Research ArticleArticle
Associations of Multiple NOTCH4 Exonic Variants with Systemic Sclerosis
Xiaodong Zhou, Hongye Li, Shicheng Guo, Jiucun Wang, Chunhua Shi, Maribel Espitia, Xinjian Guo, Qingwen Wang, Mengyuan Liu, Shervin Assassi, John D. Reveille and Maureen D. Mayes
The Journal of Rheumatology November 2018, jrheum.180094; DOI: https://doi.org/10.3899/jrheum.180094
Xiaodong Zhou
From the Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health, Houston, Texas, USA; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai; Department of Rheumatology, Jiangxi People’s Hospital, Nanchang; Department of Rheumatology, Peking University-Shenzhen Hospital, Shenzhen; Life Sciences College, Hubei University, Wuhan, China. Supported by the US National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases 1U01AI09090-01 and NIH P01-052915-01; the Major National Science and Technology Program of China, grant number 2008ZX10002-002; and the Science and Technology Committee of Shanghai Municipality (11410701800). X. Zhou, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; H. Li, MD, PhD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; S. Guo, PhD, Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health; J. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; C. Shi, MD, Department of Rheumatology, Jiangxi People’s Hospital; M. Espitia, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; X. Guo, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Q. Wang, MD, PhD, Department of Rheumatology, Peking University-Shenzhen Hospital; M. Liu, PhD, Life Sciences College, Hubei University; S. Assassi, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; J.D. Reveille, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; M.D. Mayes, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School. Address correspondence to Prof. X. Zhou, Department of Internal Medicine, Division of Rheumatology, The University of Texas Medical School at Houston, 6431 Fannin St., MSB5270, Houston, Texas 77030, USA. E-mail: Xiaodong.zhou@uth.tmc.edu. Accepted for publication August 8, 2018.
Hongye Li
From the Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health, Houston, Texas, USA; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai; Department of Rheumatology, Jiangxi People’s Hospital, Nanchang; Department of Rheumatology, Peking University-Shenzhen Hospital, Shenzhen; Life Sciences College, Hubei University, Wuhan, China. Supported by the US National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases 1U01AI09090-01 and NIH P01-052915-01; the Major National Science and Technology Program of China, grant number 2008ZX10002-002; and the Science and Technology Committee of Shanghai Municipality (11410701800). X. Zhou, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; H. Li, MD, PhD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; S. Guo, PhD, Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health; J. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; C. Shi, MD, Department of Rheumatology, Jiangxi People’s Hospital; M. Espitia, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; X. Guo, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Q. Wang, MD, PhD, Department of Rheumatology, Peking University-Shenzhen Hospital; M. Liu, PhD, Life Sciences College, Hubei University; S. Assassi, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; J.D. Reveille, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; M.D. Mayes, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School. Address correspondence to Prof. X. Zhou, Department of Internal Medicine, Division of Rheumatology, The University of Texas Medical School at Houston, 6431 Fannin St., MSB5270, Houston, Texas 77030, USA. E-mail: Xiaodong.zhou@uth.tmc.edu. Accepted for publication August 8, 2018.
Shicheng Guo
From the Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health, Houston, Texas, USA; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai; Department of Rheumatology, Jiangxi People’s Hospital, Nanchang; Department of Rheumatology, Peking University-Shenzhen Hospital, Shenzhen; Life Sciences College, Hubei University, Wuhan, China. Supported by the US National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases 1U01AI09090-01 and NIH P01-052915-01; the Major National Science and Technology Program of China, grant number 2008ZX10002-002; and the Science and Technology Committee of Shanghai Municipality (11410701800). X. Zhou, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; H. Li, MD, PhD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; S. Guo, PhD, Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health; J. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; C. Shi, MD, Department of Rheumatology, Jiangxi People’s Hospital; M. Espitia, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; X. Guo, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Q. Wang, MD, PhD, Department of Rheumatology, Peking University-Shenzhen Hospital; M. Liu, PhD, Life Sciences College, Hubei University; S. Assassi, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; J.D. Reveille, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; M.D. Mayes, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School. Address correspondence to Prof. X. Zhou, Department of Internal Medicine, Division of Rheumatology, The University of Texas Medical School at Houston, 6431 Fannin St., MSB5270, Houston, Texas 77030, USA. E-mail: Xiaodong.zhou@uth.tmc.edu. Accepted for publication August 8, 2018.
