and Coffee Consumption in a Japanese Population without Glaucoma: The Nagahama Study.

Ophthalmol Glaucoma 2021 May-Jun;4(3):268-276. Epub 2020 Nov 5.

Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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.
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http://dx.doi.org/10.1016/j.ogla.2020.09.019DOI Listing
November 2020

Extracellular-to-intracellular water ratios are associated with functional disability levels in patients with knee osteoarthritis: results from the Nagahama Study.

Clin Rheumatol 2021 Jul 23;40(7):2889-2896. Epub 2021 Jan 23.

Department of Physical Therapy, Human Health Sciences, Graduate School of Medicine, Kyoto University, 53-Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Introduction/objectives: To test the hypothesis that greater extracellular-to-intracellular water (ECW/ICW) ratios in lower-limb muscles are associated with worsened functional abilities in patients with knee osteoarthritis (OA).

Methods: We analyzed data from 787 participants (82.2% female; mean age, 69.6 ± 5.3 years) from the Nagahama Prospective Cohort who were ≥60 years old and had radiographically confirmed bilateral knee OA. The Knee Scoring System (KSS) was used to assess functional abilities. Lower-limb ECW/ICW ratios and skeletal mass index values were determined with multi-frequency bioelectrical impedance analysis (BIA). Multiple linear regression analysis was used to test for associations between ECW/ICW ratios and functional abilities. Subgroup analyses based on OA severities and symptomaticity were also conducted.

Results: Increased ECW/ICW ratios were associated with a 4.38-point decrease in the KSS function scores (95% confidence interval [CI], 3.15-5.62 points) after adjusting for covariates. This association varied according to the degree of knee symptoms, especially in individuals with radiologically mild OA. ECW/ICW ratios in individuals with asymptomatic mild OA were associated with a 2.14-point decrease in the KSS function score (95% CI, 0.32-3.96 points), whereas those in individuals with severe symptomatic mild OA were associated with a 6.16-point decrease (95% CI, 2.13-10.19 points).

Conclusions: Our findings indicate that higher ECW/ICW ratios are associated with greater functional disability in patients with knee OA. Therefore, ECW/ICW ratio measurements with multi-frequency BIA can serve as valuable indicators for functional disability in patients with knee OA. Key Points • Higher extracellular-to-intracellular water (ECW/ICW) ratios are associated with greater functional disability levels in patients with knee osteoarthritis (OA). • ECW/ICW ratios are useful clinical signs as a biomarker for poor functional abilities in patients with knee OA.
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http://dx.doi.org/10.1007/s10067-021-05591-0DOI Listing
July 2021

Publisher Correction: Genome-wide association study of individual differences of human lymphocyte profiles using large-scale cytometry data.

J Hum Genet 2021 Jun;66(6):643

Department of Statistical Genetics, Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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http://dx.doi.org/10.1038/s10038-020-00890-xDOI Listing
June 2021

Gastroesophageal reflux disease is a risk factor for sputum production in the general population: the Nagahama study.

Respir Res 2021 Jan 6;22(1). Epub 2021 Jan 6.

Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54, Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

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.
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http://dx.doi.org/10.1186/s12931-020-01601-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788913PMC
January 2021

Digenic mutations in and impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome.

Sci Adv 2020 Dec 18;6(51). Epub 2020 Dec 18.

Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.

Rs671 in the aldehyde dehydrogenase 2 gene () is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase ( ), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome. Cellular studies revealed that a decrease in the formaldehyde tolerance underlies a loss of differentiation and proliferation capacity of hematopoietic stem cells. Moreover, double-deficient mice recapitulated key clinical features of AMeDS, showing short life span, dwarfism, and hematopoietic failure. Collectively, our results suggest that the combined deficiency of formaldehyde clearance mechanisms leads to the complex clinical features due to overload of formaldehyde-induced DNA damage, thereby saturation of DNA repair processes.
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http://dx.doi.org/10.1126/sciadv.abd7197DOI Listing
December 2020

Clinical and Genetic Characteristics of Pachydrusen in Eyes with Central Serous Chorioretinopathy and General Japanese Individuals.

Ophthalmol Retina 2020 Dec 10. Epub 2020 Dec 10.

Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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.
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http://dx.doi.org/10.1016/j.oret.2020.12.004DOI Listing
December 2020

Cerebral small vessel disease genomics and its implications across the lifespan.

Nat Commun 2020 12 8;11(1):6285. Epub 2020 Dec 8.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
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http://dx.doi.org/10.1038/s41467-020-19111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722866PMC
December 2020

EYS is a major gene involved in retinitis pigmentosa in Japan: genetic landscapes revealed by stepwise genetic screening.

Sci Rep 2020 11 27;10(1):20770. Epub 2020 Nov 27.

Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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.
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http://dx.doi.org/10.1038/s41598-020-77558-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695703PMC
November 2020

Obesity with radiological changes or depression was associated with worse knee outcome in general population: a cluster analysis in the Nagahama study.

