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1. Integrative genomic analysis of blood pressure and related phenotypes in rats

Author

Fumihiko Takeuchi, Yi-Qiang Liang, Masato Isono, Michiko Tajima, Zong Hu Cui, Yoko Iizuka, Takanari Gotoda, Toru Nabika, and Norihiro Kato

Subjects
gene, locus, transcriptome, blood pressure, multifactorial disease, genome-wide association studies, Medicine, Pathology, RB1-214
Abstract

Despite remarkable progress made in human genome-wide association studies, there remains a substantial gap between statistical evidence for genetic associations and functional comprehension of the underlying mechanisms governing these associations. As a means of bridging this gap, we performed genomic analysis of blood pressure (BP) and related phenotypes in spontaneously hypertensive rats (SHR) and their substrain, stroke-prone SHR (SHRSP), both of which are unique genetic models of severe hypertension and cardiovascular complications. By integrating whole-genome sequencing, transcriptome profiling, genome-wide linkage scans (maximum n=1415), fine congenic mapping (maximum n=8704), pharmacological intervention and comparative analysis with transcriptome-wide association study (TWAS) datasets, we searched causal genes and causal pathways for the tested traits. The overall results validated the polygenic architecture of elevated BP compared with a non-hypertensive control strain, Wistar Kyoto rats (WKY); e.g. inter-strain BP differences between SHRSP and WKY could be largely explained by an aggregate of BP changes in seven SHRSP-derived consomic strains. We identified 26 potential target genes, including rat homologs of human TWAS loci, for the tested traits. In this study, we re-discovered 18 genes that had previously been determined to contribute to hypertension or cardiovascular phenotypes. Notably, five of these genes belong to the kallikrein–kinin/renin–angiotensin systems (KKS/RAS), in which the most prominent differential expression between hypertensive and non-hypertensive alleles could be detected in rat Klk1 paralogs. In combination with a pharmacological intervention, we provide in vivo experimental evidence supporting the presence of key disease pathways, such as KKS/RAS, in a rat polygenic hypertension model.

Published
2021
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2. Interethnic analyses of blood pressure loci in populations of East Asian and European descent

Author

Fumihiko Takeuchi, Masato Akiyama, Nana Matoba, Tomohiro Katsuya, Masahiro Nakatochi, Yasuharu Tabara, Akira Narita, Woei-Yuh Saw, Sanghoon Moon, Cassandra N. Spracklen, Jin-Fang Chai, Young-Jin Kim, Liang Zhang, Chaolong Wang, Huaixing Li, Honglan Li, Jer-Yuarn Wu, Rajkumar Dorajoo, Jovia L. Nierenberg, Ya Xing Wang, Jing He, Derrick A. Bennett, Atsushi Takahashi, Yukihide Momozawa, Makoto Hirata, Koichi Matsuda, Hiromi Rakugi, Eitaro Nakashima, Masato Isono, Matsuyuki Shirota, Atsushi Hozawa, Sahoko Ichihara, Tatsuaki Matsubara, Ken Yamamoto, Katsuhiko Kohara, Michiya Igase, Sohee Han, Penny Gordon-Larsen, Wei Huang, Nanette R. Lee, Linda S. Adair, Mi Yeong Hwang, Juyoung Lee, Miao Li Chee, Charumathi Sabanayagam, Wanting Zhao, Jianjun Liu, Dermot F. Reilly, Liang Sun, Shaofeng Huo, Todd L. Edwards, Jirong Long, Li-Ching Chang, Chien-Hsiun Chen, Jian-Min Yuan, Woon-Puay Koh, Yechiel Friedlander, Tanika N. Kelly, Wen Bin Wei, Liang Xu, Hui Cai, Yong-Bing Xiang, Kuang Lin, Robert Clarke, Robin G. Walters, Iona Y. Millwood, Liming Li, John C. Chambers, Jaspal S. Kooner, Paul Elliott, Pim van der Harst, The International Genomics of Blood Pressure (iGEN-BP) Consortium, Zhengming Chen, Makoto Sasaki, Xiao-Ou Shu, Jost B. Jonas, Jiang He, Chew-Kiat Heng, Yuan-Tsong Chen, Wei Zheng, Xu Lin, Yik-Ying Teo, E-Shyong Tai, Ching-Yu Cheng, Tien Yin Wong, Xueling Sim, Karen L. Mohlke, Masayuki Yamamoto, Bong-Jo Kim, Tetsuro Miki, Toru Nabika, Mitsuhiro Yokota, Yoichiro Kamatani, Michiaki Kubo, and Norihiro Kato

Subjects
Science
Abstract

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, the authors perform discovery GWAS for BP in East Asians and meta-analysis in East Asians and Europeans and report ancestry-specific BP SNPs and selection signals.

Published
2018
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3. Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.

Author

Eleanor Wheeler, Aaron Leong, Ching-Ti Liu, Marie-France Hivert, Rona J Strawbridge, Clara Podmore, Man Li, Jie Yao, Xueling Sim, Jaeyoung Hong, Audrey Y Chu, Weihua Zhang, Xu Wang, Peng Chen, Nisa M Maruthur, Bianca C Porneala, Stephen J Sharp, Yucheng Jia, Edmond K Kabagambe, Li-Ching Chang, Wei-Min Chen, Cathy E Elks, Daniel S Evans, Qiao Fan, Franco Giulianini, Min Jin Go, Jouke-Jan Hottenga, Yao Hu, Anne U Jackson, Stavroula Kanoni, Young Jin Kim, Marcus E Kleber, Claes Ladenvall, Cecile Lecoeur, Sing-Hui Lim, Yingchang Lu, Anubha Mahajan, Carola Marzi, Mike A Nalls, Pau Navarro, Ilja M Nolte, Lynda M Rose, Denis V Rybin, Serena Sanna, Yuan Shi, Daniel O Stram, Fumihiko Takeuchi, Shu Pei Tan, Peter J van der Most, Jana V Van Vliet-Ostaptchouk, Andrew Wong, Loic Yengo, Wanting Zhao, Anuj Goel, Maria Teresa Martinez Larrad, Dörte Radke, Perttu Salo, Toshiko Tanaka, Erik P A van Iperen, Goncalo Abecasis, Saima Afaq, Behrooz Z Alizadeh, Alain G Bertoni, Amelie Bonnefond, Yvonne Böttcher, Erwin P Bottinger, Harry Campbell, Olga D Carlson, Chien-Hsiun Chen, Yoon Shin Cho, W Timothy Garvey, Christian Gieger, Mark O Goodarzi, Harald Grallert, Anders Hamsten, Catharina A Hartman, Christian Herder, Chao Agnes Hsiung, Jie Huang, Michiya Igase, Masato Isono, Tomohiro Katsuya, Chiea-Chuen Khor, Wieland Kiess, Katsuhiko Kohara, Peter Kovacs, Juyoung Lee, Wen-Jane Lee, Benjamin Lehne, Huaixing Li, Jianjun Liu, Stephane Lobbens, Jian'an Luan, Valeriya Lyssenko, Thomas Meitinger, Tetsuro Miki, Iva Miljkovic, Sanghoon Moon, Antonella Mulas, Gabriele Müller, Martina Müller-Nurasyid, Ramaiah Nagaraja, Matthias Nauck, James S Pankow, Ozren Polasek, Inga Prokopenko, Paula S Ramos, Laura Rasmussen-Torvik, Wolfgang Rathmann, Stephen S Rich, Neil R Robertson, Michael Roden, Ronan Roussel, Igor Rudan, Robert A Scott, William R Scott, Bengt Sennblad, David S Siscovick, Konstantin Strauch, Liang Sun, Morris Swertz, Salman M Tajuddin, Kent D Taylor, Yik-Ying Teo, Yih Chung Tham, Anke Tönjes, Nicholas J Wareham, Gonneke Willemsen, Tom Wilsgaard, Aroon D Hingorani, EPIC-CVD Consortium, EPIC-InterAct Consortium, Lifelines Cohort Study, Josephine Egan, Luigi Ferrucci, G Kees Hovingh, Antti Jula, Mika Kivimaki, Meena Kumari, Inger Njølstad, Colin N A Palmer, Manuel Serrano Ríos, Michael Stumvoll, Hugh Watkins, Tin Aung, Matthias Blüher, Michael Boehnke, Dorret I Boomsma, Stefan R Bornstein, John C Chambers, Daniel I Chasman, Yii-Der Ida Chen, Yduan-Tsong Chen, Ching-Yu Cheng, Francesco Cucca, Eco J C de Geus, Panos Deloukas, Michele K Evans, Myriam Fornage, Yechiel Friedlander, Philippe Froguel, Leif Groop, Myron D Gross, Tamara B Harris, Caroline Hayward, Chew-Kiat Heng, Erik Ingelsson, Norihiro Kato, Bong-Jo Kim, Woon-Puay Koh, Jaspal S Kooner, Antje Körner, Diana Kuh, Johanna Kuusisto, Markku Laakso, Xu Lin, Yongmei Liu, Ruth J F Loos, Patrik K E Magnusson, Winfried März, Mark I McCarthy, Albertine J Oldehinkel, Ken K Ong, Nancy L Pedersen, Mark A Pereira, Annette Peters, Paul M Ridker, Charumathi Sabanayagam, Michele Sale, Danish Saleheen, Juha Saltevo, Peter Eh Schwarz, Wayne H H Sheu, Harold Snieder, Timothy D Spector, Yasuharu Tabara, Jaakko Tuomilehto, Rob M van Dam, James G Wilson, James F Wilson, Bruce H R Wolffenbuttel, Tien Yin Wong, Jer-Yuarn Wu, Jian-Min Yuan, Alan B Zonderman, Nicole Soranzo, Xiuqing Guo, David J Roberts, Jose C Florez, Robert Sladek, Josée Dupuis, Andrew P Morris, E-Shyong Tai, Elizabeth Selvin, Jerome I Rotter, Claudia Langenberg, Inês Barroso, and James B Meigs

Subjects
Medicine
Abstract

BackgroundGlycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findingsUsing genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.ConclusionsAs G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

Published
2017
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4. Systematic fine-mapping of association with BMI and type 2 diabetes at the FTO locus by integrating results from multiple ethnic groups.

Author

Koichi Akiyama, Fumihiko Takeuchi, Masato Isono, Sureka Chakrawarthy, Quang Ngoc Nguyen, Wanqing Wen, Ken Yamamoto, Tomohiro Katsuya, Anuradhani Kasturiratne, Son Thai Pham, Wei Zheng, Yumi Matsushita, Miyako Kishimoto, Loi Doan Do, Xiao-Ou Shu, Ananda R Wickremasinghe, Hiroshi Kajio, and Norihiro Kato

Subjects
Medicine, Science
Abstract

The 16q12.2 locus in the first intron of FTO has been robustly associated with body mass index (BMI) and type 2 diabetes in genome-wide association studies (GWAS). To improve the resolution of fine-scale mapping at FTO, we performed a systematic approach consisting of two parts.The first part is to partition the associated variants into linkage disequilibrium (LD) clusters, followed by conditional and haplotype analyses. The second part is to filter the list of potential causal variants through trans-ethnic comparison.We first examined the LD relationship between FTO SNPs showing significant association with type 2 diabetes in Japanese GWAS and between those previously reported in European GWAS. We could partition all the assayed or imputed SNPs showing significant association in the target FTO region into 7 LD clusters. Assaying 9 selected SNPs in 4 Asian-descent populations--Japanese, Vietnamese, Sri Lankan and Chinese (n≤26,109 for BMI association and n≤24,079 for type 2 diabetes association), we identified a responsible haplotype tagged by a cluster of SNPs and successfully narrowed the list of potential causal variants to 25 SNPs, which are the smallest in number among the studies conducted to date for FTO.Our data support that the power to resolve the causal variants from those in strong LD increases consistently when three distant populations--Europeans, Asians and Africans--are included in the follow-up study. It has to be noted that this fine-mapping approach has the advantage of applicability to the existing GWAS data set in combination with direct genotyping of selected variants.

Published
2014
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5. Deletion of CDKAL1 affects high-fat diet-induced fat accumulation and glucose-stimulated insulin secretion in mice, indicating relevance to diabetes.

Author

Tadashi Okamura, Rieko Yanobu-Takanashi, Fumihiko Takeuchi, Masato Isono, Koichi Akiyama, Yukiko Shimizu, Motohito Goto, Yi-Qiang Liang, Ken Yamamoto, Tomohiro Katsuya, Akihiro Fujioka, Keizo Ohnaka, Ryoichi Takayanagi, Toshio Ogihara, Yukio Yamori, and Norihiro Kato

Subjects
Medicine, Science
Abstract

Background/objectiveThe CDKAL1 gene is among the best-replicated susceptibility loci for type 2 diabetes, originally identified by genome-wide association studies in humans. To clarify a physiological importance of CDKAL1, we examined effects of a global Cdkal1-null mutation in mice and also evaluated the influence of a CDKAL1 risk allele on body mass index (BMI) in Japanese subjects.MethodsIn Cdkal1-deficient (Cdkal1⁻/⁻) mice, we performed oral glucose tolerance test, insulin tolerance test, and perfusion experiments with and without high-fat feeding. Based on the findings in mice, we tested genetic association of CDKAL1 variants with BMI, as a measure of adiposity, and type 2 diabetes in Japanese.Principal findingsOn a standard diet, Cdkal1⁻/⁻ mice were modestly lighter in weight than wild-type littermates without major alterations in glucose metabolism. On a high fat diet, Cdkal1⁻/⁻ mice showed significant reduction in fat accumulation (17% reduction in %intraabdominal fat, P = 0.023 vs. wild-type littermates) with less impaired insulin sensitivity at an early stage. High fat feeding did not potentiate insulin secretion in Cdkal1⁻/⁻ mice (1.0-fold), contrary to the results in wild-type littermates (1.6-fold, PConclusionsCdkal1 gene deletion is accompanied by modestly impaired insulin secretion and longitudinal fluctuations in insulin sensitivity during high-fat feeding in mice. CDKAL1 may affect such compensatory mechanisms regulating glucose homeostasis through interaction with diet.

Published
2012
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6. Association of genetic variants influencing lipid levels with coronary artery disease in Japanese individuals.

Author

Fumihiko Takeuchi, Masato Isono, Tomohiro Katsuya, Mitsuhiro Yokota, Ken Yamamoto, Toru Nabika, Kazuro Shimokawa, Eitaro Nakashima, Takao Sugiyama, Hiromi Rakugi, Shuhei Yamaguchi, Toshio Ogihara, Yukio Yamori, and Norihiro Kato

Subjects
Medicine, Science
Abstract

In Japanese populations, we performed a replication study of genetic loci previously identified in European-descent populations as being associated with lipid levels and risk of coronary artery disease (CAD).We genotyped 48 single nucleotide polymorphisms (SNPs) from 22 candidate loci that had previously been identified by genome-wide association (GWA) meta-analyses for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and/or triglycerides in Europeans. We selected 22 loci with 2 parallel tracks from 95 reported loci: 16 significant loci (p

Published
2012
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8. Single-nucleus ATAC-seq elucidates major modules of gene regulation in the development of non-alcoholic fatty liver disease

Author

Fumihiko Takeuchi, Yi-Qiang Liang, Hana Shimizu-Furusawa, Masato Isono, Mia Yang Ang, Kotaro Mori, Taizo Mori, Eiji Kakazu, Sachiyo Yoshio, and Norihiro Kato

Abstract

BackgroundNon-alcoholic fatty liver disease (NAFLD) develops from fatty liver to steatohepatitis during which multiple cell types may play different roles. Aiming to understand the tissue composition of cell types, their gene expression and global gene regulation in the development of NAFLD, we performed single-nucleus and bulk ATAC-seq on the liver of rats fed with a high-fat diet (HFD).MethodsMale Spontaneously Hypertensive Rats were fed a normal diet or a HFD. Rats fed HFD for 4 weeks developed fatty liver, and those fed HFD for 8 weeks further developed steatohepatitis. Under the washout condition, where 4 weeks of HFD is followed by 4 weeks of a normal diet, fatty liver was partially ameliorated. For each dietary condition, we performed single-nucleus ATAC-seq on one animal and bulk ATAC-seq on four animals.ResultsIn accordance with the pathological progression from fatty liver to steatohepatitis, the proportion of inflammatory macrophages dramatically increased. By machine learning, we divided the global gene expression into modules, such that transcription factors in a module regulate the genes in the same module. Consequently, many of the modules rediscovered known regulatory relationship between the transcription factors and biological processes. For the discovered biological processes, we searched core genes, which were defined as genes central regarding co-expression and protein-protein interaction. A large part of the core genes overlapped with previously implicated NAFLD genes.ConclusionsSingle-nucleus ATAC-seq combined with data-driven statistical analysis help elucidate the global gene regulationin vivoas a combination of modules and discover core genes of the relevant biological processes.