Jiucun Wang
From the Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health, Houston, Texas, USA; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai; Department of Rheumatology, Jiangxi People’s Hospital, Nanchang; Department of Rheumatology, Peking University-Shenzhen Hospital, Shenzhen; Life Sciences College, Hubei University, Wuhan, China. Supported by the US National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases 1U01AI09090-01 and NIH P01-052915-01; the Major National Science and Technology Program of China, grant number 2008ZX10002-002; and the Science and Technology Committee of Shanghai Municipality (11410701800). X. Zhou, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; H. Li, MD, PhD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; S. Guo, PhD, Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health; J. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; C. Shi, MD, Department of Rheumatology, Jiangxi People’s Hospital; M. Espitia, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; X. Guo, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Q. Wang, MD, PhD, Department of Rheumatology, Peking University-Shenzhen Hospital; M. Liu, PhD, Life Sciences College, Hubei University; S. Assassi, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; J.D. Reveille, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; M.D. Mayes, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School. Address correspondence to Prof. X. Zhou, Department of Internal Medicine, Division of Rheumatology, The University of Texas Medical School at Houston, 6431 Fannin St., MSB5270, Houston, Texas 77030, USA. E-mail: Xiaodong.zhou@uth.tmc.edu. Accepted for publication August 8, 2018.
Chunhua Shi
From the Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health, Houston, Texas, USA; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai; Department of Rheumatology, Jiangxi People’s Hospital, Nanchang; Department of Rheumatology, Peking University-Shenzhen Hospital, Shenzhen; Life Sciences College, Hubei University, Wuhan, China. Supported by the US National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases 1U01AI09090-01 and NIH P01-052915-01; the Major National Science and Technology Program of China, grant number 2008ZX10002-002; and the Science and Technology Committee of Shanghai Municipality (11410701800). X. Zhou, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; H. Li, MD, PhD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; S. Guo, PhD, Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health; J. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; C. Shi, MD, Department of Rheumatology, Jiangxi People’s Hospital; M. Espitia, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; X. Guo, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Q. Wang, MD, PhD, Department of Rheumatology, Peking University-Shenzhen Hospital; M. Liu, PhD, Life Sciences College, Hubei University; S. Assassi, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; J.D. Reveille, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; M.D. Mayes, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School. Address correspondence to Prof. X. Zhou, Department of Internal Medicine, Division of Rheumatology, The University of Texas Medical School at Houston, 6431 Fannin St., MSB5270, Houston, Texas 77030, USA. E-mail: Xiaodong.zhou@uth.tmc.edu. Accepted for publication August 8, 2018.
Maribel Espitia
From the Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health, Houston, Texas, USA; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai; Department of Rheumatology, Jiangxi People’s Hospital, Nanchang; Department of Rheumatology, Peking University-Shenzhen Hospital, Shenzhen; Life Sciences College, Hubei University, Wuhan, China. Supported by the US National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases 1U01AI09090-01 and NIH P01-052915-01; the Major National Science and Technology Program of China, grant number 2008ZX10002-002; and the Science and Technology Committee of Shanghai Municipality (11410701800). X. Zhou, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; H. Li, MD, PhD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; S. Guo, PhD, Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health; J. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; C. Shi, MD, Department of Rheumatology, Jiangxi People’s Hospital; M. Espitia, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; X. Guo, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Q. Wang, MD, PhD, Department of Rheumatology, Peking University-Shenzhen Hospital; M. Liu, PhD, Life Sciences College, Hubei University; S. Assassi, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; J.D. Reveille, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; M.D. Mayes, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School. Address correspondence to Prof. X. Zhou, Department of Internal Medicine, Division of Rheumatology, The University of Texas Medical School at Houston, 6431 Fannin St., MSB5270, Houston, Texas 77030, USA. E-mail: Xiaodong.zhou@uth.tmc.edu. Accepted for publication August 8, 2018.
Xinjian Guo
From the Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health, Houston, Texas, USA; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai; Department of Rheumatology, Jiangxi People’s Hospital, Nanchang; Department of Rheumatology, Peking University-Shenzhen Hospital, Shenzhen; Life Sciences College, Hubei University, Wuhan, China. Supported by the US National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases 1U01AI09090-01 and NIH P01-052915-01; the Major National Science and Technology Program of China, grant number 2008ZX10002-002; and the Science and Technology Committee of Shanghai Municipality (11410701800). X. Zhou, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; H. Li, MD, PhD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; S. Guo, PhD, Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health; J. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; C. Shi, MD, Department of Rheumatology, Jiangxi People’s Hospital; M. Espitia, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; X. Guo, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Q. Wang, MD, PhD, Department of Rheumatology, Peking University-Shenzhen Hospital; M. Liu, PhD, Life Sciences College, Hubei University; S. Assassi, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; J.D. Reveille, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; M.D. Mayes, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School. Address correspondence to Prof. X. Zhou, Department of Internal Medicine, Division of Rheumatology, The University of Texas Medical School at Houston, 6431 Fannin St., MSB5270, Houston, Texas 77030, USA. E-mail: Xiaodong.zhou@uth.tmc.edu. Accepted for publication August 8, 2018.