Arthritis Res Ther 2020 11 27;22(1):280. Epub 2020 Nov 27.

Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: In knee osteoarthritis (OA), pain is the most frequent and dominant symptom. However, which factors other than radiological changes contribute to the symptoms is unresolved. The aims of this study were to identify factors affecting knee pain from various variables with radiological changes taken into count and exploratively examine what subgroups or phenotype could be identified by cluster analysis using the identified knee pain factors.

Methods: Patients 60 years or older who underwent radiographic evaluation were included in this cross-sectional study, and those subjects who completed a questionnaire about knee symptoms without missing data were eligible for analysis. Multiple regression analysis was used to examine the associations between selected variables and The Japanese Knee Osteoarthritis Measure (JKOM) pain score. We grouped the subjects by cluster analysis using identified variables.

Results: Two thousand five hundred forty-two subjects were included in the full set of analyses. Age, body mass index (BMI), radiological grade, bone mineral density (BMD), and high-sensitivity C-reactive protein (hs-CRP) showed a statistically significant correlation with radiological showing the strongest value. For dichotomous variable, presence of depression showed a statistically significant result. We used BMI, radiological grade, BMD, hs-CRP, and presence of depression as a variable for cluster analysis and identified six subgroups: (1) minimal joint disease subgroup, (2) male and high BMD subgroup, (3) high CRP subgroup, (4) severe radiological OA subgroup, (5) depressive subgroup, and (6) moderate radiological OA with high BMI subgroup, showing the worst knee outcome.

Conclusion: This study identified the factors affecting knee pain other than radiological changes and identified six subgroups of knee outcome in the general population. The results showed that obesity with radiological changes or depression was associated with worse knee outcome.
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http://dx.doi.org/10.1186/s13075-020-02375-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694310PMC
November 2020

Genome-wide association study of individual differences of human lymphocyte profiles using large-scale cytometry data.

J Hum Genet 2021 Jun 23;66(6):557-567. Epub 2020 Nov 23.

Department of Statistical Genetics, Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Human immune systems are very complex, and the basis for individual differences in immune phenotypes is largely unclear. One reason is that the phenotype of the immune system is so complex that it is very difficult to describe its features and quantify differences between samples. To identify the genetic factors that cause individual differences in whole lymphocyte profiles and their changes after vaccination without having to rely on biological assumptions, we performed a genome-wide association study (GWAS), using cytometry data. Here, we applied computational analysis to the cytometry data of 301 people before receiving an influenza vaccine, and 1, 7, and 90 days after the vaccination to extract the feature statistics of the lymphocyte profiles in a nonparametric and data-driven manner. We analyzed two types of cytometry data: measurements of six markers for B cell classification and seven markers for T cell classification. The coordinate values calculated by this method can be treated as feature statistics of the lymphocyte profile. Next, we examined the genetic basis of individual differences in human immune phenotypes with a GWAS for the feature statistics, and we newly identified seven significant and 36 suggestive single-nucleotide polymorphisms associated with the individual differences in lymphocyte profiles and their change after vaccination. This study provides a new workflow for performing combined analyses of cytometry data and other types of genomics data.
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http://dx.doi.org/10.1038/s10038-020-00874-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144016PMC
June 2021

Medical history of nocturnal enuresis during school age is an independent risk factor for nocturia in adults: The Nagahama study.

Neurourol Urodyn 2021 01 29;40(1):326-333. Epub 2020 Oct 29.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Aim: To evaluate the relationship between nocturia and medical history of nocturnal enuresis: two conditions where diurnal urination rhythm is disturbed.

Methods: The Nagahama study is a longitudinal population-based health survey involving people aged 30-75 years in Nagahama city, Japan. Our analysis included 5,402 participants who completed enuresis and International Prostate Symptom Score questionnaires. Associations between nocturnal enuresis and nocturia were evaluated cross-sectionally and longitudinally with three models: (1) univariate analysis; (2) adjusted for basic characteristics (e.g., age, sex, body mass index, activity, alcohol, and smoking); and (3) adjusted for basic and clinical variables (e.g., hyperglycemia, hyperlipidemia, hypertension, renal insufficiency, insomnia, obstructive sleep apnea, and mental health).

Results: In total, 1,613 participants (29.9%) had a medical history of enuresis. The mean night-time frequency was 0.73 at baseline and 0.85 at the 5-year follow-up. The cross-sectional analysis showed participants with a medical history of enuresis had night-time frequency more often than those without this history (0.84 vs. 0.68, p < .0001). Significant differences were observed in Models 2 (p < .0001) and 3 (p < .0001). The longitudinal analysis showed nocturia progression was significantly related to a history of enuresis, with odds ratios of 1.32 (p < .0001) in Model 1, 1.21 (p < .01) in Model 2, and 1.22 (p < .01) in Model 3.