Published
2022

9. Clinical Implication of Smoking-Related Aryl-Hydrocarbon Receptor Repressor (AHRR) Hypomethylation in Japanese Adults

Author

Fumihiko, Takeuchi, Kozue, Takano, Masaya, Yamamoto, Masato, Isono, Wataru, Miyake, Kotaro, Mori, Hisao, Hara, Yukio, Hiroi, and Norihiro, Kato

Subjects
Adult, Repressor Proteins, Japan, Smoking, Basic Helix-Loop-Helix Transcription Factors, Tobacco Smoking, Humans, RNA, Messenger, DNA Methylation, Biomarkers, Hydrocarbons, Transcription Factors
Abstract

Tobacco smoking is a leading preventable cause of morbidity and mortality worldwide; still, the success rate of smoking cessation is low in general. From the viewpoint of public health and clinical care, an objective biomarker of long-term smoking behavior is sought.Methods and Results: This study assessed DNA methylation as a biomarker of smoking in a hospital setting through a combination of molecular approaches including genetic, DNA methylation and mRNA expression analyses. First, in an epigenome-wide association study involving Japanese individuals with chronic cardiovascular disease (n=94), genome-wide significant smoking association was identified at 2 CpG sites on chromosome 5, with the strongest signal at cg05575921 located in intron 3 of the aryl-hydrocarbon receptor repressor (AHRR) gene. Highly significant (P1×10The present study results support that reversion of AHRR hypomethylation can be a quantifiable biomarker for progress in and observance of smoking cessation, although some methodological points need to be considered.

Published
2022

10. Alterations of lipid metabolism, blood pressure and fatty liver in spontaneously hypertensive rats transgenic for human cholesteryl ester transfer protein

Author

Fumihiko Takeuchi, Norihiro Kato, Tadashi Okamura, Masato Isono, and Yi-Qiang Liang

Subjects
medicine.medical_specialty, Physiology, Blood Pressure, 030204 cardiovascular system & hematology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Insulin resistance, Rats, Inbred SHR, Internal medicine, Cholesterylester transfer protein, Internal Medicine, medicine, Animals, 030212 general & internal medicine, Aorta, biology, Triglyceride, Chemistry, Cholesterol, Reverse cholesterol transport, Fatty liver, Lipid metabolism, Lipid Metabolism, medicine.disease, Cholesterol Ester Transfer Proteins, Rats, Fatty Liver, carbohydrates (lipids), Endocrinology, Liver, Hypertension, biology.protein, lipids (amino acids, peptides, and proteins), Rats, Transgenic, Metabolic syndrome, Cardiology and Cardiovascular Medicine
Abstract

Cholesteryl ester transfer protein (CETP) mediates a step in reverse cholesterol transport, which channels cholesterol from peripheral tissues back to the liver. Mice and rats are CETP-deficient species, which assumedly contribute to rodent atherosclerosis resistance. Both pro- and anti-atherogenic effects have been shown in studies of CETP-transgenic rodent models thus far. As the results of pharmacological studies of CETP modification are largely controversial in humans, further knowledge about the impact of CETP on atherogenic phenotypes is required to evaluate its clinical utility for the prevention of cardiovascular and other organ damage associated with metabolic syndrome. Therefore, we newly generated a human CETP-transgenic (Tg[hCETP]) strain on the genetic background of spontaneously hypertensive rats (SHRs), which are characterized by the spontaneous occurrence of hypertension and insulin resistance. This allowed us to assess the in vivo role of CETP on cardiometabolic phenotypes in combination with hypertension. In Tg[hCETP] SHRs fed normal rat chow, systolic blood pressure was markedly elevated by 20-37 mmHg throughout the study period, and the development of fatty liver was accelerated with appreciable changes in the plasma lipid profile (HDL cholesterol reduction and triglyceride elevation). These phenotypic changes are in accordance with the assumption of proatherogenic effects inducible by the overexpression of CETP. However, with plasma LDL cholesterol levels concomitantly reduced, no apparent progression of atherosclerosis was detected in either the aorta or coronary arteries of Tg[hCETP] SHRs fed a high-fat, high-cholesterol diet. Our data provide new insight into the multifaceted regulation of cardiometabolic phenotypes via the modification of CETP.

Published
2020

11. Transcriptomic Response in the Heart and Kidney to Different Types of Antihypertensive Drug Administration

Author

Fumihiko Takeuchi, Yi-Qiang Liang, Masato Isono, Mia Yang Ang, Kotaro Mori, and Norihiro Kato

Subjects
Male, Myocardium, Biphenyl Compounds, Tetrazoles, Angiotensin-Converting Enzyme Inhibitors, Blood Pressure, Heart, Calcium Channel Blockers, Hydralazine, Kidney, Rats, Inbred WKY, Rats, Renin-Angiotensin System, Angiotensin Receptor Antagonists, Hydrochlorothiazide, Enalapril, Rats, Inbred SHR, Internal Medicine, Animals, Benzimidazoles, Carvedilol, Amlodipine, Diuretics, Transcriptome, Antihypertensive Agents
Abstract

Certain classes of antihypertensive drug may exert specific, blood pressure (BP)-independent protective effects on end-organ damages such as left ventricular hypertrophy, although the overall evidence has not been definitive in clinical trials. To unravel antihypertensive drug-induced gene expression changes that are potentially related to the amelioration of end-organ damages, we performed in vivo phenotypic evaluation and transcriptomic analysis on the heart and the kidney, with administration of antihypertensive drugs to two inbred strains (ie, hypertensive and normotensive) of rats. We chose 6 antihypertensive classes: enalapril (angiotensin-converting enzyme inhibitor), candesartan (angiotensin receptor blocker), hydrochlorothiazide (diuretics), amlodipine (calcium-channel blocker), carvedilol (vasodilating β-blocker), and hydralazine. In the tested rat strains, 4 of 6 drugs, including 2 renin-angiotensin system inhibitors, were effective for BP lowering, whereas the remaining 2 drugs were not. Besides BP lowering, there appeared to be some interdrug heterogeneity in phenotypic changes, such as suppressed body weight gain and body weight-adjusted heart weight reduction. For the transcriptomic response, a considerable number of genes showed prominent mRNA expression changes either in a BP-dependent or BP-independent manner with substantial diversity between the target organs. Noticeable changes of mRNA expression were induced particularly by renin-angiotensin system blockade, for example, for genes in the natriuretic peptide system ( Nppb and Corin ) in the heart and for those in the renin-angiotensin system/kallikrein-kinin system ( Ren and rat Klk1 paralogs) and those related to calcium ion binding ( Calb1 and Slc8a1 ) in the kidney. The research resources constructed here will help corroborate occasionally inconclusive evidence in clinical settings.

Published
2021

12. Integrative genomic analysis of blood pressure and related phenotypes in rats

Author

Zong Hu Cui, Masato Isono, Fumihiko Takeuchi, Norihiro Kato, Yoko Iizuka, Takanari Gotoda, Yi-Qiang Liang, Michiko Tajima, and Toru Nabika

Subjects
0301 basic medicine, Male, Genetic Linkage, Medicine (miscellaneous), Genome-wide association study, Kinins, 030204 cardiovascular system & hematology, Rats, Inbred WKY, Transcriptome, Renin-Angiotensin System, 0302 clinical medicine, Immunology and Microbiology (miscellaneous), Rats, Inbred SHR, Pathology, RB1-214, Phylogeny, Genetics, blood pressure, Genomics, Physical Chromosome Mapping, Phenotype, Stroke, Medicine, Female, Kallikreins, Research Article, Quantitative Trait Loci, Neuroscience (miscellaneous), Congenic, Locus (genetics), Biology, multifactorial disease, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Genetic model, Animals, Rat as a Disease Model, RNA, Messenger, Allele, gene, Antihypertensive Agents, Crosses, Genetic, Genetic association, locus, Genetic Variation, 030104 developmental biology, Gene Expression Regulation, Haplotypes, genome-wide association studies, transcriptome
Abstract

Despite remarkable progress made in human genome-wide association studies, there remains a substantial gap between statistical evidence for genetic associations and functional comprehension of the underlying mechanisms governing these associations. As a means of bridging this gap, we performed genomic analysis of blood pressure (BP) and related phenotypes in spontaneously hypertensive rats (SHR) and their substrain, stroke-prone SHR (SHRSP), both of which are unique genetic models of severe hypertension and cardiovascular complications. By integrating whole-genome sequencing, transcriptome profiling, genome-wide linkage scans (maximum n=1415), fine congenic mapping (maximum n=8704), pharmacological intervention and comparative analysis with transcriptome-wide association study (TWAS) datasets, we searched causal genes and causal pathways for the tested traits. The overall results validated the polygenic architecture of elevated BP compared with a non-hypertensive control strain, Wistar Kyoto rats (WKY); e.g. inter-strain BP differences between SHRSP and WKY could be largely explained by an aggregate of BP changes in seven SHRSP-derived consomic strains. We identified 26 potential target genes, including rat homologs of human TWAS loci, for the tested traits. In this study, we re-discovered 18 genes that had previously been determined to contribute to hypertension or cardiovascular phenotypes. Notably, five of these genes belong to the kallikrein–kinin/renin–angiotensin systems (KKS/RAS), in which the most prominent differential expression between hypertensive and non-hypertensive alleles could be detected in rat Klk1 paralogs. In combination with a pharmacological intervention, we provide in vivo experimental evidence supporting the presence of key disease pathways, such as KKS/RAS, in a rat polygenic hypertension model., Summary: Genome sequencing, transcriptome profiling and genetic mapping, with utilization of human transcriptome-wide association study data, identified 26 potential target genes that regulate blood pressure and related phenotypes in an animal model of hypertension.

Published
2021

13. Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

Author

Anubha Mahajan, Cassandra N Spracklen, Weihua Zhang, Maggie CY Ng, Lauren E Petty, Hidetoshi Kitajima, Grace Z Yu, Sina Rüeger, Leo Speidel, Young Jin Kim, Momoko Horikoshi, Josep M Mercader, Daniel Taliun, Sanghoon Moon, Soo-Heon Kwak, Neil R Robertson, Nigel W Rayner, Marie Loh, Bong-Jo Kim, Joshua Chiou, Irene Miguel-Escalada, Pietro della Briotta Parolo, Kuang Lin, Fiona Bragg, Michael H Preuss, Fumihiko Takeuchi, Jana Nano, Xiuqing Guo, Amel Lamri, Masahiro Nakatochi, Robert A Scott, Jung-Jin Lee, Alicia Huerta-Chagoya, Mariaelisa Graff, Jin-Fang Chai, Esteban J Parra, Jie Yao, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Valgerdur Steinthorsdottir, James P Cook, Mart Kals, Niels Grarup, Ellen M Schmidt, Ian Pan, Tamar Sofer, Matthias Wuttke, Chloe Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Meraj Ahmad, Raymond Noordam, Victor JY Lim, Claudia HT Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M Raffield, Cécile Lecoeur, Nisa M Maruthur, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Richard A Jensen, Salman Tajuddin, Edmond Kabagambe, Ping An, Anny H Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, Fernando Abaitua, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Masato Akiyama, Sonia S Anand, Alain Bertoni, Zheng Bian, Jette Bork-Jensen, Ivan Brandslund, Jennifer A Brody, Chad M Brummett, Thomas A Buchanan, Mickaël Canouil, Juliana CN Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, Swapan K Das, H. Janaka de Silva, George Dedoussis, Latchezar Dimitrov, Ayo P Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Myriam Fornage, Oscar H Franco, Timothy M Frayling, Barry I Freedman, Christian Fuchsberger, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio González-Villalpando, Maria Elena González-Villalpando, Mark O Goodarzi, Penny Gordon-Larsen, David Gorkin, Myron Gross, Yu Guo, Sophie Hackinger, Sohee Han, Andrew T Hattersley, Christian Herder, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md. Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Marit E Jørgensen, Torben Jørgensen, Yoichiro Kamatani, Fouad R Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G Kibriya, Duk-Hwan Kim, Katsuhiko Kohara, Jennifer Kriebel, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A Lange, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian’an Luan, Andrea O Luk, Xi Luo, Jun Lv, Valeriya Lyssenko, Vasiliki Mamakou, K Radha Mani, Thomas Meitinger, Andres Metspalu, Andrew D Morris, Girish N. Nadkarni, Jerry L Nadler, Michael A Nalls, Uma Nayak, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R Patel, Mark A Pereira, Annette Peters, Fraser J Pirie, Bianca Porneala, Gauri Prasad, Sebastian Preissl, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Katheryn Roll, Charumathi Sabanayagam, Maike Sander, Kevin Sandow, Naveed Sattar, Sebastian Schönherr, Claudia Schurmann, Mohammad Shahriar, Jinxiu Shi, Dong Mun Shin, Daniel Shriner, Jennifer A Smith, Wing Yee So, Alena Stančáková, Adrienne M Stilp, Konstantin Strauch, Ken Suzuki, Atsushi Takahashi, Kent D Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Brian Tomlinson, Jason M Torres, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam S Udler, Adan Valladares-Salgado, Rob M van Dam, Jan B van Klinken, Rohit Varma, Marijana Vujkovic, Niels Wacher-Rodarte, Ellie Wheeler, Eric A Whitsel, Ananda R Wickremasinghe, Konstantin Willems van Dijk, Daniel R Witte, Chittaranjan S Yajnik, Ken Yamamoto, Toshimasa Yamauchi, Loïc Yengo, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Liang Zhang, Wei Zheng, null FinnGen, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Craig L Hanis, Patricia A Peyser, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N Rotimi, Diane M Becker, Fumihiko Matsuda, Yongmei Liu, Eleftheria Zeggini, Mitsuhiro Yokota, Stephen S Rich, Charles Kooperberg, James S Pankow, James C Engert, Yii-Der Ida Chen, Philippe Froguel, James G Wilson, Wayne HH Sheu, Sharon LR Kardia, Jer-Yuarn Wu, M Geoffrey Hayes, Ronald CW Ma, Tien-Yin Wong, Leif Groop, Dennis O Mook-Kanamori, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J Wouter Jukema, Miguel Cruz, Roberta McKean-Cowdin, Harald Grallert, Ching-Yu Cheng, Erwin P Bottinger, Abbas Dehghan, E-Shyong Tai, Josee Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon-Puay Koh, Colin NA Palmer, Simin Liu, Goncalo Abecasis, Jaspal S Kooner, Ruth JF Loos, Kari E North, Christopher A Haiman, Jose C Florez, Danish Saleheen, Torben Hansen, Oluf Pedersen, Reedik Mägi, Claudia Langenberg, Nicholas J Wareham, Shiro Maeda, Takashi Kadowaki, Juyoung Lee, Iona Y Millwood, Robin G Walters, Kari Stefansson, Simon R Myers, Jorge Ferrer, Kyle J Gaulton, James B Meigs, Karen L Mohlke, Anna L Gloyn, Donald W Bowden, Jennifer E Below, John C Chambers, Xueling Sim, Michael Boehnke, Jerome I Rotter, Mark I McCarthy, and Andrew P Morris

Subjects
0303 health sciences, Transferability, Translation (biology), Type 2 diabetes, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Evolutionary biology, Global health, medicine, Genetic risk, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

Published
2020

14. LOX-1 (Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1) Deletion Has Protective Effects on Stroke in the Genetic Background of Stroke-Prone Spontaneously Hypertensive Rat

Author

Lei Li, Yi-Qiang Liang, Tatsuya Sawamura, Hana Shimizu, Fumihiko Takeuchi, Norihiro Kato, Yasunari Matsuzaka, Akemi Kakino, Michiko Tajima, Tomoji Mashimo, Takehito Kaneko, Tomohisa Akamatsu, and Masato Isono

