Asahi Hishida1, Masahiro Nakatochi2, Masato Akiyama3, Yoichiro Kamatani3,4, Takeshi Nishiyama5, Hidemi Ito6, Isao Oze6, Yuichiro Nishida7, Megumi Hara7, Naoyuki Takashima8, Tanvir Chowdhury Turin9, Miki Watanabe10, Sadao Suzuki10, Rie Ibusuki11, Ippei Shimoshikiryo11, Yohko Nakamura12, Haruo Mikami12, Hiroaki Ikezaki13, Norihiro Furusyo13, Kiyonori Kuriki14, Kaori Endoh14, Teruhide Koyama15, Daisuke Matsui15, Hirokazu Uemura16, Kokichi Arisawa16, Tae Sasakabe1, Rieko Okada1, Sayo Kawai1, Mariko Naito1, Yukihide Momozawa3, Michiaki Kubo3, Kenji Wakai1. 1. Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. 2. Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan. 3. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 4. Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 5. Department of Public Health, Aichi Medical University School of Medicine, Nagakute, Japan. 6. Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan. 7. Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan. 8. Department of Health Science, Shiga University of Medical Science, Otsu, Japan. 9. Department of Family Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. 10. Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. 11. Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. 12. Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan. 13. Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 14. Laboratory of Public Health, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan. 15. Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. 16. Department of Preventive Medicine, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
Abstract
BACKGROUND: Chronic kidney disease (CKD) is a rapidly growing, worldwide public health problem. Recent advances in genome-wide-association studies (GWAS) revealed several genetic loci associated with renal function traits worldwide. METHODS: We investigated the association of genetic factors with the levels of serum creatinine (SCr) and the estimated glomerular filtration rate (eGFR) in Japanese population-based cohorts analyzing the GWAS imputed data with 11,221 subjects and 12,617,569 variants, and replicated the findings with the 148,829 hospital-based Japanese subjects. RESULTS: In the discovery phase, 28 variants within 4 loci (chromosome [chr] 2 with 8 variants including rs3770636 in the LDL receptor related protein 2 gene locus, on chr 5 with 2 variants including rs270184, chr 17 with 15 variants including rs3785837 in the BCAS3 gene locus, and chr 18 with 3 variants including rs74183647 in the nuclear factor of -activated T-cells 1 gene locus) reached the suggestive level of p < 1 × 10-6 in association with eGFR and SCr, and 2 variants on chr 4 (including rs78351985 in the microsomal triglyceride transfer protein gene locus) fulfilled the suggestive level in association with the risk of CKD. In the replication phase, 25 variants within 3 loci (chr 2 with 7 variants, chr 17 with 15 variants and chr 18 with 3 variants) in association with eGFR and SCr, and 2 variants on chr 4 associated with the risk of CKD became nominally statistically significant after Bonferroni correction, among which 15 variants on chr 17 and 3 variants on chr 18 reached genome-wide significance of p < 5 × 10-8 in the combined study meta-analysis. The associations of the loci on chr 2 and 18 with eGFR and SCr as well as that on chr 4 with CKD risk have not been previously reported in the Japanese and East Asian populations. CONCLUSION: Although the present GWAS of renal function traits included the largest sample of Japanese participants to date, we did not identify novel loci for renal traits. However, we identified the novel associations of the genetic loci on chr 2, 4, and 18 with renal function traits in the Japanese population, suggesting these are transethnic loci. Further investigations of these associations are expected to further validate our findings for the potential establishment of personalized prevention of renal disease in the Japanese and East Asian populations.
BACKGROUND:Chronic kidney disease (CKD) is a rapidly growing, worldwide public health problem. Recent advances in genome-wide-association studies (GWAS) revealed several genetic loci associated with renal function traits worldwide. METHODS: We investigated the association of genetic factors with the levels of serum creatinine (SCr) and the estimated glomerular filtration rate (eGFR) in Japanese population-based cohorts analyzing the GWAS imputed data with 11,221 subjects and 12,617,569 variants, and replicated the findings with the 148,829 hospital-based Japanese subjects. RESULTS: In the discovery phase, 28 variants within 4 loci (chromosome [chr] 2 with 8 variants including rs3770636 in the LDL receptor related protein 2 gene locus, on chr 5 with 2 variants including rs270184, chr 17 with 15 variants including rs3785837 in the BCAS3 gene locus, and chr 18 with 3 variants including rs74183647 in the nuclear factor of -activated T-cells 1 gene locus) reached the suggestive level of p < 1 × 10-6 in association with eGFR and SCr, and 2 variants on chr 4 (including rs78351985 in the microsomal triglyceride transfer protein gene locus) fulfilled the suggestive level in association with the risk of CKD. In the replication phase, 25 variants within 3 loci (chr 2 with 7 variants, chr 17 with 15 variants and chr 18 with 3 variants) in association with eGFR and SCr, and 2 variants on chr 4 associated with the risk of CKD became nominally statistically significant after Bonferroni correction, among which 15 variants on chr 17 and 3 variants on chr 18 reached genome-wide significance of p < 5 × 10-8 in the combined study meta-analysis. The associations of the loci on chr 2 and 18 with eGFR and SCr as well as that on chr 4 with CKD risk have not been previously reported in the Japanese and East Asian populations. CONCLUSION: Although the present GWAS of renal function traits included the largest sample of Japanese participants to date, we did not identify novel loci for renal traits. However, we identified the novel associations of the genetic loci on chr 2, 4, and 18 with renal function traits in the Japanese population, suggesting these are transethnic loci. Further investigations of these associations are expected to further validate our findings for the potential establishment of personalized prevention of renal disease in the Japanese and East Asian populations.
