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A Genome-Wide Association Study in the Diabetic Patients Finds The Clinica of l D l ia a b rn e t u e o s J Journal of Clinical Diabetes Nakamura et al., J Clin Diabetes 2018, 2:1 Research article Open Access A Genome-wide Association Study in the Diabetic Patients Finds the 13q35.43–35.46 Locus Associated with Estimated Glomerular Filtration Rate: The Japan Multi-Institutional Collaborative Cohort study. Yasuyuki Nakamura1,2*, Akira Narita3, Tsuyoshi Hachiya4, Yoichi Sutoh4 , Atsushi Shimizu4 , Seiko Ohno5, Naoyuki Takashima2, Harumitsu Suzuki6, Keitaro Tanaka7, Megumi Hara7 Kiyonori Kuriki8, Kaori Endoh8, Isao Oze9, Hidemi Ito10,11, Hirokazu Uemura12, Sakurako Katsuura-Kamano12, Haruo Mikami13, Yohko Nakamura13, Ippei Shimoshikiryo14, Toshiro Takezaki14, Sadao Suzuki15, Miki Watanabe15, Nagato Kuriyama16, Teruhide Koyama16, Norihiro Furusyo17, Hiroaki Ikezaki17, Masahiro Nakatochi18, Sayo Kawai19, Asahi Hishida19, Rieko Okada19, Takashi Tamura19, Mariko Naito20, Kenji Wakai19, Yukihide Momozawa21, Michiaki Kubo21, Hirotsugu Ueshima6 and Yoshikuni Kita 2,22 1Department of Food Science and Human Nutrition, Ryukoku University, Otsu, Japan 2Department of Public Health, Shiga University of Medical Science, Otsu, Japan 3Department of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan 4Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Shiwa-gun, Iwate, Japan 5Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Suita, Japan 6Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan 7Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan 8Laboratory of Public Health, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan 9Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan 10Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan 11Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan 12Department of Preventive Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan 13Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan 14Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan 15Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan 16Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan 17Department of Environmental Medicine and Infectious Disease, Kyushu University, Fukuoka, Japan 18Statistical Analysis Section, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan 19Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan 20Department of Maxillofacial Functional Development, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan 21Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan 22Faculty of Nursing Science, Tsuruga Nursing University, Tsuruga, Japan *Corresponding authors: Yasuyuki Nakamura, Department of Food Science and Human Nutrition, Ryukoku University, Otsu, Japan, Tel : +81-77-559-5646; Fax: +81-77-559-5646; E-mail: [email protected] Received date: July 15, 2018; Accepted date: July 19, 2018; Published date: July 27, 2018 Copyright: ©2018 Nakamura Y, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Objective: To conduct a genome-wide association studies (GWAS) to find genetic variations that affected renal function in the diabetic patients in Japan. Research design and methods: In a Japanese population of 955 patients with type 2 diabetes mellitus (T2D), extracted from 14,091 participants appropriate for GWAS from the Japan Multi-Institutional Collaborative Cohort (J- MICC) study. Genotyping was performed at a central laboratory with use of a HumanOmniExpressExome-8 v1.2 BeadChip array. Genotype imputation was conducted with use of SHAPEIT, followed by Minimac3 software (with the 1000 Genomes phase 3 as the reference panel). We calculated the estimated glomerular filtration rate (eGFR) for each patient according to Matsuo et al. Association for the imputed variants with eGFR was performed by linear regression analysis with adjustments for age and sex. Results: We found 77 SNVs upstream of the NBEA gene that was significantly associated with eGFR in T2D participants with P values<5 × 10-8. This gene was reported as participatory in several metabolic functions and was associated with some disease conditions. However, no previous reports implied that the gene was related to nephropathy in diabetes. J Clin Diabetes, an open access journal Volume 2 • Issue 1 • 1000102 Citation: Nakamura Y, Narita A, Hachiya T, Sutoh