Subjects
medicine.medical_specialty, Knockout rat, Ischemia, Brain damage, medicine.disease_cause, Brain Ischemia, 03 medical and health sciences, 0302 clinical medicine, Spontaneously hypertensive rat, Internal medicine, Rats, Inbred SHR, medicine, Animals, Circulating MicroRNA, Endothelial dysfunction, Stroke, 030304 developmental biology, Advanced and Specialized Nursing, 0303 health sciences, business.industry, medicine.disease, Scavenger Receptors, Class E, Rats, MicroRNAs, Endocrinology, Blood-Brain Barrier, Hypertension, Neurology (clinical), medicine.symptom, Rats, Transgenic, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery, Oxidative stress, Gene Deletion, Lipoprotein
Abstract

Background and Purpose— oxLDL (oxidized low-density lipoprotein) has been known for its potential to induce endothelial dysfunction and used as a major serological marker of oxidative stress. Recently, LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1), a lectin-like receptor for oxLDL, has attracted attention in studies of neuronal apoptosis and stroke. We aim to investigate the impact of LOX-1 -deficiency on spontaneous hypertension-related brain damage in the present study. Methods— We generated a LOX-1 deficient strain on the genetic background of stroke-prone spontaneously hypertensive rat (SHRSP), an animal model of severe hypertension and spontaneous stroke. In this new disease model with stroke-proneness, we monitored the occurrence of brain abnormalities with and without salt loading by multiple procedures including T 2 weighted magnetic resonance imaging and also explored circulatory miRNAs as diagnostic biomarkers for cerebral ischemic injury by microarray analysis. Results— Both T 2 weighted magnetic resonance imaging abnormalities and physiological parameter changes could be detected at significantly delayed timing in LOX-1 knockout rats compared with wild-type SHRSP, in either case of normal rat chow and salt loading ( P LOX-1 knockout rats). There were no significant differences in the form of magnetic resonance imaging findings between the strains. A number of miRNAs expressed in the normal rat plasma, including rno-miR-150-5p and rno-miR-320-3p, showed significant changes after spontaneous brain damage in SHRSP, whereas the corresponding changes were modest or almost unnoticeable in LOX-1 knockout rats. There appeared to be the lessening of correlation of postischemic miRNA alterations between the injured brain tissue and plasma in LOX-1 knockout rats. Conclusions— Our data show that deficiency of LOX-1 has a protective effect on spontaneous brain damage in a newly generated LOX-1 -deficient strain of SHRSP. Further, our analysis of miRNAs as biomarkers for ischemic brain damage supports a potential involvement of LOX-1 in blood brain barrier disruption after cerebral ischemia. Visual Overview— An online visual overview is available for this article.

Published
2020

15. Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels

Author

Alan B. Feranil, Cassandra N. Spracklen, Sing-Hui Lim, Cathy S.J. Fann, Tin Aung, Yii-Der Ida Chen, Yonghong Zhang, Li-Hsin Chien, Jirong Long, Xiuqing Guo, Chien-Hsiun Chen, Jyh-Ming Jimmy Juang, Fumihiko Takeuchi, Xueling Sim, Norihiro Kato, Wen-Harn Pan, Masato Isono, Tzung-Dau Wang, Jer-Yuarn Wu, Dongfeng Gu, Xu Wang, Xuhong Hou, Peng Chen, Wen-Jane Lee, Kae-Woei Liang, Sun-Ju Lee, Chao A. Hsiung, Meian He, Lee-Ming Chuang, Devin Absher, Chii-Min Hwu, Tangchun Wu, Li-Ching Chang, Sanghoon Moon, Mi Yeong Hwang, Chew-Kiat Heng, Sun Ha Jee, Feijie Wang, Yik Ying Teo, Kent D. Taylor, Shufa Du, Wen Bin Wei, Ching-Yu Cheng, I-Te Lee, Elias Salfati, Jie Wang, Cheng Hu, Chiea Chuen Khor, Qiuyin Cai, James E. Hixson, Toru Nabika, Wayne Huey-Herng Sheu, Qiao Fan, Woon-Puay Koh, Linda S. Adair, Jianjun Liu, Pok Chien Tan, Penny Gordon-Larsen, Yechiel Friedlander, Bok-Ghee Han, Keng-Hung Lin, Ying Wu, Hao Peng, E-Shyong Tai, Young-Jin Kim, Koichi Akiyama, Bong-Jo Kim, Rajkumar Dorajoo, Wanting Zhao, Tomohiro Katsuya, Stephen S. Rich, Sue-Anne Toh, Rong Zhang, Shengxu Li, Yuan-Tsong Chen, Ya Xing Wang, Keum Ji Jung, Xu Lin, Zhirong Guo, Wei Zheng, Karen L. Mohlke, Shu-Pei Tan, Rob M. van Dam, Liang Sun, Jiang He, Lixuan Gui, Tatsuhiko Tsunoda, Hui Cai, Aili Wang, Huaixing Li, Wei Huang, Yao Hu, Kevin Sandow, Toshihiro Tanaka, Thomas Quertermous, Themistocles L. Assimes, Jerome I. Rotter, Maren E Cannon, Tamara S. Roman, Yong-Bing Xiang, Yoon Shin Cho, Todd A. Johnson, Shi Jinxiu, Weiping Jia, Tien Yin Wong, Yun Kyoung Kim, Jie Yao, Xiao-Ou Shu, Jian-Min Yuan, Blanche Lim, Michiaki Kubo, Shu-Chun Chuang, Charumathi Sabanayagam, and Jost B. Jonas

Subjects
Adult, Male, 0301 basic medicine, Linkage disequilibrium, Quantitative Trait Loci, Locus (genetics), Genome-wide association study, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Asian People, Gene Frequency, Ethnicity, Genetics, Humans, Allele, Molecular Biology, Allele frequency, Alleles, Genetic Association Studies, Triglycerides, Genetics (clinical), Genetic association, Cholesterol, Association Studies Articles, General Medicine, Middle Aged, Lipids, Lipoproteins, LDL, 030104 developmental biology, chemistry, Female, Lipoproteins, HDL, Corrigendum, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P

Published
2017

16. Identification of type 2 diabetes loci in 433,540 East Asian individuals

Author

Chien-Hsiun Chen, Anna L. Gloyn, Atsushi Takahashi, Sohee Han, Ken Suzuki, Mark A Pereira, Shi Jinxiu, Fiona Bragg, Yii-Der Ida Chen, Robin G. Walters, Takashi Kadowaki, Charumathi Sabanayagam, Annie-Green Howard, Mark I. McCarthy, Zheng Bian, Zhengming Chen, E-Shyong Tai, Chii-Min Hwu, Cassandra N. Spracklen, Yuan-Tsong Chen, Linda S. Adair, Momoko Horikoshi, Guozhi Jiang, Ching-Yu Cheng, Mi Yeong Hwang, Andrew P. Morris, Karen L. Mohlke, John C. Chambers, Jian-Min Yuan, Woon-Puay Koh, Hyeok Sun Choi, Ju Young Lee, Bong-Jo Kim, Masato Akiyama, Sahoko Ichihara, Xueling Sim, Norihiro Kato, Kuang Lin, Jirong Long, Xiuqing Guo, Fumihiko Takeuchi, Penny Gordon-Larsen, Hannah J Perrin, Young Jin Kim, Lee-Ming Chuang, Weihua Zhang, Rob M. van Dam, Andrea O.Y. Luk, Masahiro Nakatochi, Yukinori Okada, Katsuhiko Kohara, Yoichiro Kamatani, Jerome I. Rotter, Iona Y Millwood, Jer-Yuarn Wu, Canqing Yu, Wayne Huey-Herng Sheu, Shiro Maeda, Jost B. Jonas, Yasuharu Tabara, Mitsuhiro Yokota, Li-Ching Chang, Toshimasa Yamauchi, Shufa Du, Yu Guo, Yoon Shin Cho, Yi-Jen Hung, Jie Yao, Soo Heon Kwak, Hye-Mi Jang, Maggie C.Y. Ng, Xiao-Ou Shu, Myung-Shik Lee, Kyungheon Yoon, Sarah M Brotman, Sanghoon Moon, Tien Yin Wong, Martijn van de Bunt, Michiya Igase, Claudia H. T. Tam, Fumihiko Matsuda, Wei Zheng, Liang Zhang, Yong-Bing Xiang, Victor Jun Yu Lim, Ronald Cw Ma, Liming Li, Tomohiro Katsuya, Jianjun Liu, Jun Lv, Jennifer E. Below, Anubha Mahajan, Kyong-Soo Park, Masato Isono, Wing-Yee So, Nanette R. Lee, Brian Tomlinson, Juliana C.N. Chan, Lauren E. Petty, Chiea Chuen Khor, Miao-Li Chee, Ken Yamamoto, Wei Huang, Michael Boehnke, Jin-Fang Chai, Donald W. Bowden, Apoorva K Iyengar, Dong Mun Shin, Myron D. Gross, Takahisa Kawaguchi, Ya Xing Wang, and Fuu Jen Tsai

Subjects
Ankyrins, Male, 0301 basic medicine, Transcription, Genetic, endocrine system diseases, Nerve Tissue Proteins, 030209 endocrinology & metabolism, Locus (genetics), Genome-wide association study, Type 2 diabetes, Biology, Article, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Asian People, ANK1, medicine, Humans, Genetic Predisposition to Disease, RNA, Messenger, Allele, Eye Proteins, Gene, Alleles, 030304 developmental biology, ALDH2, Genetic association, 2. Zero hunger, Homeodomain Proteins, Genetics, 0303 health sciences, Multidisciplinary, Asia, Eastern, Aldehyde Dehydrogenase, Mitochondrial, Case-control study, nutritional and metabolic diseases, medicine.disease, Europe, 030104 developmental biology, Diabetes Mellitus, Type 2, Case-Control Studies, Meta-analysis, Expression quantitative trait loci, Female, Body mass index, 030217 neurology & neurosurgery, Genome-Wide Association Study, Transcription Factors
Abstract

SUMMARYMeta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.Type 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic β cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

Published
2019
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17. Further dissection of QTLs for salt-induced stroke and identification of candidate genes in the stroke-prone spontaneously hypertensive rat

Author

Minoru Isomura, Hiroyuki Matsuo, Koichi Fujikawa, Masato Isono, Abdullah Md. Sheikh, Norihiro Kato, Hiroki Ohara, Kaoru Niiya, and Toru Nabika

Subjects
Male, 0301 basic medicine, Candidate gene, Sequence analysis, Quantitative Trait Loci, Congenic, lcsh:Medicine, Sodium Chloride, Quantitative trait locus, Biology, Kidney, Article, 03 medical and health sciences, Spontaneously hypertensive rat, Rats, Inbred SHR, Complementary DNA, Animals, Humans, lcsh:Science, Gene, Oligonucleotide Array Sequence Analysis, Genetics, Multidisciplinary, lcsh:R, food and beverages, Kidney metabolism, Rats, Stroke, MicroRNAs, 030104 developmental biology, Chromosomes, Human, Pair 1, lcsh:Q, Chemokines, Chromosomes, Human, Pair 18, Chemokines, CXC
Abstract

We previously revealed that two major quantitative trait loci (QTLs) for stroke latency of the stroke-prone spontaneously hypertensive rat (SHRSP) under salt-loading were located on chromosome (Chr) 1 and 18. Here, we attempted further dissection of the stroke-QTLs using multiple congenic strains between SHRSP and a stroke-resistant hypertensive rat (SHR). Cox hazard model among subcongenic strains harboring a chromosomal fragment of Chr-1 QTL region showed that the most promising region was a 2.1 Mbp fragment between D1Rat177 and D1Rat97. The QTL region on Chr 18 could not be narrowed down by the analysis, which may be due to multiple QTLs in this region. Nonsynonymous sequence variations were found in four genes (Cblc, Cxcl17, Cic, and Ceacam 19) on the 2.1 Mbp fragment of Chr-1 QTL by whole-genome sequence analysis of SHRSP/Izm and SHR/Izm. Significant changes in protein structure were predicted in CBL-C and CXCL17 using I-TASSER. Comprehensive gene expression analysis in the kidney with a cDNA microarray identified three candidate genes (LOC102548695 (Zinc finger protein 45-like, Zfp45L), Ethe1, and Cxcl17). In conclusion, we successfully narrowed down the QTL region on Chr 1, and identified six candidate genes in this region.

Published
2018

18. Heterogeneous Effects of Association Between Blood Pressure Loci and Coronary Artery Disease in East Asian Individuals

Author

Norihiro Kato, Jeong Euy Park, Hyo-Soo Kim, Yangsoo Jang, Ji-Young Lee, Mitsuhiro Yokota, Ken Yamamoto, Koichi Akiyama, Masato Isono, Fumihiko Takeuchi, Tomohiro Katsuya, and Jong-Young Lee

Subjects
Adult, Male, medicine.medical_specialty, Blood Pressure, Single-nucleotide polymorphism, Coronary Artery Disease, Type 2 diabetes, Polymorphism, Single Nucleotide, Coronary artery disease, Plasma Membrane Calcium-Transporting ATPases, Asian People, Cyclins, Internal medicine, Epidemiology, medicine, Genetic predisposition, Humans, Allele, Cation Transport Proteins, Genotyping, Aged, Genetics, business.industry, General Medicine, Middle Aged, medicine.disease, Blood pressure, Genetic Loci, Cardiology, Female, Cardiology and Cardiovascular Medicine, business
Abstract

BACKGROUND A coronary artery disease (CAD) association study of genetic loci previously identified as being associated with blood pressure (BP) was performed in east Asian populations. METHODS AND RESULTS Nine single nucleotide polymorphisms (SNPs) from 9 candidate loci robustly confirmed to be associated with BP in east Asian people, were genotyped. Genotyping was done in up to 17,785 CAD case-control samples (6,522 cases and 11,263 controls). We then tested the associations with other metabolic traits (n≤17,900) and with type 2 diabetes (931 cases and 1,404 controls), and looked up the datasets in silico in other populations. Significant (adjusted P

Published
2015

19. Multiple Nonglycemic Genomic Loci Are Newly Associated With Blood Level of Glycated Hemoglobin in East Asians

Author

Jong-Young Lee, Yasuharu Tabara, Daniel O. Stram, Lu Qi, Rob M. van Dam, Tien Yin Wong, Masato Isono, Yii-Der Ida Chen, Terri L. Young, Jer-Yuarn Wu, Chao A. Hsiung, Ling Lu, Jian-Min Yuan, Norihiro Kato, Min Jin Go, Tao Huang, Young-Jin Kim, Jianjun Liu, Jiemin Liao, Tetsuro Miki, Bong-Jo Kim, Wen-Harn Pan, Huaixing Li, Joo-Yeon Hwang, Jinrui Cui, Jirong Long, Yukinori Okada, Wayne Huey-Herng Sheu, Fumihiko Takeuchi, Mark O. Goodarzi, Chris Hsu, Qibin Qi, Peng Chen, Mark A. Pereira, Xingwang Ye, Yu-Tang Gao, Themistocles L. Assimes, Toshihiro Tanaka, Xiao-Ou Shu, Ken Yamamoto, Yechiel Friedlander, Tin Aung, Jerome I. Rotter, Jun Liang, Ryoichi Takayanagi, Frank J. A. van Rooij, Yiqin Wang, Yik Ying Teo, Atsushi Takahashi, Ching-Yu Cheng, Keizo Ohnaka, Michiaki Kubo, Li-Ching Chang, Jinyan Huang, Chiea Chuen Khor, Jeannette Lee, Xu Lin, Qiuyin Cai, Ah Chuan Thai, Yuan-Tson Chen, Chien-Hsiun Chen, Wei Zheng, Eranga N. Vithana, Myron D. Gross, Chew-Kiat Heng, E-Shyong Tai, Santhi K. Ganesh, Yoshikuni Kita, Woon-Puay Koh, and Hirotsugu Ueshima

Subjects
Adult, Blood Glucose, Male, Diabetes risk, Endocrinology, Diabetes and Metabolism, Genome-wide association study, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, Cohort Studies, Genetic Heterogeneity, chemistry.chemical_compound, Asian People, Polymorphism (computer science), Diabetes mellitus, Internal Medicine, medicine, Humans, CDKAL1, Aged, Genetic association, Glycated Hemoglobin, Genetics, Asia, Eastern, Genetics/Genomes/Proteomics/Metabolomics, Middle Aged, medicine.disease, 3. Good health, chemistry, Genetic Loci, Female, Glycated hemoglobin, Genome-Wide Association Study
Abstract