Authors: Matthias Wuttke; Yong Li; Man Li; Karsten B Sieber; Mary F Feitosa; Mathias Gorski; Adrienne Tin; Lihua Wang; Audrey Y Chu; Anselm Hoppmann; Holger Kirsten; Ayush Giri; Jin-Fang Chai; Gardar Sveinbjornsson; Bamidele O Tayo; Teresa Nutile; Christian Fuchsberger; Jonathan Marten; Massimiliano Cocca; Sahar Ghasemi; Yizhe Xu; Katrin Horn; Damia Noce; Peter J van der Most; Sanaz Sedaghat; Zhi Yu; Masato Akiyama; Saima Afaq; Tarunveer S Ahluwalia; Peter Almgren; Najaf Amin; Johan Ärnlöv; Stephan J L Bakker; Nisha Bansal; Daniela Baptista; Sven Bergmann; Mary L Biggs; Ginevra Biino; Michael Boehnke; Eric Boerwinkle; Mathilde Boissel; Erwin P Bottinger; Thibaud S Boutin; Hermann Brenner; Marco Brumat; Ralph Burkhardt; Adam S Butterworth; Eric Campana; Archie Campbell; Harry Campbell; Mickaël Canouil; Robert J Carroll; Eulalia Catamo; John C Chambers; Miao-Ling Chee; Miao-Li Chee; Xu Chen; Ching-Yu Cheng; Yurong Cheng; Kaare Christensen; Renata Cifkova; Marina Ciullo; Maria Pina Concas; James P Cook; Josef Coresh; Tanguy Corre; Cinzia Felicita Sala; Daniele Cusi; John Danesh; E Warwick Daw; Martin H de Borst; Alessandro De Grandi; Renée de Mutsert; Aiko P J de Vries; Frauke Degenhardt; Graciela Delgado; Ayse Demirkan; Emanuele Di Angelantonio; Katalin Dittrich; Jasmin Divers; Rajkumar Dorajoo; Kai-Uwe Eckardt; Georg Ehret; Paul Elliott; Karlhans Endlich; Michele K Evans; Janine F Felix; Valencia Hui Xian Foo; Oscar H Franco; Andre Franke; Barry I Freedman; Sandra Freitag-Wolf; Yechiel Friedlander; Philippe Froguel; Ron T Gansevoort; He Gao; Paolo Gasparini; J Michael Gaziano; Vilmantas Giedraitis; Christian Gieger; Giorgia Girotto; Franco Giulianini; Martin Gögele; Scott D Gordon; Daniel F Gudbjartsson; Vilmundur Gudnason; Toomas Haller; Pavel Hamet; Tamara B Harris; Catharina A Hartman; Caroline Hayward; Jacklyn N Hellwege; Chew-Kiat Heng; Andrew A Hicks; Edith Hofer; Wei Huang; Nina Hutri-Kähönen; Shih-Jen Hwang; M Arfan Ikram; Olafur S Indridason; Erik Ingelsson; Marcus Ising; Vincent W V Jaddoe; Johanna Jakobsdottir; Jost B Jonas; Peter K Joshi; Navya Shilpa Josyula; Bettina Jung; Mika Kähönen; Yoichiro Kamatani; Candace M Kammerer; Masahiro Kanai; Mika Kastarinen; Shona M Kerr; Chiea-Chuen Khor; Wieland Kiess; Marcus E Kleber; Wolfgang Koenig; Jaspal S Kooner; Antje Körner; Peter Kovacs; Aldi T Kraja; Alena Krajcoviechova; Holly Kramer; Bernhard K Krämer; Florian Kronenberg; Michiaki Kubo; Brigitte Kühnel; Mikko Kuokkanen; Johanna Kuusisto; Martina La Bianca; Markku Laakso; Leslie A Lange; Carl D Langefeld; Jeannette Jen-Mai Lee; Benjamin Lehne; Terho Lehtimäki; Wolfgang Lieb; Su-Chi Lim; Lars Lind; Cecilia M Lindgren; Jun Liu; Jianjun Liu; Markus Loeffler; Ruth J F Loos; Susanne Lucae; Mary Ann Lukas; Leo-Pekka