Y, Shimizu A, et al. (2018) A Genome-wide Association Study in the Diabetic Patients Finds the 13q35.43–35.46 Locus Associated with Estimated Glomerular Filtration Rate: The Japan Multi-Institutional Collaborative Cohort study.. J Clin Diabetes 2: 102. Page 2 of 8 Conclusion: We found the 13q35.43-35.46 locus upstream of the NBEA gene was significantly associated with eGFR in participants with T2D in a Japanese population. Keywords: Genome-wide association study; Diabetes mellitus; Questionnaire and measurements Estimated glomerular filtration rate; Chronic kidney disease The J-MICC study questionnaire consisted of questions on medical history, weight, height, smoking and alcohol drinking habits. Introduction Measurements of participants’ body and blood drawing were done as Diabetic nephropathy is the most common cause of chronic kidney part of the health examination or for research purposes at the J-MICC disease (CKD) in developed countries [1]. The clinical characteristics study participating institutions [5]. Weight and height were measured do not fully predict development of nephropathy in diabetes patients. to the nearest 0.1 kg and 0.1 cm, respectively. Body mass index (BMI) Epidemiological findings suggested genetic background plays an was calculated by dividing body weight in kilograms by the square of important role in the development of this renal disease [2,3]. height in meters. The HbA1c percentage was obtained with use of a latex aggregation immunoassay (Japan Diabetes Society [JDS] value). There have been several genome-wide association studies (GWAS). The HbA1c percentage was estimated as the National In a recent meta-analysis by Pattaro et al. on associations of estimated Glycohemoglobin Standardization Program (NGSP) equivalent glomerular filtration rate (eGFR) based on serum creatinine (Scr), percentage obtained according to the following formula: HbA1c cystatin C, and CKD (defined as eGFR based on Scr<60 ml/min/ (NGSP (%))=1.02 × HbA1c (JDS [%])+0.25% [7]. We defined T2D as a 2 1.73m ) with about 2.5 million autosomal single-nucleotide variations fasting blood glucose concentration ≥ 126 mg/dL, or ≥ 200 mg/dL if (SNVs) in 133,413 individuals of European ancestry in the stage 1 less than 8 h after meals, or NGSP HbA1c ≥ 47 mmol/mol (6.5%), or discovery analysis, 29 previously identified loci were confirmed and 48 participants diagnosed as having DM. Scr was measured enzymatically. independent novel loci newly identified [4]. In their trans-ethnic The eGFR of each participant was obtained based on SCr, age, and sex analyses in 42,296 Asian participants, 7 out of 24 newly identified loci with use of the following Japanese eGFR equation proposed by the with eGFR based on Scr achieved direction-consistent significance. If Japanese Society of Nephrology: eGFR (mL/min/1.73 m2)=194 × Scr the GWAS discovery analysis had been started in an Asian population, (mg/dL)-1.094 × age-0.287 (× 0.739 if female) [8]. 6emL-quantLfied some different SNVs may have been found. Here we found 77 SNVs dip-stick urine protein data were available in a part of the patients upstream of NBEA that affected renal function in a Japanese (N=516) that were classified as 0, 15, 30, 100, or ≥ 250 mg/dL. population with type 2 diabetes mellitus (T2D). Genotyping and quality control filtering Research Design and Methodology Buffy coat fractions were prepared from blood specimen and stored at -80°C at the central office for J-MICC Study. DNA was prepared Study population from all buffy coat fractions with use of a BioRobot M48 Workstation A cross-sectional GWAS was performed in participants at ages from (Qiagen Group, Tokyo, Japan) at the central study office. For the 35 to 69 years in the Japan Multi-Institutional Collaborative Cohort (J- specimen from two locations (Fukuoka and Kyushu-KOPS), DNA was MICC) study. The participants in the J-MICC study were invited from prepared locally from specimen of whole blood with use of an 12 different locations in Japan between 2004 and 2013 (Number of automatic nucleic acid isolation system (NA-3000, Kurabo, Co., Ltd, participants: 14,539). The J-MICC study is a cohort study started in Osaka, Japan). The 14,539 study participants from the 12 locations of 2005 to examine interactions between gene and environment factors
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