Glycated hemoglobin A1c(HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1cin East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [ P value = 1.3 × 10-23], HBS1L/MYB [8.5 × 10-15], MYO9B [9.0 × 10-12], and CYBA [1.1 × 10-8] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (

Published
2014

20. Genetic Impact on Uric Acid Concentration and Hyperuricemia in the Japanese Population

Author

Masato Isono, Ryoichi Takayanagi, Toshio Ogihara, Hiromi Rakugi, Ken Yamamoto, Keizo Ohnaka, Yukio Yamori, Norihiro Kato, Koichi Akiyama, Tomohiro Katsuya, and Fumihiko Takeuchi

Subjects
Male, medicine.medical_specialty, Population, Coronary Disease, Single-nucleotide polymorphism, Hyperuricemia, Polymorphism, Single Nucleotide, chemistry.chemical_compound, Asian People, Japan, Polymorphism (computer science), Internal medicine, Internal Medicine, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, education, Aged, Genetics, education.field_of_study, biology, Biochemistry (medical), Middle Aged, medicine.disease, Uric Acid, Gout, Endocrinology, Diabetes Mellitus, Type 2, chemistry, Genetic Loci, biology.protein, Uric acid, Female, SLC22A12, Cardiology and Cardiovascular Medicine
Abstract

AIM: Using general Japanese populations, we performed a replication study of genetic loci previously identified in European-descent populations as being associated with uric acid and gout. The relative contribution of non-genetic and genetic factors to the variances in serum uric acid concentration was then evaluated. METHODS: Seven single nucleotide polymorphisms (SNPs) were genotyped from 7 candidate loci robustly confirmed in Europeans. Genotyping was performed in up to 17,226 individuals, from which 237 hyperuricemia cases and 3,218 controls were chosen for a case-control study. For 6 SNPs showing a replication of uric acid association in 17,076 general population samples, we further tested the associations with other metabolic traits (n≤5,745) and with type 2 diabetes (931 cases and 1404 controls) and coronary artery disease (806 cases and 1337 controls). RESULTS: Significant uric acid associations (one-tailed p

Published
2013

21. Genome-wide association studies in East Asians identify new loci for waist-hip ratio and waist circumference

Author

Dabeeru C. Rao, Mitsuhiro Yokota, Yoon Shin Cho, Chien-Hsiun Chen, Tangchun Wu, Joo Yeon Hwang, Juyoung Lee, Dmitry Shungin, Bo Youl Choi, Xingwang Ye, Masahiro Nakatochi, Karen L. Mohlke, Matthew A. Allison, Tetsuro Miki, Jiajun Shi, Wei Zheng, Yong-Bing Xiang, Zengnan Mo, Xu Lin, Yoshikuni Kita, Jer-Yuarn Wu, Jun Liang, Tao Huang, Dongxin Lin, Sanghoon Moon, Meian He, Sun Ha Jee, Shengxu Li, Linda S. Adair, Lu Qi, Qiuyin Cai, James E. Hixson, Jae Woong Sull, Jiang He, Min Jin Go, Yanling Hu, Xingyi Guo, Masato Isono, Keum Ji Jung, Jianjun Liu, E. Shyong Tai, Yan Zheng, Nanette R. Lee, Aihua Tan, Jeannette Lee, Xiaomin Zhang, Fuu Jen Tsai, Ken Yamamoto, Norihiro Kato, Soriul Kim, Koichi Akiyama, Rajkumar Dorajoo, Young Jin Kim, Ying Wu, Daehee Kang, Jie Yao, Hirotsugu Ueshima, Jerome I. Rotter, Xiaobo Yang, Li Ching Chang, Keizo Ohnaka, Huaixing Li, Bok Ghee Han, Yuan-Tsong Chen, Jirong Long, Xiuqing Guo, Dongfeng Gu, Yasuharu Tabara, Bong Jo Kim, Yiqin Wang, Chen Wu, Yasuyuki Nakamura, Xiao-Ou Shu, Wanqing Wen, Yu Tang Gao, and Fumihiko Takeuchi

Subjects
Male, 0301 basic medicine, Genome-wide association study, 030105 genetics & heredity, Cardiovascular, Waist–hip ratio, 2.1 Biological and endogenous factors, Aetiology, 10. No inequality, Abdominal obesity, 2. Zero hunger, Genetics, Multidisciplinary, Public Health, Global Health, Social Medicine and Epidemiology, Single Nucleotide, Other Physical Sciences, Female, Waist Circumference, medicine.symptom, Asian Continental Ancestry Group, Asia, Waist, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, abdominal obesity, Quantitative Trait, 03 medical and health sciences, Quantitative Trait, Heritable, Sex Factors, Asian People, Clinical Research, medicine, Humans, Genetic Predisposition to Disease, Obesity, Polymorphism, Heritable, Waist-Hip Ratio, nutritional and metabolic diseases, genetic loci, medicine.disease, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, 030104 developmental biology, Biochemistry and Cell Biology, Body mass index, Genome-Wide Association Study
Abstract

Sixty genetic loci associated with abdominal obesity, measured by waist circumference (WC) and waist-hip ratio (WHR), have been previously identified, primarily from studies conducted in European-ancestry populations. We conducted a meta-analysis of associations of abdominal obesity with approximately 2.5 million single nucleotide polymorphisms (SNPs) among 53,052 (for WC) and 48,312 (for WHR) individuals of Asian descent and replicated 33 selected SNPs among 3,762 to 17,110 additional individuals. We identified four novel loci near the EFEMP1, ADAMTSL3 , CNPY2 and GNAS genes that were associated with WC after adjustment for body mass index (BMI); two loci near the NID2 and HLA-DRB5 genes associated with WHR after adjustment for BMI and three loci near the CEP120, TSC22D2 and SLC22A2 genes associated with WC without adjustment for BMI. Functional enrichment analyses revealed enrichment of corticotropin-releasing hormone signaling, GNRH signaling, and/or CDK5 signaling pathways for those newly-identified loci. Our study provides additional insight on genetic contribution to abdominal obesity.