Lyytikäinen; Reedik Mägi; Patrik K E Magnusson; Anubha Mahajan; Nicholas G Martin; Jade Martins; Winfried März; Deborah Mascalzoni; Koichi Matsuda; Christa Meisinger; Thomas Meitinger; Olle Melander; Andres Metspalu; Evgenia K Mikaelsdottir; Yuri Milaneschi; Kozeta Miliku; Pashupati P Mishra; Karen L Mohlke; Nina Mononen; Grant W Montgomery; Dennis O Mook-Kanamori; Josyf C Mychaleckyj; Girish N Nadkarni; Mike A Nalls; Matthias Nauck; Kjell Nikus; Boting Ning; Ilja M Nolte; Raymond Noordam; Jeffrey O'Connell; Michelle L O'Donoghue; Isleifur Olafsson; Albertine J Oldehinkel; Marju Orho-Melander; Willem H Ouwehand; Sandosh Padmanabhan; Nicholette D Palmer; Runolfur Palsson; Brenda W J H Penninx; Thomas Perls; Markus Perola; Mario Pirastu; Nicola Pirastu; Giorgio Pistis; Anna I Podgornaia; Ozren Polasek; Belen Ponte; David J Porteous; Tanja Poulain; Peter P Pramstaller; Michael H Preuss; Bram P Prins; Michael A Province; Ton J Rabelink; Laura M Raffield; Olli T Raitakari; Dermot F Reilly; Rainer Rettig; Myriam Rheinberger; Kenneth M Rice; Paul M Ridker; Fernando Rivadeneira; Federica Rizzi; David J Roberts; Antonietta Robino; Peter Rossing; Igor Rudan; Rico Rueedi; Daniela Ruggiero; Kathleen A Ryan; Yasaman Saba; Charumathi Sabanayagam; Veikko Salomaa; Erika Salvi; Kai-Uwe Saum; Helena Schmidt; Reinhold Schmidt; Ben Schöttker; Christina-Alexandra Schulz; Nicole Schupf; Christian M Shaffer; Yuan Shi; Albert V Smith; Blair H Smith; Nicole Soranzo; Cassandra N Spracklen; Konstantin Strauch; Heather M Stringham; Michael Stumvoll; Per O Svensson; Silke Szymczak; E-Shyong Tai; Salman M Tajuddin; Nicholas Y Q Tan; Kent D Taylor; Andrej Teren; Yih-Chung Tham; Joachim Thiery; Chris H L Thio; Hauke Thomsen; Gudmar Thorleifsson; Daniela Toniolo; Anke Tönjes; Johanne Tremblay; Ioanna Tzoulaki; André G Uitterlinden; Simona Vaccargiu; Rob M van Dam; Pim van der Harst; Cornelia M van Duijn; Digna R Velez Edward; Niek Verweij; Suzanne Vogelezang; Uwe Völker; Peter Vollenweider; Gerard Waeber; Melanie Waldenberger; Lars Wallentin; Ya Xing Wang; Chaolong Wang; Dawn M Waterworth; Wen Bin Wei; Harvey White; John B Whitfield; Sarah H Wild; James F Wilson; Mary K Wojczynski; Charlene Wong; Tien-Yin Wong; Liang Xu; Qiong Yang; Masayuki Yasuda; Laura M Yerges-Armstrong; Weihua Zhang; Alan B Zonderman; Jerome I Rotter; Murielle Bochud; Bruce M Psaty; Veronique Vitart; James G Wilson; Abbas Dehghan; Afshin Parsa; Daniel I Chasman; Kevin Ho; Andrew P Morris; Olivier Devuyst; Shreeram Akilesh; Sarah A Pendergrass; Xueling Sim; Carsten A Böger; Yukinori Okada; Todd L Edwards; Harold Snieder; Kari Stefansson; Adriana M Hung; Iris M Heid; Markus Scholz; Alexander Teumer; Anna Köttgen; Cristian Pattaro Journal: Nat Genet Date: 2019-05-31 Impact factor: 38.330