Conclusions: Medical history of enuresis during school age was significantly related to nocturia in adulthood in the cross-sectional analysis, and to progression to nocturia in the longitudinal analysis. These two conditions may possess a common causative association.
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http://dx.doi.org/10.1002/nau.24562DOI Listing
January 2021

Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease.

Nat Genet 2020 11 5;52(11):1169-1177. Epub 2020 Oct 5.

Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.

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.
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http://dx.doi.org/10.1038/s41588-020-0705-3DOI Listing
November 2020

Night-time frequency of urination as a manifestation of sleep-disordered breathing: the Nagahama study.

Sleep Med 2021 01 12;77:288-294. Epub 2020 Sep 12.

Department of Respiratory Care and Sleep Control Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Aims: Sleep-disordered breathing (SDB) is a well-known risk factor for cardiovascular outcomes. Studies of patients with SDB have identified frequent night-time urination as a manifestation related to SDB. We aimed to clarify whether night-time frequency of urination is independently associated with SDB in a general population. We also investigated whether night-time frequency of urination can help presumptive diagnose SDB.

Methods: Study participants consisted of 7151 community residents. Oxygen saturation during sleep was measured for four nights using a pulse oximeter. SDB was defined as ≥15 events per hour in which oxygen desaturation exceeded or equal to 3% during an actigraphy-determined sleep period. Night-time frequency of urination was recorded for one week using a sleep diary.

Results: Significant positive correlations were evident between night-time frequency of urination and SDB (none, 5.8%; once/night, 14.1%; twice/night, 20.1%; thrice/night, 28.7%; >thrice/night, 44.1%, P < 0.001). This association was independent of possible covariates, including sleep duration (adjusted odds ratio: once/night = 1.50, twice/night = 2.15, thrice/night = 3.07, >thrice/night = 3.73, P < 0.001). Other factors significantly associated with SDB were age, sex, obesity, observation of sleep apnea, and short sleep duration. The area under the curve of the risk score for SDB consisting of these conventional six items (0.834) significantly improved (0.842, P = 0.001) when night-time frequency of urination was considered as a risk score item.

Conclusion: Night-time frequency of urination was associated with SDB. Our findings suggest that the urination frequency should be considered a manifestation of SDB even in a general population.
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http://dx.doi.org/10.1016/j.sleep.2020.09.007DOI Listing
January 2021

Impact of sleep-disordered breathing on glucose metabolism among individuals with a family history of diabetes: the Nagahama study.

J Clin Sleep Med 2021 02;17(2):129-140

Department of Respiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Study Objectives: It is well known that a family history of diabetes (FHD) is a definitive risk factor for type 2 diabetes. It has not been known whether sleep-disordered breathing (SDB) increases the prevalence of diabetes in those with an FHD.

Methods: We assessed SDB severity in 7,477 study participants by oximetry corrected by objective sleep duration determined by wrist actigraphy. Glycated hemoglobin ≥6.5% and/or current medication for diabetes indicated the presence of diabetes. In addition to the overall prevalence, the prevalence of recent-onset diabetes during the nearly 5 years before the SDB measurements were made was investigated.

Results: Of the 7,477 participants (mean age: 57.9; range: 34.2-80.7; SD: 12.1 years; 67.7% females), 1,569 had an FHD. The prevalence of diabetes in FHD participants with moderate-to-severe SDB (MS-SDB) was higher than in those without SDB (MS-SDB vs without SDB: all, 29.3% vs 3.3% [P < .001]; females, 32.6% vs 1.9% [P < .001]; males, 26.2% vs 11.7% [P = .037]). However, multivariate analysis showed that MS-SDB was significantly associated with a higher prevalence of diabetes only in FHD-positive females (odds ratio [95% confidence interval]: females, 7.43 [3.16-17.45]; males, 0.92 [0.37-2.31]). Among the FHD-positive participants, the prevalence of recent-onset diabetes was higher in those with MS-SDB than those without SDB, but only in females (MS-SDB vs without SDB: 21.4% vs 1.1%; P < 0.001).

Conclusions: MS-SDB was associated with diabetes risk in females with an FHD, and future studies are needed on whether treatment of SDB in females with an FHD would prevent the onset of diabetes.
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http://dx.doi.org/10.5664/jcsm.8796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853232PMC
February 2021

Cohort Profile: The Network (GEN), a Network of Japanese Ophthalmological Epidemiology Studies.

Ophthalmic Epidemiol 2021 Jun 13;28(3):237-243. Epub 2020 Sep 13.

Department of Vision Informatics, Osaka University Graduate School of Medicine, Osaka, Japan.

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.
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http://dx.doi.org/10.1080/09286586.2020.1815803DOI Listing
June 2021

Reply by Authors.

J Urol 2020 11 4;204(5):1002. Epub 2020 Sep 4.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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http://dx.doi.org/10.1097/JU.0000000000001138.02DOI Listing
November 2020
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