Published
2016

22. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author

Peter Kovacs, Alan F. Wright, Stephen Turner, Michèle M. Sale, Siim Sõber, Janoš Terzić, Elin Org, Richard S. Cooper, Alena Stančáková, Jerome I. Rotter, W. H. Linda Kao, Albert Hofman, Andrew B. Singleton, Florian Kronenberg, Jianjun Liu, Nicole L. Glazer, Christopher W. Knouff, Jennifer L. Bragg-Gresham, Juha Karjalainen, Li Ching Chang, Benjamin J. Wright, Jacqueline C.M. Witteman, Martin G. Larson, Klaus Stark, Richard J. Rodeheffer, Sharon L.R. Kardia, Douglas M. Ruderfer, Sheila Ulivi, Madhumathi Rao, Andrew A. Hicks, Eva Brand, Viviane Nicaud, Stephen G. Ball, Anna Köttgen, Germaine C. Verwoert, Anders Hamsten, Nick Shrine, Uwe Völker, Stefan Kloiber, Stephen Hancock, Emelia J. Benjamin, Bok Ghee Han, Kenneth Rice, Mark Woodward, Veronique Vitart, Karl Andersen, Nicholas J. Wareham, Robert Roberts, Maja Barbalić, David Couper, Yukinori Okada, André G. Uitterlinden, Sekar Kathiresan, Leo-Pekka Lyytikäinen, Pankaj Arora, Tatijana Zemunik, David S. Siscovick, Simonetta Guarrera, Dawn M. Waterworth, Tatjana Stojakovic, Braxton D. Mitchell, Devin Absher, Carmen A. Peralta, Mika Kivimäki, Xueling Sim, Norihiro Kato, Philippe Froguel, Keith L. Keene, Donna K. Arnett, Naoyuki Kamatani, Tazeen H. Jafar, Idris Guessous, Gunnar Jacobs, Michael M. Hoffmann, Kari Stefansson, Christian Hengstenberg, Tomonori Okamura, Inga Prokopenko, Christina Willenborg, Peter S. Braund, Rainer Rettig, Francesco U.S. Mattace-Raso, Vikal Tripathy, F. Gerald R. Fowkes, Laura R. Loehr, Harry Campbell, Margherita Cavalieri, Olle Melander, Hao Mei, I. Mateo Leach, Nicholette D. Palmer, Eva Albrecht, Naoharu Iwai, Stefan Martin Brand, Toshiko Tanaka, Jackie A. Cooper, Omri Gottesman, Manuela Uda, Angelo Scuteri, Aroon D. Hingorani, Cristiano Fava, Yusuke Nakamura, Jiang He, Min Jin Go, Serge Hercberg, Wendy L. McArdle, Philipp S. Wild, Florian Ernst, Paul Mitchell, Wolfgang Koenig, Caroline S. Fox, S. J.Cathy Fann, Janine F. Felix, Anna F. Dominiczak, Mike A. Nalls, Erik Ingelsson, Mario A. Morken, Susana Eyheramendy, Christopher Newton-Cheh, Igor Rudan, D. G. Vinay, Christopher P. Nelson, Ervin R. Fox, Xiuqing Guo, Jing Hua Zhao, Rick Twee-Hee Ong, Margaret M. Redfield, Oscar H. Franco, Yongmei Liu, Fulvio Ricceri, Mark A. Hlatky, Bernhard Paulweber, Mingyao Li, Themistocles L. Assimes, Karl Winkler, Inês Barroso, Sylvia E. Rosas, M Walker, Richard W Morris, Bo Hedblad, Hakon Hakonarson, Sonny Dandona, Peter H. Whincup, Martin Adam, Vilmundur Gudnason, Daniel Ackermann, Qiong Yang, Cuno S. P. M. Uiterwaal, Paul M. Ridker, George Davey Smith, Li Chen, C. Sinning, Terri L. Young, Jer-Yuarn Wu, Walter Palmas, Will Longstreth, Joe Devaney, Pavel Hamet, Xiaofeng Zhu, Fredrik Nyberg, Wilfried Renner, Anuj Goel, L. Adrienne Cupples, Nish Chaturvedi, Iftikhar J. Kullo, Nicholas D. Hastie, Aude Saint-Pierre, Panos Deloukas, Smita R. Kulkarni, Eric Boerwinkle, Wolfram Goessling, Gian Andri Thun, Eric J.G. Sijbrands, Shih-Jen Hwang, Carole Proust, Hirotsugu Ueshima, Kristian Hveem, Pierre Meneton, Joshua C. Denny, Olivier Devuyst, Kerri L. Wiggins, Ming-Huei Chen, Robert W. Lawrence, Robert L. Wilensky, Andre Franke, Nicole Soranzo, Simon Heath, Margot Haun, Karlhans Endlich, David Altshuler, Harald Grallert, Laurence Tiret, Luigi Ferrucci, Caroline Hayward, Sudha Seshadri, Bénédicte Stengel, Lynne E. Wagenknecht, John Attia, Andreas Ziegler, Renate B. Schnabel, Stefan Schreiber, Santosh Dahgam, Kurt Lohman, Christian M. Shaffer, Barbara Ludwig, Katalin Susztak, Chien-Hsiun Chen, Michele K. Evans, Paolo Vineis, Guo Li, Thomas J. Wang, Meena Kumari, Heather M. Stringham, Bruce M. Psaty, Norman Klopp, Halit Ongen, Ben A. Oostra, Stefan Coassin, Petra Bruse, Wei-Min Chen, Unnur Thorsteinsdottir, Charles N. Rotimi, Robert J. Carroll, Muredach P. Reilly, Niek Verweij, Dena G. Hernandez, Amy J. Swift, Barbara Kollerits, Hyung Lae Kim, Cristian Pattaro, Ivana Kolcic, Ronit Katz, John M. C. Connell, Dan E. Arking, Albert W. Dreisbach, Peter Vollenweider, C. S. Janipalli, Jian'an Luan, Erkki Vartiainen, James T. Willerson, John R. Thompson, Daniela Toniolo, Lyle J. Palmer, Alexander Teumer, Serkalem Demissie-Banjaw, Stella Trompet, James E. Hixson, Sue Shaw-Hawkins, Rossella Sorice, Bernhard R. Winkelmann, John Danesh, Anthony J. Balmforth, Toshio Ogihara, Jyotika K. Fernandes, Ulf Gyllensten, Ville Aalto, Åsa Johansson, Andres Metspalu, John F. Peden, Diana Kuh, Medea Imboden, Antonio Lupo, Su Chi Lim, Young-Jin Kim, Giovanni Malerba, Yurii S. Aulchenko, Satoshi Umemura, Ioanna Tzoulaki, Alan B. Weder, Helena Schmidt, Gerjan Navis, Susan R. Heckbert, Hans J. Rupprecht, Edward G. Lakatta, Christian Gieger, Najaf Amin, Paul Muntner, Lenore J. Launer, Ivana Persico, Hugh Watkins, Ian Ford, K. Radha Mani, Sylvia Stracke, Johanna Kuusisto, John Chalmers, Muhammad Islam, Lars Lind, Stefan R. Bornstein, Marjo-Riitta Järvelin, J. H. Young, Reiner Biffar, Santhi K. Ganesh, Kazuhiko Yamamoto, Annette Peters, Linda S. Adair, Tõnu Esko, Rebecca Hardy, Olga Jarinova, Antonietta Robino, Ruth McPherson, Benjamin F. Voight, Anne U. Jackson, Gang Shi, Stefania Bandinelli, Peter J. van der Most, John S. Gottdiener, Ying A. Wang, Mariza de Andrade, Joshua C. Bis, Leslie J. Raffel, Man Li, Jemma C. Hopewell, Bernhard O. Böhm, Aaron R. Folsom, Noël P. Burtt, S. Sidney, Diana Zelenika, Yuri Milaneschi, Pilar Galan, Iris M. Heid, Bernhard K. Krämer, Jean-Michel Gaspoz, Lynda M. Rose, Massimiliano Cocca, Jaap W. Deckers, Martin Farrall, Kent D. Taylor, Albert V. Smith, Candace Guiducci, Alan R. Shuldiner, Shiro Maeda, Liming Qu, Marilyn C. Cornelis, Xiaoling Wang, Daniel Shriner, Jutta Palmen, Yingchang Lu, Heyo K. Kroemer, Pio D'Adamo, Stephan J. L. Bakker, Tamara B. Harris, Myriam Rheinberger, Tetsuro Miki, Audrey Y. Chu, Ramachandran S. Vasan, Fuu Jen Tsai, Jan A. Staessen, Daniel I. Chasman, Jan Stritzke, Jasmin Divers, Meredith C. Foster, Jeanette M. Stafford, Maksim Struchalin, Arne Schillert, Jacques S. Beckmann, Mark E. Cooper, Jean-Charles Lambert, Mario Pirastu, Katja Butterbach, Carl G. P. Platou, Yan V. Sun, Marcus Fischer, Maciej Tomaszewski, Karl Werdan, Peng Chen, Daniel J. Rader, Thomas Münzel, Lowell F. Satler, Tom R. Gaunt, Brenda W.J.H. Penninx, William H. Matthai, John Whitfield, Rita P.S. Middelberg, Margus Viigimaa, Toshihiro Tanaka, Ida Yii Der Chen, Morris J. Brown, Valur Emilsson, J. Viikari, Wolfgang Lieb, Stephen E. Epstein, Harald Dobnig, Aravinda Chakravarti, Patrick Linsel-Nitschke, Stefan Pilz, Angela Doering, Sarah H. Wild, Patricia B. Munroe, Megan E. Rudock, Nicole Probst-Hensch, Danish Saleheen, Diederick E. Grobbee, Anke Tönjes, Narisu Narisu, Annika Rosengren, Masato Isono, Catherine Helmer, M. J.Kranthi Kumar, Alanna C. Morrison, Kay-Tee Khaw, Tanja Zeller, Jeffrey R. O'Connell, Christian Müller, Georg Homuth, Giriraj R. Chandak, Pankaj Sharma, Marcus Dörr, Veikko Salomaa, Paul F. O'Reilly, David Hadley, Hermann Brenner, Paolo Gasparini, Nanette R. Lee, Bamidele O. Tayo, Robert Clarke, Henri Wallaschofski, Marketa Sjögren, Abbas Dehghan, Melanie Waldenberger, Neil Risch, Vasyl Pihur, Jessica D. Faul, François Cambien, Christian Fuchsberger, Nicholas G. Martin, John C. Chambers, Zouhair Aherrahrou, Karl J. Lackner, Leif Groop, Matthias Olden, Wiek H. van Gilst, Mathias Gorski, Yvonne T. van der Schouw, Patrick Diemert, Christoph Bickel, Yik Ying Teo, Giorgio Pistis, Ruth J. F. Loos, Gudrun Veldre, Thorsten Reffelmann, Lude Franke, Karen L. Mohlke, Stefan Blankenberg, Massimo Mangino, Ian N. M. Day, Atsushi Takahashi, Alan B. Zonderman, Hua Tang, Reijo Laaksonen, Holly Kramer, Gary C. Curhan, Adrienne Tin, Talin Haritunians, Loic Yengo, Philip Howard, Arnika Kathleen Wagner, Anna Maria Corsi, Yen Pei C. Chang, Karin Halina Greiser, Jeanette Erdmann, Solveig Gretarsdottir, Sanjay Kinra, Alex Parker, Belen Ponte, Marina Ciullo, Michael Preuss, Tin Aung, Nicholas L. Smith, Michiaki Kubo, Richard N. Bergman, Alan S. Go, Patricia P. Chang, Gudmundur Thorgeirsson, Christa Meisinger, Gonçalo R. Abecasis, Maria Blettner, Jaana Laitinen, Daniel Taliun, Carlos Iribarren, Paavo Zitting, Thomas Lumley, Andreas Meinitzer, Wayne D. Rosamond, Daehee Kang, Johanne Tremblay, Stephan B. Felix, Colin A. McKenzie, Yuan-Tsong Chen, Lyudmyla Kedenko, Mladen Boban, Fadi J. Charchar, Adebowale Adeyemo, Brendan M. Buckley, Jennifer A. Smith, Reinhold Schmidt, Jaspal S. Kooner, Gavin Lucas, Paul Elliott, Dorairajan Prabhakaran, Tune H. Pers, Tunde Salako, Terrence Forrester, Paul Burton, Jeffrey R. Gulcher, Kelly A. Volcik, Richard M. Myers, Andreas Tomaschitz, H.-Erich Wichmann, Jie Yao, Giuseppe Matullo, Carsten A. Böger, Henry Völzke, Daniela Ruggiero, Federico Murgia, Yoshikuni Kita, Augustine Kong, Giovanni Gambaro, Cinzia Sala, Peter P. Pramstaller, James Scott, Maris Laan, Laura J. Scott, Alistair S. Hall, Sanaz Sedaghat, James F. Wilson, Joanne M. Murabito, Yi-An Ko, Honghuang Lin, Mark Seielstad, Leena Peltonen, Sven Bergmann, Thomas Meitinger, Matthias Nauck, María Soler Artigas, Thomas Illig, Nanette I. Steinle, Samer S. Najjar, Christina Loley, Debbie A Lawlor, Steven C. Hunt, Yali Li, Weihua Zhang, Jie Jin Wang, Daniele Cusi, Marco Orrù, Stephen P. Fortmann, Melissa Garcia, Barry I. Freedman, Joseph M. Lindsay, Juan P. Casas, Tomohiro Katsuya, Grant W. Montgomery, Hubert Scharnagl, Khanh-Dung H. Nguyen, Steven M. Schwartz, Afshin Parsa, Elizabeth G. Holliday, Murielle Bochud, Kiran Musunuru, Bruno H. Stricker, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Stefan Enroth, Michiel L. Bots, Mark J. Caulfield, Laura Portas, Vincent Chouraki, Carl D. Langefeld, Eran Halperin, Shufeng Chen, Philippa J. Talmud, Terho Lehtimäki, Steve E. Humphries, Gudmar Thorleifsson, Anika Grosshennig, Norbert Watzinger, Fumihiko Takeuchi, Pim van der Harst, Takayoshi Ohkubo, Nabila Bouatia-Naji, Erwin P. Bottinger, Roberto Elosua, Andrew Wong, Vladan Mijatovic, Maija K. Garnaas, Robert Zweiker, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Inke R. König, Frank B. Hu, Marcus E. Kleber, Francis S. Collins, Elena Rochtchina, Ewa Zukowska-Szczechowska, Yong Li, Ayse Demirkan, Gina Hilton, G. Ehret, Thomas H. Mosley, Markus Perola, Alexandre F.R. Stewart, Josef Coresh, Olli T. Raitakari, Feng Zhang, Mark Lathrop, Michael Marmot, Yanbin Dong, Christopher J. O'Donnell, Kristin D. Marciante, Asif Rasheed, Mary F. Feitosa, Mary Susan Burnett, Rory Collins, J. Wouter Jukema, Nele Friedrich, Aida Karina Dieffenbach, Ying Wu, Yoon Shin Cho, Aaron Isaacs, Haidong Zhu, Marie Metzger, Myriam Alexander, Tanja B. Grammer, Tatiana Kuznetsova, Dabeeru C. Rao, Jayashri Aragam, Augusto D. Pichard, Jaakko Tuomilehto, Louise V. Wain, Elizabeth J. Atkinson, Tim D. Spector, Reedik Mägi, Tiit Nikopensius, Kenneth M. Kent, Guangju Zhai, Andrew D. Johnson, Menno Pruijm, David P. Strachan, Martin D. Tobin, Joban Sehmi, Janja Nahrstedt, E. Shyong Tai, Thor Aspelund, Jürgen Grässler, Hilma Holm, Matthew Denniff, Joshua W. Knowles, Tien Yin Wong, Erika Salvi, James F. Meschia, Dongfeng Gu, Ron Waksman, Stacey Gabriel, Judith A. Hoffman Bolton, Michael Boehnke, Johannes Haerting, Darina Czamara, Heribert Schunkert, Thomas Quertermous, Peter M. Nilsson, Jong-Young Lee, Yasuharu Tabara, Chittaranjan S. Yajnik, Daniel Levy, John Beilby, Fernando Rivadeneira, Claire Perret, Gudny Eiriksdottir, Jingzhong Ding, George A. Wells, Harold Snieder, Ayo P. Doumatey, Dag S. Thelle, Anja Medack, N. Charlotte Onland-Moret, Michael Stumvoll, David Ellinghaus, Ingrid B. Borecki, Tatsuhiko Tsunoda, Ian H. de Boer, M. Arfan Ikram, Andrew M. Taylor, Johannes H. Smit, Gary F. Mitchell, Anna-Liisa Hartikainen, Markku Laakso, Mark McEvoy, Andrew S. Plump, Toby Johnson, Cornelia M. van Duijn, Ozren Polasek, Wilmar Igl, Vincent Mooser, Rodney J. Scott, Mika Kähönen, Peter Schwarz, Psychiatry, EMGO - Mental health, Pattaro, Cristian, Teumer, Alexander, Gorski, Mathia, Chu, Audrey Y., Li, Man, Mijatovic, Vladan, Garnaas, Maija, Tin, Adrienne, Sorice, Rossella, Li, Yong, Taliun, Daniel, Olden, Matthia, Foster, Meredith, Yang, Qiong, Chen, Ming Huei, Pers, Tune H., Johnson, Andrew D., Ko, Yi An, Fuchsberger, Christian, Tayo, Bamidele, Nalls, Michael, Feitosa, Mary F., Isaacs, Aaron, Dehghan, Abba, D'Adamo, ADAMO PIO, Adeyemo, Adebowale, Dieffenbach, Aida Karina, Zonderman, Alan B., Nolte, Ilja M., Van Der Most, Peter J., Wright, Alan F., Shuldiner, Alan R., Morrison, Alanna C., Hofman, Albert, Smith, Albert V., Dreisbach, Albert W., Franke, Andre, Uitterlinden, Andre G., Metspalu, Andre, Tonjes, Anke, Lupo, Antonio, Robino, Antonietta, Johansson, Åsa, Demirkan, Ayse, Kollerits, Barbara, Freedman, Barry I., Ponte, Belen, Oostra, Ben A., Paulweber, Bernhard, Krämer, Bernhard K., Mitchell, Braxton D., Buckley, Brendan M., Peralta, Carmen A., Hayward, Caroline, Helmer, Catherine, Rotimi, Charles N., Shaffer, Christian M., Müller, Christian, Sala, Cinzia, Van Duijn, Cornelia M., Saint Pierre, Aude, Ackermann, Daniel, Shriner, Daniel, Ruggiero, Daniela, Toniolo, Daniela, Lu, Yingchang, Cusi, Daniele, Czamara, Darina, Ellinghaus, David, Siscovick, David S., Ruderfer, Dougla, Gieger, Christian, Grallert, Harald, Rochtchina, Elena, Atkinson, Elizabeth J., Holliday, Elizabeth G., Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P., Murgia, Federico, Rivadeneira, Fernando, Ernst, Florian, Kronenberg, Florian, Hu, Frank B., Navis, Gerjan J., Curhan, Gary C., Ehret, George B., Homuth, Georg, Coassin, Stefan, Thun, Gian Andri, Pistis, Giorgio, Gambaro, Giovanni, Malerba, Giovanni, Montgomery, Grant W., Eiriksdottir, Gudny, Jacobs, Gunnar, Li, Guo, Wichmann, H. Erich, Campbell, Harry, Schmidt, Helena, Wallaschofski, Henri, Völzke, Henry, Brenner, Hermann, Kroemer, Heyo K., Kramer, Holly, Lin, Honghuang, Leach, I. Mateo, Ford, Ian, Guessous, Idri, Rudan, Igor, Prokopenko, Inga, Borecki, Ingrid, Heid, Iris M., Kolcic, Ivana, Persico, Ivana, Jukema, J. Wouter, Wilson, James F., Felix, Janine F., Divers, Jasmin, Lambert, Jean Charle, Stafford, Jeanette M., Gaspoz, Jean Michel, Smith, Jennifer A., Faul, Jessica D., Wang, Jie Jin, Ding, Jingzhong, Hirschhorn, Joel N., Attia, John, Whitfield, John B., Chalmers, John, Viikari, Jorma, Coresh, Josef, Denny, Joshua C., Karjalainen, Juha, Fernandes, Jyotika K., Endlich, Karlhan, Butterbach, Katja, Keene, Keith L., Lohman, Kurt, Portas, Laura, Launer, Lenore J., Lyytikäinen, Leo Pekka, Yengo, Loic, Franke, Lude, Ferrucci, Luigi, Rose, Lynda M., Kedenko, Lyudmyla, Rao, Madhumathi, Struchalin, Maksim, Kleber, Marcus E., Cavalieri, Margherita, Haun, Margot, Cornelis, Marilyn C., Ciullo, Marina, Pirastu, Mario, De Andrade, Mariza, Mcevoy, Mark A., Woodward, Mark, Adam, Martin, Cocca, Massimiliano, Nauck, Matthia, Imboden, Medea, Waldenberger, Melanie, Pruijm, Menno, Metzger, Marie, Stumvoll, Michael, Evans, Michele K., Sale, Michele M., Kähönen, Mika, Boban, Mladen, Bochud, Murielle, Rheinberger, Myriam, Verweij, Niek, Bouatia Naji, Nabila, Martin, Nicholas G., Hastie, Nick, Probst Hensch, Nicole, Soranzo, Nicole, Devuyst, Olivier, Raitakari, Olli, Gottesman, Omri, Franco, Oscar H., Polasek, Ozren, Gasparini, Paolo, Munroe, Patricia B., Ridker, Paul M., Mitchell, Paul, Muntner, Paul, Meisinger, Christa, Smit, Johannes H., Abecasis, Goncalo R., Adair, Linda S., Alexander, Myriam, Altshuler, David, Amin, Najaf, Arking, Dan E., Arora, Pankaj, Aulchenko, Yurii, Bakker, Stephan J. L., Bandinelli, Stefania, Barroso, Ine, Beckmann, Jacques S., Beilby, John P., Bergman, Richard N., Bergmann, Sven, Bis, Joshua C., Boehnke, Michael, Bonnycastle, Lori L., Bornstein, Stefan R., Bots, Michiel L., Bragg Gresham, Jennifer L., Brand, Stefan Martin, Brand, Eva, Braund, Peter S., Brown, Morris J., Burton, Paul R., Casas, Juan P., Caulfield, Mark J., Chakravarti, Aravinda, Chambers, John C., Chandak, Giriraj R., Chang, Yen Pei C., Charchar, Fadi J., Chaturvedi, Nish, Cho, Yoon Shin, Clarke, Robert, Collins, Francis S., Collins, Rory, Connell, John M., Cooper, Jackie A., Cooper, Matthew N., Cooper, Richard S., Corsi, Anna Maria, Dörr, Marcu, Dahgam, Santosh, Danesh, John, Smith, George Davey, Day, Ian N. M., Deloukas, Pano, Denniff, Matthew, Dominiczak, Anna F., Dong, Yanbin, Doumatey, Ayo, Elliott, Paul, Elosua, Roberto, Erdmann, Jeanette, Eyheramendy, Susana, Farrall, Martin, Fava, Cristiano, Forrester, Terrence, Fowkes, F. Gerald R., Fox, Ervin R., Frayling, Timothy M., Galan, Pilar, Ganesh, Santhi K., Garcia, Melissa, Gaunt, Tom R., Glazer, Nicole L., Go, Min Jin, Goel, Anuj, Grässler, Jürgen, Grobbee, Diederick E., Groop, Leif, Guarrera, Simonetta, Guo, Xiuqing, Hadley, David, Hamsten, Ander, Han, Bok Ghee, Hardy, Rebecca, Hartikainen, Anna Liisa, Heath, Simon, Heckbert, Susan R., Hedblad, Bo, Hercberg, Serge, Hernandez, Dena, Hicks, Andrew A., Hilton, Gina, Hingorani, Aroon D., Hoffman Bolton, Judith A., Hopewell, Jemma C., Howard, Philip, Humphries, Steve E., Hunt, Steven C., Hveem, Kristian, Ikram, M. Arfan, Islam, Muhammad, Iwai, Naoharu, Jarvelin, Marjo Riitta, Jackson, Anne U., Jafar, Tazeen H., Janipalli, Charles S., Johnson, Toby, Kathiresan, Sekar, Khaw, Kay Tee, Kim, Hyung Lae, Kinra, Sanjay, Kita, Yoshikuni, Kivimaki, Mika, Kooner, Jaspal S., Kumar, M. J. Kranthi, Kuh, Diana, Kulkarni, Smita R., Kumari, Meena, Kuusisto, Johanna, Kuznetsova, Tatiana, Laakso, Markku, Laan, Mari, Laitinen, Jaana, Lakatta, Edward G., Langefeld, Carl D., Larson, Martin G., Lathrop, Mark, Lawlor, Debbie A., Lawrence, Robert W., Lee, Jong Young, Lee, Nanette R., Levy, Daniel, Li, Yali, Longstreth, Will T., Luan, Jian'An, Lucas, Gavin, Ludwig, Barbara, Mangino, Massimo, Mani, K. Radha, Marmot, Michael G., Mattace Raso, Francesco U. S., Matullo, Giuseppe, Mcardle, Wendy L., Mckenzie, Colin A., Meitinger, Thoma, Melander, Olle, Meneton, Pierre, Meschia, James F., Miki, Tetsuro, Milaneschi, Yuri, Mohlke, Karen L., Mooser, Vincent, Morken, Mario A., Morris, Richard W., Mosley, Thomas H., Najjar, Samer, Narisu, Narisu, Newton Cheh, Christopher, Nguyen, Khanh Dung Hoang, Nilsson, Peter, Nyberg, Fredrik, O'Donnell, Christopher J., Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ong, Rick Twee Hee, Ongen, Halit, Onland Moret, N. Charlotte, O'Reilly, Paul F., Org, Elin, Orru, Marco, Palmas, Walter, Palmen, Jutta, Palmer, Lyle J., Palmer, Nicholette D., Parker, Alex N., Peden, John F., Peltonen, Leena, Perola, Marku, Pihur, Vasyl, Platou, Carl G. P., Plump, Andrew, Prabhakaran, Dorairajan, Psaty, Bruce M., Raffel, Leslie J., Rao, Dabeeru C., Rasheed, Asif, Ricceri, Fulvio, Rice, Kenneth M., Rosengren, Annika, Rotter, Jerome I., Rudock, Megan E., Sõber, Siim, Salako, Tunde, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Schwartz, Steven M., Schwarz, Peter E. H., Scott, Laura J., Scott, Jame, Scuteri, Angelo, Sehmi, Joban S., Seielstad, Mark, Seshadri, Sudha, Sharma, Pankaj, Shaw Hawkins, Sue, Shi, Gang, Shrine, Nick R. G., Sijbrands, Eric J. G., Sim, Xueling, Singleton, Andrew, Sjögren, Marketa, Smith, Nicholas L., Artigas, Maria Soler, Spector, Tim D., Staessen, Jan A., Stancakova, Alena, Steinle, Nanette I., Strachan, David P., Stringham, Heather M., Sun, Yan V., Swift, Amy J., Tabara, Yasuharu, Tai, E. 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S., Carroll, Robert J., Penninx, Brenda W., Scott, Rodney J., Katz, Ronit, Sedaghat, Sanaz, Wild, Sarah H., Kardia, Sharon L. R., Ulivi, Sheila, Hwang, Shih Jen, Enroth, Stefan, Kloiber, Stefan, Trompet, Stella, Stengel, Benedicte, Hancock, Stephen J., Turner, Stephen T., Rosas, Sylvia E., Stracke, Sylvia, Harris, Tamara B., Zeller, Tanja, Zemunik, Tatijana, Lehtimäki, Terho, Illig, Thoma, Aspelund, Thor, Nikopensius, Tiit, Esko, Tonu, Tanaka, Toshiko, Gyllensten, Ulf, Völker, Uwe, Emilsson, Valur, Vitart, Veronique, Aalto, Ville, Gudnason, Vilmundur, Chouraki, Vincent, Chen, Wei Min, Igl, Wilmar, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Loos, Ruth J. F., Liu, Yongmei, Snieder, Harold, Pramstaller, Peter P., Parsa, Afshin, O'Connell, Jeffrey R., Susztak, Katalin, Hamet, Pavel, Tremblay, Johanne, De Boer, Ian H., Böger, Carsten A., Goessling, Wolfram, Chasman, Daniel I., Köttgen, Anna, Kao, W. H. 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Plump, A., Prabhakaran, D., Psaty, BM., Raffel, LJ., Rao, DC., Rasheed, A., Ricceri, F., Rice, KM., Rosengren, A., Rotter, JI., Rudock, ME., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, NJ., Schwartz, SM., Schwarz, PE., Scott, LJ., Scott, J., Scuteri, A., Sehmi, JS., Seielstad, M., Seshadri, S., Sharma, P., Shaw-Hawkins, S., Shi, G., Shrine, NR., Sijbrands, EJ., Sim, X., Singleton, A., Sjögren, M., Smith, NL., Soler Artigas, M., Spector, TD., Staessen, JA., Stancakova, A., Steinle, NI., Strachan, DP., Stringham, HM., Sun, YV., Swift, AJ., Tabara, Y., Tai, ES., Talmud, PJ., Taylor, A., Terzic, J., Thelle, DS., Tobin, MD., Tomaszewski, M., Tripathy, V., Tuomilehto, J., Tzoulaki, I., Uda, M., Ueshima, H., Uiterwaal, CS., Umemura, S., van der Harst, P., van der Schouw YT., van Gilst WH., Vartiainen, E., Vasan, RS., Veldre, G., Verwoert, GC., Viigimaa, M., Vinay, DG., Vineis, P., Voight, BF., Vollenweider, P., Wagenknecht, LE., Wain, LV., Wang, X., Wang, TJ., Wareham, NJ., 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Subjects
0301 basic medicine, Nephrology, Genetics and Molecular Biology (all), estimated glomerular filtration rate, estimated glomerular filtration rate, chronic kidney disease, genetic determinants, General Physics and Astronomy, Kidney development, Genome-wide association study, Biochemistry, Settore MED/14 - NEFROLOGIA, Renal Insufficiency, Chronic, Genetics, AGEN Consortium, ddc:616, education.field_of_study, Kidney, Stage renal-disease, Multidisciplinary, Genome-wide association, CHARGe-Heart Failure Group, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Renal Insufficiency, Chronic, Genetic Predisposition to Disease, Biochemistry, Genetics and Molecular Biology (all), Chemistry (all), Physics and Astronomy (all), Metaanalysis, Renal Insufficiency, Chronic/genetics, Biological sciences, Serum creatinine, medicine.anatomical_structure, Efficient, Ronyons -- Fisiologia, Hypertension, ICBP Consortium, Transmembrane transporter activity, genetic association, loci, kidney function, CARDIOGRAM, Human, medicine.medical_specialty, Science, Population, Renal function, ECHOGen Consortium, Replication, Biology, Environment, Research Support, General Biochemistry, Genetics and Molecular Biology, N.I.H, genetic determinants, 03 medical and health sciences, GENOME-WIDE ASSOCIATION, FALSE DISCOVERY RATES, STAGE RENAL-DISEASE, SERUM CREATININE, METAANALYSIS, VARIANTS, INDIVIDUALS, POPULATION, RISK, HYPERTENSION, Kidney function, Research Support, N.I.H., Extramural, Internal medicine, MD Multidisciplinary, medicine, Journal Article, eGFRcrea, eGFRcys, ddc:610, Genetik, Mortality, education, ddc:613, urogenital system, Individuals, Extramural, General Chemistry, ta3121, medicine.disease, R1, 030104 developmental biology, 570 Life sciences, biology, Genètica, chronic kidney disease, Kidney disease, Meta-Analysis
Abstract

