Significant association of RNF213 p.R4810K, a moyamoya susceptibility variant, with coronary artery disease

PLOS ONE, Dec 2019

Background The genetic architecture of coronary artery disease has not been fully elucidated, especially in Asian countries. Moyamoya disease is a progressive cerebrovascular disease that is reported to be complicated by coronary artery disease. Because most Japanese patients with moyamoya disease carry the p.R4810K variant of the ring finger 213 gene (RNF213), this may also be a risk factor for coronary artery disease; however, this possibility has never been tested. Methods and results We genotyped the RNF213 p.R4810K variant in 956 coronary artery disease patients and 716 controls and tested the association between p.R4810K and coronary artery disease. We also validated the association in an independent population of 311 coronary artery disease patients and 494 controls. In the replication study, the p.R4810K genotypes were imputed from genome-wide genotyping data based on the 1000 Genomes Project. We used multivariate logistic regression analyses to adjust for well-known risk factors such as dyslipidemia and smoking habits. In the primary study population, the frequency of the minor variant allele was significantly higher in patients with coronary artery disease than in controls (2.04% vs. 0.98%), with an odds ratio of 2.11 (p = 0.017). Under a dominant model, after adjustment for risk factors, the association remained significant, with an odds ratio of 2.90 (95% confidence interval: 1.37–6.61; p = 0.005). In the replication study, the association was significant after adjustment for age and sex (odds ratio = 4.99; 95% confidence interval: 1.16–21.53; p = 0.031), although it did not reach statistical significance when further adjusted for risk factors (odds ratio = 3.82; 95% confidence interval: 0.87–16.77; p = 0.076). Conclusions The RNF213 p.R4810K variant appears to be significantly associated with coronary artery disease in the Japanese population.

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Significant association of RNF213 p.R4810K, a moyamoya susceptibility variant, with coronary artery disease

April Significant association of RNF213 p.R4810K, a moyamoya susceptibility variant, with coronary artery disease Takaaki Morimoto 1 2 Yohei Mineharu 1 2 Koh Ono 0 2 Masahiro Nakatochi 2 5 Sahoko Ichihara 2 Risako Kabata 2 Yasushi Takagi 1 2 Yang Cao 2 4 Lanying Zhao 2 3 Hatasu Kobayashi 2 Kouji H. Harada 2 Katsunobu Takenaka 2 6 Takeshi Funaki 1 2 Mitsuhiro Yokota 2 Tatsuaki Matsubara 2 Ken Yamamoto 2 Hideo Izawa 2 Takeshi Kimura 0 2 Susumu Miyamoto 1 2 Akio Koizumi 2 0 Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine , Kyoto , Japan 1 Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan, 2 Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine , Kyoto , Japan 2 Editor: Johnson Rajasingh, University of Kansas Medical Center , UNITED STATES 3 Congenital Anomaly Research Center, Kyoto University Graduate School of Medicine , Kyoto , Japan 4 Department of Preventive Medicine, St. Marianna University School of Medicine , Kawasaki , Japan 5 Statistical Analysis Section, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital , Nagoya , Japan , 5 Graduate School of Regional Innovation Studies, Mie University , Tsu , Japan 6 Department of Neurosurgery, Takayama Red Cross Hospital , Gifu , Japan , 9 Department of Genome Science, School of Dentistry, Aichi Gakuin University , Nagoya , Japan , 10 Department of Internal Medicine, School of Dentistry, Aichi Gakuin University , Nagoya , Japan , 11 Department of Medical Biochemistry, Kurume University School of Medicine, Fukuoka, Japan, 12 Department of Cardiology, Fujita Health University, Banbuntane Hotokukai Hospital , Nagoya , Japan - Data Availability Statement: All relevant data are within the paper. Funding: The primary study was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, including those for Scientific Research (A) to AK (25253047), Scientific Research (B) to KO (26293186), and Young Scientists (B) to YM (15K19963) and HK (15K19243), and grants from the St. Luke Life Science Institute to YM, the Shimizu Foundation for Immunology and Background The genetic architecture of coronary artery disease has not been fully elucidated, especially in Asian countries. Moyamoya disease is a progressive cerebrovascular disease that is reported to be complicated by coronary artery disease. Because most Japanese patients with moyamoya disease carry the p.R4810K variant of the ring finger 213 gene (RNF213), this may also be a risk factor for coronary artery disease; however, this possibility has never been tested. Methods and results We genotyped the RNF213 p.R4810K variant in 956 coronary artery disease patients and 716 controls and tested the association between p.R4810K and coronary artery disease. We also validated the association in an independent population of 311 coronary artery disease patients and 494 controls. In the replication study, the p.R4810K genotypes were imputed from genome-wide genotyping data based on the 1000 Genomes Project. We used multivariate logistic regression analyses to adjust for well-known risk factors such as dyslipidemia and smoking habits. In the primary study population, the frequency of the minor variant allele was significantly higher in patients with coronary artery disease than in controls (2.04% vs. 0.98%), with an odds ratio of 2.11 (p = 0.017). Under a dominant model, after Neuroscience to YM, the Japan Brain Foundation to YM, and the Fujiwara Foundation of Science to YM. The replication study was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, including those for Scientific Research (B) to MY (24390169, 16H05250), Scientific Research (C) to KY (15K08290), and Scientific Research on Innovative Areas to MN (16H06277), and grant from the Suzuken Memorial Foundation to MY (14003). Competing interests: The authors have declared that no competing interests exist. adjustment for risk factors, the association remained significant, with an odds ratio of 2.90 (95% confidence interval: 1.37±6.61; p = 0.005). In the replication study, the association was significant after adjustment for age and sex (odds ratio = 4.99; 95% confidence interval: 1.16±21.53; p = 0.031), although it did not reach statistical significance when further adjusted for risk factors (odds ratio = 3.82; 95% confidence interval: 0.87±16.77; p = 0.076). Conclusions The RNF213 p.R4810K variant appears to be significantly associated with coronary artery disease in the Japanese population. Introduction Together with the Westernization of lifestyles, the number of patients with coronary artery disease (CAD) has increased in Japan and become a major public health concern.[ 1 ] Although the mortality rate of CAD in Japan is one-third to one-fifth of that in the United States,[2±5] cardiovascular (...truncated)


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Takaaki Morimoto, Yohei Mineharu, Koh Ono, Masahiro Nakatochi, Sahoko Ichihara, Risako Kabata, Yasushi Takagi, Yang Cao, Lanying Zhao, Hatasu Kobayashi, Kouji H. Harada, Katsunobu Takenaka, Takeshi Funaki, Mitsuhiro Yokota, Tatsuaki Matsubara, Ken Yamamoto, Hideo Izawa, Takeshi Kimura, Susumu Miyamoto, Akio Koizumi. Significant association of RNF213 p.R4810K, a moyamoya susceptibility variant, with coronary artery disease, PLOS ONE, 2017, Volume 12, Issue 4, DOI: 10.1371/journal.pone.0175649