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.

Published
2016

23. Genome-wide association study of coronary artery disease in the Japanese

Author

Tomohiro Katsuya, Ryoichi Takayanagi, Hiroyuki Asano, Norihiro Kato, Eitaro Nakashima, Nobuhisa Awata, Jiro Nakamura, Ken Yamamoto, Akihiro Fujioka, Shuhei Yamaguchi, Mitsuhiro Yokota, Yukio Yamori, Fumihiko Takeuchi, Masahiro Nakatochi, Hidetoshi Kitajima, Takayoshi Ohkubo, Yutaka Imai, Keizo Ohnaka, Toshio Ogihara, Takao Sugiyama, Toru Nabika, Hiromi Rakugi, Shotai Kobayashi, Kazuaki Shimamoto, and Masato Isono

Subjects
Adult, Male, coronary artery disease, gene, association study, Japanese, Single-nucleotide polymorphism, Genome-wide association study, Coronary Artery Disease, Biology, Polymorphism, Single Nucleotide, Article, Coronary artery disease, Asian People, Japan, Polymorphism (computer science), Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Genotyping, Alleles, Genetics (clinical), Aged, Haplotype, Case-control study, Reproducibility of Results, Middle Aged, medicine.disease, Haplotypes, Genetic Loci, Case-Control Studies, Female, Genome-Wide Association Study
Abstract

A new understanding of the genetic basis of coronary artery disease (CAD) has recently emerged from genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs), thus far performed mostly in European-descent populations. To identify novel susceptibility gene variants for CAD and confirm those previously identified mostly in populations of European descent, a multistage GWA study was performed in the Japanese. In the discovery phase, we first genotyped 806 cases and 1337 controls with 451 382 SNP markers and subsequently assessed 34 selected SNPs with direct genotyping (541 additional cases) and in silico comparison (964 healthy controls). In the replication phase, involving 3052 cases and 6335 controls, 12 SNPs were tested; CAD association was replicated and/or verified for 4 (of 12) SNPs from 3 loci: near BRAP and ALDH2 on 12q24 (P=1.6 × 10(-34)), HLA-DQB1 on 6p21 (P=4.7 × 10(-7)), and CDKN2A/B on 9p21 (P=6.1 × 10(-16)). On 12q24, we identified the strongest association signal with the strength of association substantially pronounced for a subgroup of myocardial infarction cases (P=1.4 × 10(-40)). On 6p21, an HLA allele, DQB1(*)0604, could show one of the most prominent association signals in an ∼8-Mb interval that encompasses the LTA gene, where an association with myocardial infarction had been reported in another Japanese study. CAD association was also identified at CDKN2A/B, as previously reported in different populations of European descent and Asians. Thus, three loci confirmed in the Japanese GWA study highlight the likely presence of risk alleles with two types of genetic effects - population specific and common - on susceptibility to CAD.

Published
2012

24. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

Author

Masato Isono, Jorma Viikari, Jianjun Liu, Xingwang Ye, Hao Peng, James Scott, Nanette R. Lee, Chris Hsu, Woon-Puay Koh, Torben Hansen, Vinicius Tragante, Christian Gieger, Tomohiro Katsuya, Aaron Isaacs, Norihiro Kato, Kjell Nikus, Dingliang Zhu, Tetsuro Miki, Zhirong Guo, Uzma Afzal, Hiroshi Kajio, Mika Kähönen, Terri L. Young, Jer-Yuarn Wu, Terho Lehtimäki, Oscar H. Franco, Niels Grarup, Stella Trompet, Rob M. van Dam, John Danesh, Weihua Zhang, Joanna D. Holbrook, Ryoichi Takayanagi, Miyako Kishimoto, Shuhei Yamaguchi, Jemma CHopewell, Thorkild I. A. Sørensen, André G. Uitterlinden, James Abbott, Cisca Wijmenga, Iris Postmus, Wilko Spiering, Gianluca Campanella, Michela Traglia, Ian J. Deary, Hirotsugu Ueshima, Tanja B. Grammer, Daniel OStram, Panos Deloukas, Huaixing Li, Tatsuaki Matsubara, Koichi Akiyama, Fumihiko Takeuchi, Young Jin Kim, Silke Szymczak, Dirk J. van Veldhuisen, Alexander W. Drong, Yu-Tang Gao, Imke Aits, Mark A. Pereira, Rajkumar Dorajoo, Marc Chadeau-Hyam, Benjamin Lehne, Bastiaan THeijman, Zuan Yu Mok, Timothy R. Braun, Mitsuhiro Yokota, Yechiel Friedlander, David C. Liewald, Pim van der Harst, Mahfuzar Rahman, Takayoshi Ohkubo, Aili Wang, Robert Clarke, Lisette Stolk, Pieter A. Doevendans, Wolfgang Lieb, Rebecca Mills, Sarah Parish, Katsuhiko Kohara, Martina Müller-Nurasyid, Nina Mononen, Steve Franks, Niek Verweij, Johanne Marie Justesen, Tin Aung, Rory Collins, J. Wouter Jukema, M.J. Pinidiyapathirage, Rory P. Wilson, Hong Kiat Ng, Joyce B. J. van Meurs, Yik Ying Teo, Wiek H. van Gilst, Wei Zheng, Robert WKoivula, John C. Chambers, Molly Scannell Bryan, Peng Chen, Gurpreet SWander, Lise Lotte N. Husemoen, David J. Stott, Li Ching Chang, Teresa Nutile, Lude Franke, Jaana Hartiala, Karen L. Mohlke, Folkert W. Asselbergs, Daniela Toniolo, Linda S. Adair, Tõnu Esko, Xueya Zhou, Marja Vääräsmäki, Ralhan Sarju, Hui Cai, Chiea Chuen Khor, Albert Hofman, Marc Jan Bonder, Shikta Das, Väinö Turjanmaa, Ying Wu, Masahiro Nakatochi, Habibul Ahsan, Michelle Ann Rozario, Andrew Bjonnes, Jaspal S. Kooner, Marcus E. Kleber, Rossella Sorice, Lavinia Paternoster, Yumi Matsushita, Tanika NKelly, Quang NNguyen, Stanley L. Hazen, Richa Saxena, Lin Tong, Kenneth Kwek, Keizo Ohnaka, Paolo Vineis, Sahoko Ichihara, Jos C. S. Kleinjans, Irene Mateo Leach, Yonghong Zhang, K. Sangher, Robin Young, Mika Kivimäki, Soterios A. Kyrtopoulos, Ching-Yu Cheng, William R. Scott, Andres Metspalu, Eranga N. Vithana, Ai Ling Teh, Tarunveer S. Ahluwalia, Alexandre F.R. Stewart, John M. Starr, Toru Nabika, Jeannette Lee, Andre Franke, Inês Barroso, Gail Davies, Olov Rolandsson, Wei Huang, Myron D. Gross, Yong-Bing Xiang, Cinzia Sala, Marjo-Riitta Järvelin, W. Frank Paul, Jian'an Luan, Jon White, Robert A. Scott, Torben Jørgensen, Jing He, Tien Yin Wong, Michiya Igase, Yi Zhang, Nur Sabrina Sapari, Simone Wahl, Ron T. Gansevoort, Rasheed Asif, Bruce H W Wolffenbuttel, Alauddin Ahmed, Annette Peters, Silva Kasela, Jiang He, Min Jin Go, Takao Sugiyama, Dongfeng Gu, Jagvir Grewal, Satoshi Umemura, Thomas Sparsø, Anna-Liisa Hartikainen, Hooman Allayee, Xu Wang, Meena Kumari, Eitaro Nakashima, Xu Lin, Harold Snieder, Ananda R. Wickremasinghe, Yun Kyoung Kim, Yuan-Tsong Chen, Chew-Kiat Heng, Alexessander Couto Alves, E. James Ames Hixso, Daniela Ruggiero, Kazuro Shimokawa, Muhammad GKibriya, Jong-Young Lee, Yasuharu Tabara, Oluf Pedersen, Bong Jo Kim, Marie Loh, Lili Milani, Loi D. Do, Dharambir Harambir, Joo Yeon Hwang, Thomas Meitinger, Todd L. Edwards, Danish Saleheen, Anuradhani Kasturiratne, Hiromi Rakugi, Sian Tsung Tan, Paul Elliott, Ken Yamamoto, Chien Hsiun Chen, Abbas Dehghan, Evelin Mihailov, Leo-Pekka Lyytikäinen, Xiao-Ou Shu, Richie Soong, Yiqin Wang, Marina Ciullo, Graciela E. Delgado, Olli TRaitakari, Jian-Min Yuan, Melanie Waldenberger, Jiemin Liao, E. Shyong Tai, Mark I. McCarthy, Winfried März, Nilesh J. Samani, Yap Seng Chong, Son TPham, Sarah E. Harris, Regina Courtney, Allan Linneberg, W.H. Wilson Tang, Epidemiology, Ophthalmology, Medical Microbiology & Infectious Diseases, Cardiology, Radiology & Nuclear Medicine, Internal Medicine, Erasmus MC other, Biochemie, Interne Geneeskunde, Toxicogenomics, RS: GROW - Oncology, RS: GROW - R1 - Prevention, Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
Male, Vascular smooth muscle, Performance, Research Support, U.S. Gov't, P.H.S, Genome-wide association study, Blood Pressure, Expression, 030204 cardiovascular system & hematology, VARIANTS, P.H.S, genome-wide, 0302 clinical medicine, Risk Factors, Natriuretic Peptide, Brain, Disease, Non-U.S. Gov't, CENTRIC ARRAY, Genetics, Genetics & Heredity, Aged, 80 and over, 0303 health sciences, Research Support, Non-U.S. Gov't, 11 Medical And Health Sciences, Middle Aged, REGIONS, Phenotype, CpG site, Cardiovascular Diseases, CARDIOVASCULAR-DISEASE, DNA methylation, BIOS-consortium, Regression Analysis, Female, Life Sciences & Biomedicine, Adult, PULMONARY ARTERIAL-HYPERTENSION, Genotype, Population, Single-nucleotide polymorphism, Biology, Research Support, ta3111, Polymorphism, Single Nucleotide, White People, Article, N.I.H, 03 medical and health sciences, KIDNEY, Asian People, Research Support, N.I.H., Extramural, Journal Article, Humans, Genetic Predisposition to Disease, Gene, METAANALYSIS, 030304 developmental biology, Aged, Science & Technology, CARDIo GRAMplusCD, ta1184, Extramural, Genetic Variation, InterAct Consortium, 06 Biological Sciences, DNA Methylation, ta3121, Peptide Fragments, INDIVIDUALS, Blood pressure, Genetic Loci, TISSUE, RISK-FACTORS, U.S. Gov't, LifeLines Cohort Study, Developmental Biology, Genome-Wide Association Study
Abstract

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 x 10(-11) to 5.0 x 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 x 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

Published
2015

25. Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians

Author

Masato Isono, Toshio Ogihara, Rick Twee-Hee Ong, Toru Nabika, Jiang He, Shotai Kobayashi, Min Jin Go, Sung Soo Kim, Xueling Sim, Norihiro Kato, Fumihiko Takeuchi, Mitsuhiro Yokota, Jong-Young Lee, Yasuharu Tabara, Xuegong Zhang, Dingliang Zhu, Mark Seielstad, Naoharu Iwai, Tien Yin Wong, Tin Aung, Wei Huang, Dongfeng Gu, Yun Ju Sung, Bok Ghee Han, Tomohiro Katsuya, Ryoichi Takayanagi, Xueya Zhou, Yuan-Tsong Chen, Tanika N. Kelly, Yoshihiro Kokubo, Li Ching Chang, Wan Ting Tay, Jer-Yuarn Wu, Yoon Shin Cho, Keizo Ohnaka, Cashell E. Jaquish, Young-Jin Kim, Jianjun Liu, Tetsuro Miki, Ken Yamamoto, E. Shyong Tai, Chien Hsiun Chen, Yik Ying Teo, Eitaro Nakashima, James E. Hixson, Takao Sugiyama, Yi Zhang, Yukio Yamori, and Jae Pil Jeon

Subjects
Genetics, Asia, Eastern, Systole, Hemodynamics, Blood Pressure, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, White People, Blood pressure, Asian People, Gene Frequency, Diastole, Polymorphism (computer science), Meta-analysis, Humans, cardiovascular diseases, Allele frequency, Genotyping, circulatory and respiratory physiology, Genome-Wide Association Study, Genetic association
Abstract

We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of east Asian ancestry from the AGEN-BP consortium followed up with de novo genotyping (n = 10,518) and further replication (n = 20,247) in east Asian samples. We identified genome-wide significant (P < 5 × 10(-8)) associations with SBP or DBP, which included variants at four new loci (ST7L-CAPZA1, FIGN-GRB14, ENPEP and NPR3) and a newly discovered variant near TBX3. Among the five newly discovered variants, we obtained significant replication in the independent samples for all of these loci except NPR3. We also confirmed seven loci previously identified in populations of European descent. Moreover, at 12q24.13 near ALDH2, we observed strong association signals (P = 7.9 × 10(-31) and P = 1.3 × 10(-35) for SBP and DBP, respectively) with ethnic specificity. These findings provide new insights into blood pressure regulation and potential targets for intervention.

Published
2011

26. Confirmation of ALDH2 as a Major Locus of Drinking Behavior and of Its Variants Regulating Multiple Metabolic Phenotypes in a Japanese Population

Author

Fumihiko Takeuchi, Masato Isono, Tomohiro Katsuya, Shuhei Yamaguchi, Shotai Kobayashi, Toshio Ogihara, Akihiro Fujioka, Takao Sugiyama, Toru Nabika, Norihiro Kato, and Yukio Yamori

Subjects
Adult, Male, Linkage disequilibrium, Candidate gene, Population, Mutation, Missense, Drinking Behavior, Poison control, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, Asian People, Japan, Risk Factors, Humans, Medicine, Genetic Predisposition to Disease, education, Aged, Aged, 80 and over, Genetics, education.field_of_study, business.industry, Aldehyde Dehydrogenase, Mitochondrial, ADH1B, General Medicine, Odds ratio, Aldehyde Dehydrogenase, Middle Aged, Biotechnology, Amino Acid Substitution, Cardiovascular Diseases, Genetic Loci, Cardiology and Cardiovascular Medicine, business, Genome-Wide Association Study
Abstract

Background: Normative alcohol use (or drinking behavior) influences the risk of cardiovascular disease in a multi-faceted manner. To identify susceptibility gene variants for drinking behavior, a 2-staged genome-wide association study was performed in a Japanese population. Methods and Results: In the stage-1 scan, 733 cases and 729 controls were genotyped with 456,827 SNP markers. The associated loci without redundancy of linkage disequilibrium were further examined in the stage-2 general population panel comprising 2,794 drinkers (≥once per week), 1,521 chance drinkers (

Published
2011

27. Induction of efficient apoptosis and cell-cycle arrest in tumor cells by adenovirus-mediated p53 A4 mutant

Author

Kenzo Sato, Akihiro Maeda, Masato Isono, Seiichi Nakamura, Hisao Ito, and Mitsuhiko Osaki

Subjects
Programmed cell death, Blotting, Western, Genetic Vectors, Molecular Sequence Data, Apoptosis, Protein degradation, Adenoviridae, Pathology and Forensic Medicine, HeLa, Multiplicity of infection, Cell Line, Tumor, Humans, Amino Acid Sequence, biology, Cell Cycle, Gene Transfer Techniques, General Medicine, Blotting, Northern, Flow Cytometry, Genes, p53, biology.organism_classification, Molecular biology, Cell culture, Mutation, Cancer cell, DNA fragmentation
Abstract

p53 is an effective tumor suppressor and is inactivated in numerous cancer cells. In the present study, p53 mutant A4, which carries mutations in C-terminus of the protein and is resistant to murine double minute 2-mediated degradation, was exploited to introduce p53 function in tumor cells. The effect of p53 A4 mutant with recombinant adenovirus vector (Ad-p53 A4) was examined. Ad-p53 A4 infection at a low multiplicity of infection showed significant accumulation of p53 protein and strongly induced a killing effect on osteosarcoma cell line MG-63 that is less sensitive to transduction of wild-type p53. DNA fragmentation assay and caspase assay showed that the cell death induced by Ad-p53 A4 was more rapid and higher than that by Ad-p53 wild-type infection. It is also showed Ad-p53 A4 induces cell-cycle arrest in G1 phase. Moreover, a similar effect was observed in some human cancer cell lines (HeLa, HepG2, KATO III and Saos-2) in various status of endogenous p53 expression. These results suggest that Ad-p53 A4 has the ability to strongly suppress tumor cells and is a promising, novel tool for cancer gene therapy.

Published
2006

28. Systematic Fine-Mapping of Association with BMI and Type 2 Diabetes at the FTO Locus by Integrating Results from Multiple Ethnic Groups

Author

Ananda R. Wickremasinghe, Son Thai Pham, Anuradhani Kasturiratne, Fumihiko Takeuchi, Xiao-Ou Shu, Miyako Kishimoto, Norihiro Kato, Wei-Wei Zheng, Sureka Chakrawarthy, Masato Isono, Yumi Matsushita, Quang Ngoc Nguyen, Tomohiro Katsuya, Koichi Akiyama, Wanqing Wen, Ken Yamamoto, Hiroshi Kajio, and Loi Doan Do

Subjects
Adult, Male, Linkage disequilibrium, endocrine system diseases, Gene Identification and Analysis, lcsh:Medicine, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Computational biology, Type 2 diabetes, Bioinformatics, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Body Mass Index, Asian People, Genetics, Genome-Wide Association Studies, Medicine and Health Sciences, Diabetes Mellitus, Medicine, Humans, lcsh:Science, Genetic Association Studies, Genetic association, Multidisciplinary, business.industry, lcsh:R, nutritional and metabolic diseases, Biology and Life Sciences, Proteins, Human Genetics, Middle Aged, medicine.disease, Haplotypes, Dyslipidemia, Diabetes Mellitus, Type 2, Genetic Loci, Metabolic Disorders, lcsh:Q, Female, business, Body mass index, Population Genetics, Research Article
Abstract

Background/Objective The 16q12.2 locus in the first intron of FTO has been robustly associated with body mass index (BMI) and type 2 diabetes in genome-wide association studies (GWAS). To improve the resolution of fine-scale mapping at FTO, we performed a systematic approach consisting of two parts. Methods The first part is to partition the associated variants into linkage disequilibrium (LD) clusters, followed by conditional and haplotype analyses. The second part is to filter the list of potential causal variants through trans-ethnic comparison. Results We first examined the LD relationship between FTO SNPs showing significant association with type 2 diabetes in Japanese GWAS and between those previously reported in European GWAS. We could partition all the assayed or imputed SNPs showing significant association in the target FTO region into 7 LD clusters. Assaying 9 selected SNPs in 4 Asian-descent populations—Japanese, Vietnamese, Sri Lankan and Chinese (n≤26,109 for BMI association and n≤24,079 for type 2 diabetes association), we identified a responsible haplotype tagged by a cluster of SNPs and successfully narrowed the list of potential causal variants to 25 SNPs, which are the smallest in number among the studies conducted to date for FTO. Conclusions Our data support that the power to resolve the causal variants from those in strong LD increases consistently when three distant populations—Europeans, Asians and Africans—are included in the follow-up study. It has to be noted that this fine-mapping approach has the advantage of applicability to the existing GWAS data set in combination with direct genotyping of selected variants.

Published
2014

29. Association of genetic variants with non-alcoholic fatty liver disease in an urban Sri Lankan community

Author

Arjuna P. De Silva, Anuradhani Kasturiratne, Madunil A. Niriella, Fumihiko Takeuchi, Masato Isono, Anuradha S Dassanayake, Hithanadura Janaka de Silva, Koichi Akiyama, Rajitha Wickremasinghe, and Norihiro Kato

Subjects
Genotype, Urban Population, Genome-wide association study, Disease, Polymorphism, Single Nucleotide, Cohort Studies, Interviews as Topic, Non-alcoholic Fatty Liver Disease, Environmental health, Odds Ratio, Prevalence, Medicine, Humans, Genetic Predisposition to Disease, Sri Lanka, Ultrasonography, Hepatology, Traditional medicine, business.industry, Fatty liver, Genetic variants, Genetic Variation, Non alcoholic, Odds ratio, medicine.disease, Liver, Linear Models, Sri lanka, business, Blood Chemical Analysis, Genome-Wide Association Study
Published
2014

30. Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index

Author

Jeannette Lee, Xueling Sim, Norihiro Kato, Jirong Long, Xiuqing Guo, Mi Kyung Kim, Jerome I. Rotter, Fuu Jen Tsai, Yu-Tang Gao, Meian He, Wei-Yen Lim, Mark Seielstad, Jiang He, Min Jin Go, Rick Th Ong, Devin Absher, Jianjun Liu, Yii-Der Ida Chen, Yoon Shin Cho, Lu Qi, Yong Gao, Dingliang Zhu, I-Te Lee, Ling Lu, Ying Wu, Qiuyin Cai, James E. Hixson, Wei Lu, Ryan J. Delahanty, Bok-Ghee Han, Huai-Dong Song, Young-Hoon Lee, Xiaobo Yang, Masato Isono, Chii-Min Hwu, Myeong Chan Cho, Juyoung Lee, Min-Ho Shin, Ryoichi Takayanagi, Satoshi Umemura, I-Chien Wu, Nanette R. Lee, Byung-Yeol Chun, Themistocles L. Assimes, Matthew A. Allison, Dong Hoon Shin, Minoru Isomura, Koichi Akiyama, Tin Aung, Aihua Tan, Bong-Jo Kim, Young-Jin Kim, Rajkumar Dorajoo, Tetsuro Miki, Jiajun Shi, Wei Zheng, Yong-Bing Xiang, Shengxu Li, Ken Yamamoto, Tzung-Dao Wang, Ching-Chu Chen, Terri L. Young, Jer-Yuarn Wu, Soonil Kwon, Xiaofei Yan, Wanqing Wen, Lixuan Gui, Tangchun Wu, Toshihiro Tanaka, Chao A. Hsiung, Treva Rice, Toru Nabika, Jun Liang, Huaixing Li, Naoyuki Takashima, Yi Zhang, Bo Youl Choi, Wen-Jane Lee, Jyh-Ming Jimmy Juang, Linda S. Adair, Bu-Tian Ji, Kent D. Taylor, Xueya Zhou, Xu Lin, Fumihiko Takeuchi, Daehee Kang, Tatsuhiko Tsunoda, Takayoshi Ohkubo, Xingyi Guo, Tien Yin Wong, Karen L. Mohlke, Dongfeng Gu, Jong-Young Lee, Yasuharu Tabara, Wei Gan, Eric Kim, Jie Yao, Chien-Hsiun Chen, Michiaki Kubo, Chen Wu, Yukinori Okada, Wayne Huey-Herng Sheu, Xiao-Ou Shu, Zengnan Mo, Jane Z. Kuo, E. Shyong Tai, Frank B. Hu, and Joo-Yeon Hwang

Subjects
Male, Myosin Light Chains, Proteinase Inhibitory Proteins, Secretory, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Genome, Body Mass Index, Asian People, Polymorphism (computer science), Genetics, medicine, Humans, Genetic Predisposition to Disease, Obesity, 5'-Nucleotidase, Molecular Biology, Gene, Genetics (clinical), Glycoproteins, Genetic association, Asia, Eastern, Aldehyde Dehydrogenase, Mitochondrial, Association Studies Articles, Blood Proteins, General Medicine, Aldehyde Dehydrogenase, medicine.disease, KCNQ1 Potassium Channel, Female, Cardiac Myosins, Body mass index, Genome-Wide Association Study
Abstract

Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10(-13)), ALDH2/MYL2 (rs671, P = 3.40 × 10(-11); rs12229654, P = 4.56 × 10(-9)), ITIH4 (rs2535633, P = 1.77 × 10(-10)) and NT5C2 (rs11191580, P = 3.83 × 10(-8)) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10(-8)) and an additional 14 at P < 1.0 × 10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity.

Published
2014
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31. Adenovirus-Mediated Hepatocyte Growth Factor Gene Transfer Prevents Lethal Liver Failure in Rats

Author

Masato Isono, Kenzo Sato, Hironaka Kawasaki, Goshi Shiota, and Takahiro Nomi

Subjects
Male, medicine.medical_specialty, Lipopolysaccharide, Biophysics, Caspase 3, Biology, Transfection, Biochemistry, Adenoviridae, chemistry.chemical_compound, Internal medicine, medicine, Animals, RNA, Messenger, Molecular Biology, Survival rate, DNA Primers, Base Sequence, Hepatocyte Growth Factor, Gene Transfer Techniques, RNA, Alanine Transaminase, Cell Biology, Molecular biology, Rats, Inbred F344, Rats, Endocrinology, chemistry, Apoptosis, Caspases, Concomitant, Hepatocyte growth factor, Liver Failure, medicine.drug
Abstract

Hepatocyte growth factor (HGF) has a potent antiapoptotic effect on hepatocytes in D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-treated rats. Here, we report that adenovirus mediated HGF gene transfer into liver prevents liver failure and reduces mortality of rats treated with d-GalN/LPS. Fisher 344 rats, which were given intraperitoneal injections of pAxCAHGF 48 h before, were treated with D-GalN/LPS. Serum ALT in the HGF group at 6 and 12 h after D-GalN/LPS was decreased to 1/6 and 1/12 of the control group (P < 0.01, each). Concomitant reduction of apoptotic cells were also observed. The Kaplan-Meier analysis showed that a survival rate in the HGF group was improved, compared to that in the control group (P < 0.05). Caspase-3 activity in the HGF group decreased, compared to that in the control group, especially at 12 h (P < 0.05), although it maintained a high level in the control group. Expression of Bcl-xL and cyclooxygenase-2 (Cox-2) was induced in liver by HGF gene transfer. These data suggest that HGF exerts an antiapoptotic effect through dual induction of Bcl-xL and Cox-2, which suppresses caspase-3 activity.

Published
2000

32. In vivo transfer of hepatocyte growth factor gene accelerates proliferation of hepatic oval cells in a 2-acetylaminofluorene/partial hepatectomy model in rats

Author

Hironaka Kawasaki, Stewart Sell, Takahiro Nomi, Akihide Udagawa, Takahiro Kunisada, Kiwamu Tanaka, Kenzo Sato, Goshi Shiota, Masato Isono, Hisao Ito, Kenji Oyama, Hirofumi Hamada, Takafumi Nakamura, Atsushi Tsutsumi, and Takashi Sakatani

Subjects
Male, medicine.medical_specialty, Time Factors, Liver cytology, medicine.medical_treatment, Cell, Biophysics, Stem cell factor, Biochemistry, Solt–Farber model, chemistry.chemical_compound, Structural Biology, In vivo, Proliferating Cell Nuclear Antigen, Internal medicine, Genetics, medicine, Animals, Hepatectomy, RNA, Messenger, Molecular Biology, Stem Cell Factor, Hepatocyte Growth Factor, Chemistry, Gene Transfer Techniques, Cell Biology, 2-Acetylaminofluorene, Proto-Oncogene Proteins c-met, Immunohistochemistry, Molecular biology, Rats, Inbred F344, Liver regeneration, Rats, Disease Models, Animal, Proto-Oncogene Proteins c-kit, Oval cell, Endocrinology, medicine.anatomical_structure, Liver, Hepatocyte growth factor, Cell Division, medicine.drug
Abstract

To clarify the effect of hepatocyte growth factor (HGF) on proliferation of hepatic oval cells, we transferred HGF gene into liver of the Solt–Farber rat model. Male Fisher 344 rats were infected with a recombinant adenovirus carrying the cDNA for HGF (pAxCAHGF) from tail vein. HGF mRNA showed its peak at 4 days, and diminished thereafter. The total and proliferating cell nuclear antigen-positive hepatic oval cells were significantly elevated in HGF-transferred rats, in which stem cell factor and c-kit mRNA increased at each time point. Our results suggest that in vivo transfer of the HGF gene into liver accelerates proliferation of hepatic oval cells in the Solt–Farber model in rats.

Published
2000

33. Dissociation of eusperm bundles by acids, especially by succinate accumulated in the spermatophore of the silkmoth,Bombyx mori

Author

Masato Isono and Minoru Osanai

Subjects
Sucrose, biology, Initiatorin, biology.organism_classification, Sperm, Dissociation (chemistry), Staining, chemistry.chemical_compound, chemistry, Biochemistry, Bombyx mori, Spermatophore, Animal Science and Zoology, Centrifugation, Developmental Biology
Abstract

Summary Eusperm bundles and separated parasperm in the vesicula seminalis of the silkmoth, Bombyx mori, were separated by centrifugation in sucrose density gradients. Staining with aceto-orcein showed dissociation of eusperm bundles as well as stained nuclei. This dissociation was induced in the presence of all acids tested. Dilute solutions of endopeptidases dissociated the head part of the eusperm bundle, whereas dilute solutions of acids mainly dissociated the trunk and tail parts. On HPLC on a strongly acidic cation-exchanger column, seven acids were detected in the spermatophore. Of these, succinate was the main component, and only its concentration increased with time. We concluded that with initiatorin, a serine-endopeptidase secreted from the glandula prostatica, succinate serves as eupyrene sperm bundle-dissociating factor in the spermatophore. The possible mechanism of formation of succinate in the spermaophore, which may be associated with glycolysis and the arginine degradation cascade under h...

Published
1997

34. Deletion of CDKAL1 affects high-fat diet-induced fat accumulation and glucose-stimulated insulin secretion in mice, indicating relevance to diabetes

Author

Rieko Yanobu-Takanashi, Fumihiko Takeuchi, Keizo Ohnaka, Yukiko Shimizu, Koichi Akiyama, Tomohiro Katsuya, Motohito Goto, Masato Isono, Ryoichi Takayanagi, Yukio Yamori, Ken Yamamoto, Akihiro Fujioka, Norihiro Kato, Tadashi Okamura, Toshio Ogihara, and Yi Qiang Liang

Subjects
Anatomy and Physiology, medicine.medical_treatment, Adipose tissue, Type 2 diabetes, Body Mass Index, Gene Knockout Techniques, Mice, Endocrinology, Insulin Secretion, Homeostasis, Insulin, tRNA Methyltransferases, Multidisciplinary, Middle Aged, Phenotype, Adipose Tissue, Medicine, Female, Research Article, Adult, medicine.medical_specialty, Science, Nerve Tissue Proteins, Endocrine System, Biology, Diet, High-Fat, Insulin resistance, Diabetes mellitus, Internal medicine, medicine, Genetics, Animals, Humans, Obesity, CDKAL1, Pancreas, Genetic Association Studies, Nutrition, Diabetic Endocrinology, Endocrine Physiology, Body Weight, Human Genetics, Diabetes Mellitus Type 2, medicine.disease, Glucose, Diabetes Mellitus, Type 2, Genetic Loci, Genetics of Disease, Insulin Resistance, Gene Function, Body mass index, Animal Genetics
Abstract

Background/objectiveThe CDKAL1 gene is among the best-replicated susceptibility loci for type 2 diabetes, originally identified by genome-wide association studies in humans. To clarify a physiological importance of CDKAL1, we examined effects of a global Cdkal1-null mutation in mice and also evaluated the influence of a CDKAL1 risk allele on body mass index (BMI) in Japanese subjects.MethodsIn Cdkal1-deficient (Cdkal1⁻/⁻) mice, we performed oral glucose tolerance test, insulin tolerance test, and perfusion experiments with and without high-fat feeding. Based on the findings in mice, we tested genetic association of CDKAL1 variants with BMI, as a measure of adiposity, and type 2 diabetes in Japanese.Principal findingsOn a standard diet, Cdkal1⁻/⁻ mice were modestly lighter in weight than wild-type littermates without major alterations in glucose metabolism. On a high fat diet, Cdkal1⁻/⁻ mice showed significant reduction in fat accumulation (17% reduction in %intraabdominal fat, P = 0.023 vs. wild-type littermates) with less impaired insulin sensitivity at an early stage. High fat feeding did not potentiate insulin secretion in Cdkal1⁻/⁻ mice (1.0-fold), contrary to the results in wild-type littermates (1.6-fold, PConclusionsCdkal1 gene deletion is accompanied by modestly impaired insulin secretion and longitudinal fluctuations in insulin sensitivity during high-fat feeding in mice. CDKAL1 may affect such compensatory mechanisms regulating glucose homeostasis through interaction with diet.

Published
2012

35. Association of genetic variants for susceptibility to obesity with type 2 diabetes in Japanese individuals

Author

Shuhei Yamaguchi, Fumihiko Takeuchi, Tomomi Fujisawa, Toshio Ogihara, Masato Isono, Ken Yamamoto, Shotai Kobayashi, Toru Nabika, Ryoichi Takayanagi, Eitaro Nakashima, Hiroshi Ikegami, Yukio Yamori, Norihiro Kato, Jiro Nakamura, Tomohiro Katsuya, Akihiro Fujioka, T. Sugiyama, and Keizo Ohnaka

Subjects
Adult, Male, Genotype, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Comorbidity, Biology, Mitochondrial Membrane Transport Proteins, Polymorphism, Single Nucleotide, European descent, Body Mass Index, Mitochondrial Proteins, Asian People, Japan, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, Obesity, Aged, Genetics, Brain-Derived Neurotrophic Factor, Genetic variants, Membrane Proteins, Membrane Transport Proteins, Nutritional status, Human physiology, Middle Aged, medicine.disease, Diabetes Mellitus, Type 2, Case-Control Studies, Female
Abstract

In populations of East Asian descent, we performed a replication study of loci previously identified in populations of European descent as being associated with obesity measures such as BMI and type 2 diabetes.We genotyped 14 single nucleotide polymorphisms (SNPs) from 13 candidate loci that had previously been identified by genome-wide association meta-analyses for obesity measures in Europeans. Genotyping was done in 18,264 participants from two general Japanese populations. For SNPs showing an obesity association in Japanese individuals, we further examined diabetes associations in up to 6,781 cases and 7,307 controls from a subset of the original, as well as from additional populations.Significant obesity associations (p0.1 two-tailed, concordant direction with previous reports) were replicated for 11 SNPs from the following ten loci in Japanese participants: SEC16B, TMEM18, GNPDA2, BDNF, MTCH2, BCDIN3D-FAIM2, SH2B1-ATP2A1, FTO, MC4R and KCTD15. The strongest effect was observed at TMEM18 rs4854344 (p = 7.1 × 10(-7) for BMI). Among the 11 SNPs showing significant obesity association, six were also associated with diabetes (OR 1.05-1.17; p = 0.04-2.4 × 10(-7)) after adjustment for BMI in the Japanese. When meta-analysed with data from the previous reports, the BMI-adjusted diabetes association was found to be highly significant for the FTO locus in East Asians (OR 1.13; 95% CI 1.09-1.18; p = 7.8 × 10(-10)) with substantial inter-ethnic heterogeneity (p = 0.003).We confirmed that ten candidate loci are associated with obesity measures in the general Japanese populations. Six (of ten) loci exert diabetogenic effects in the Japanese, although relatively modest in size, and independently of increased adiposity.

Published
2010

36. Blood pressure and hypertension are associated with 7 loci in the Japanese population

Author

Mitsuhiro Yokota, Toru Nabika, Toshio Ogihara, Ken Yamamoto, Ryoichi Takayanagi, Shuhei Yamaguchi, Hiroyuki Asano, Shotai Kobayashi, Takao Sugiyama, Yukio Yamori, Akihiro Fujioka, Masato Isono, Norihiro Kato, Keizo Ohnaka, Fumihiko Takeuchi, and Tomohiro Katsuya

Subjects
Adult, Male, medicine.medical_specialty, Integrins, Adolescent, Cross-sectional study, Fibroblast Growth Factor 5, Diastole, Hemodynamics, Blood Pressure, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Plasma Membrane Calcium-Transporting ATPases, Young Adult, Fibroblast growth factor-5, Asian People, Japan, Physiology (medical), Internal medicine, Medicine, Humans, Genetic association, Aged, Aged, 80 and over, biology, business.industry, Steroid 17-alpha-Hydroxylase, Odds ratio, Middle Aged, Surgery, DNA-Binding Proteins, Blood pressure, Cross-Sectional Studies, Genetic Loci, Methylenetetrahydrofolate reductase, Hypertension, biology.protein, Female, biology.gene, Cardiology and Cardiovascular Medicine, business, Transcription Factors
Abstract

Background— Two consortium-based genome-wide association studies have recently identified robust and significant associations of common variants with systolic and diastolic blood pressures in populations of European descent, warranting further investigation in populations of non-European descent. Methods and Results— We examined the associations at 27 loci reported by the genome-wide association studies on Europeans in a screening panel of Japanese subjects (n=1526) and chose 11 loci showing association signals (1-tailed test in the screening, P CASZ1 , MTHFR, ITGA9 , FGF5 , CYP17A1-CNNM2 , ATP2B1 , and CSK-ULK3 —with any or all of these 3 traits: systolic blood pressure ( P =1.4×10 −14 to 0.05), diastolic blood pressure ( P =1.9×10 −12 to 0.05), and hypertension ( P =2.0×10 −14 to 0.006; odds ratio, 1.10 to 1.29). The strongest association was observed for FGF5 . In the whole study panel, the variance ( R 2 ) for blood pressure explained by the 7 single-nucleotide polymorphism loci was calculated to be R 2 =0.003 for male and 0.006 for female participants. Stratified analysis implied the potential presence of a gene-age-sex interaction, although it did not reach a conclusive level of statistical significance after adjustment for multiple testing. Conclusions— We have confirmed 7 loci associated with blood pressure and/or hypertension in the Japanese. These loci can guide fine-mapping efforts to pinpoint causal variants and causal genes with the integration of multiethnic results.

Published
2010

37. Evaluation of genetic loci influencing adult height in the Japanese population

Author

Masato Isono, Shuhei Yamaguchi, Norihiro Kato, Toru Nabika, Takao Sugiyama, Yukio Yamori, Shotai Kobayashi, Toshio Ogihara, Fumihiko Takeuchi, and Tomohiro Katsuya

Subjects
Adult, Multifactorial Inheritance, Locus (genetics), Biology, Polymorphism, Single Nucleotide, White People, Asian People, Gene Frequency, Japan, Genetics, SNP, Humans, Allele, Allele frequency, Genetics (clinical), Alleles, Genetic association, Korea, Genome, Human, Chromosome Mapping, Japanese population, Adult height, Body Height, Normal variation, Genome-Wide Association Study
Abstract

Adult height is a highly heritable, classic polygenic trait. The recent advent of genome-wide association studies has led to the identification of robust association at common variants influencing the normal variation of height; the number of loci has now risen to 50. The present study tested the potential overlap of height associations at 46 loci that were previously reported in European-descent populations with those among 1530 Japanese subjects and also attempted to replicate the suggestive association signals that were previously reported in East Asians alone. We found a total of 20 independent loci to be significantly (P

Published
2009

38. Reverse transformation of hepatic myofibroblast-like cells by TGFbeta1/LAP

Author

Masato Isono, Hideo Akiyoshi, Asuka Inoue, Mariko Soda, and Kenzo Sato

Subjects
Liver Cirrhosis, Male, Biophysics, Biology, Biochemistry, Cell Line, Extracellular matrix, Transforming Growth Factor beta1, Transforming Growth Factor beta, Animals, Protein Precursors, Rats, Wistar, Molecular Biology, Carbon Tetrachloride, Glial fibrillary acidic protein, Cell growth, Cell Differentiation, Cell Biology, Fibroblasts, Peptide Fragments, Recombinant Proteins, Cell biology, Extracellular Matrix, Rats, Liver, Cell culture, biology.protein, Hepatic stellate cell, Hepatic fibrosis, Myofibroblast, Transforming growth factor
Abstract

The activation of hepatic stellate cells (HSCs) to myofibroblasts (MFBs) is a key process for initiation of hepatic fibrosis and accumulation of the extracellular matrix (ECM). In this process, transforming growth factor beta1 (TGFbeta1) plays an important role in activating HSCs. In this study, we determined whether the activation of HSC was suppressed by latency-associated peptide (LAP) that is a part of TGFbeta1 precursor peptide. An MFB-like cell line (MFBY2) established from a fibrotic rat liver was infected with a recombinant adenovirus expressing LAP (AxCALAP). As results, AxCALAP-infected MFBY2 arrested cell proliferation and significantly decreased in expression of TGFbeta1 and ECM components. Interestingly, the expression of glial fibrillary acidic protein and up-take of retinoic acid were enhanced by AxCALAP-infection, while expression of alpha-smooth muscle actin was inhibited. These results suggested that overexpression of LAP in MFBs induces the reverse transformation to HSC phenotype. The adenoviral vector used in this study may have possible therapeutic applications in liver fibrosis.

Published
2003

39. Hepatoprotective action of adenovirus-transferred HNF-3gamma gene in acute liver injury caused by CCl(4)

Author

Masato Isono, Kenzo Sato, Takafumi Nakamura, Goshi Shiota, Hideo Akiyoshi, Masatsugu Moriyama, and Kyoko Nakamura

Subjects
Male, medicine.medical_specialty, Hepatocyte Nuclear Factor 3-Gamma, medicine.medical_treatment, Intraperitoneal injection, Genetic Vectors, Biophysics, CCL4, medicine.disease_cause, Protective Agents, Biochemistry, digestive system, Adenoviridae, Gene therapy, Structural Biology, Internal medicine, Genetics, medicine, Acute liver injury, Adenovirus, Animals, Rats, Wistar, Molecular Biology, Carbon Tetrachloride, Regulation of gene expression, Chemistry, Hepatocyte Growth Factor, Gene Transfer Techniques, Hepatocyte nuclear factor-3γ, Nuclear Proteins, Cell Biology, Rats, DNA-Binding Proteins, medicine.anatomical_structure, Endocrinology, Hepatocyte nuclear factor 4, Gene Expression Regulation, Liver, Hepatocyte, embryonic structures, Acute Disease, Hepatocyte growth factor, Transcription factor, Chemical and Drug Induced Liver Injury, Hepatocyte Nuclear Factor 3-gamma, medicine.drug, Transcription Factors
Abstract

Hepatocyte nuclear factor-3gamma (HNF-3gamma) is an important regulator of liver-specific genes and the expression of this factor is reduced in the liver injured by carbon tetrachloride (CCl(4)). Wistar rats were infected with a recombinant adenovirus carrying the cDNA for HNF-3gamma (AxCAHNF3gamma) via the tail vein and were treated with CCl(4) by intraperitoneal injection. Liver damage, such as swelling of the hepatocytes and increases in serum marker enzymes were markedly alleviated by AxCAHNF3gamma infection. Interestingly, hepatocyte growth factor (HGF) was strongly induced in the AxCAHNF3gamma-infected liver. Likewise, HNF-1alpha and HNF-1beta levels were increased, but HNF-3alpha and HNF-3beta levels were depressed in the liver. Our results suggest that the transduced HNF-3gamma gene leads to a hepatoprotective effect via the induction of HGF by the combined actions of liver-enriched transcription factors.

Published
1999

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