Qingwen Wang
From the Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health, Houston, Texas, USA; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai; Department of Rheumatology, Jiangxi People’s Hospital, Nanchang; Department of Rheumatology, Peking University-Shenzhen Hospital, Shenzhen; Life Sciences College, Hubei University, Wuhan, China. Supported by the US National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases 1U01AI09090-01 and NIH P01-052915-01; the Major National Science and Technology Program of China, grant number 2008ZX10002-002; and the Science and Technology Committee of Shanghai Municipality (11410701800). X. Zhou, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; H. Li, MD, PhD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; S. Guo, PhD, Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health; J. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; C. Shi, MD, Department of Rheumatology, Jiangxi People’s Hospital; M. Espitia, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; X. Guo, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Q. Wang, MD, PhD, Department of Rheumatology, Peking University-Shenzhen Hospital; M. Liu, PhD, Life Sciences College, Hubei University; S. Assassi, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; J.D. Reveille, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; M.D. Mayes, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School. Address correspondence to Prof. X. Zhou, Department of Internal Medicine, Division of Rheumatology, The University of Texas Medical School at Houston, 6431 Fannin St., MSB5270, Houston, Texas 77030, USA. E-mail: Xiaodong.zhou@uth.tmc.edu. Accepted for publication August 8, 2018.
Mengyuan Liu
From the Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health, Houston, Texas, USA; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai; Department of Rheumatology, Jiangxi People’s Hospital, Nanchang; Department of Rheumatology, Peking University-Shenzhen Hospital, Shenzhen; Life Sciences College, Hubei University, Wuhan, China. Supported by the US National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases 1U01AI09090-01 and NIH P01-052915-01; the Major National Science and Technology Program of China, grant number 2008ZX10002-002; and the Science and Technology Committee of Shanghai Municipality (11410701800). X. Zhou, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; H. Li, MD, PhD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; S. Guo, PhD, Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health; J. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; C. Shi, MD, Department of Rheumatology, Jiangxi People’s Hospital; M. Espitia, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; X. Guo, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Q. Wang, MD, PhD, Department of Rheumatology, Peking University-Shenzhen Hospital; M. Liu, PhD, Life Sciences College, Hubei University; S. Assassi, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; J.D. Reveille, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; M.D. Mayes, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School. Address correspondence to Prof. X. Zhou, Department of Internal Medicine, Division of Rheumatology, The University of Texas Medical School at Houston, 6431 Fannin St., MSB5270, Houston, Texas 77030, USA. E-mail: Xiaodong.zhou@uth.tmc.edu. Accepted for publication August 8, 2018.
Shervin Assassi
From the Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health, Houston, Texas, USA; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai; Department of Rheumatology, Jiangxi People’s Hospital, Nanchang; Department of Rheumatology, Peking University-Shenzhen Hospital, Shenzhen; Life Sciences College, Hubei University, Wuhan, China. Supported by the US National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases 1U01AI09090-01 and NIH P01-052915-01; the Major National Science and Technology Program of China, grant number 2008ZX10002-002; and the Science and Technology Committee of Shanghai Municipality (11410701800). X. Zhou, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; H. Li, MD, PhD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; S. Guo, PhD, Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health; J. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; C. Shi, MD, Department of Rheumatology, Jiangxi People’s Hospital; M. Espitia, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; X. Guo, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Q. Wang, MD, PhD, Department of Rheumatology, Peking University-Shenzhen Hospital; M. Liu, PhD, Life Sciences College, Hubei University; S. Assassi, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; J.D. Reveille, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; M.D. Mayes, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School. Address correspondence to Prof. X. Zhou, Department of Internal Medicine, Division of Rheumatology, The University of Texas Medical School at Houston, 6431 Fannin St., MSB5270, Houston, Texas 77030, USA. E-mail: Xiaodong.zhou@uth.tmc.edu. Accepted for publication August 8, 2018.
John D. Reveille
From the Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health, Houston, Texas, USA; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai; Department of Rheumatology, Jiangxi People’s Hospital, Nanchang; Department of Rheumatology, Peking University-Shenzhen Hospital, Shenzhen; Life Sciences College, Hubei University, Wuhan, China. Supported by the US National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases 1U01AI09090-01 and NIH P01-052915-01; the Major National Science and Technology Program of China, grant number 2008ZX10002-002; and the Science and Technology Committee of Shanghai Municipality (11410701800). X. Zhou, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; H. Li, MD, PhD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; S. Guo, PhD, Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health; J. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; C. Shi, MD, Department of Rheumatology, Jiangxi People’s Hospital; M. Espitia, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; X. Guo, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Q. Wang, MD, PhD, Department of Rheumatology, Peking University-Shenzhen Hospital; M. Liu, PhD, Life Sciences College, Hubei University; S. Assassi, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; J.D. Reveille, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; M.D. Mayes, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School. Address correspondence to Prof. X. Zhou, Department of Internal Medicine, Division of Rheumatology, The University of Texas Medical School at Houston, 6431 Fannin St., MSB5270, Houston, Texas 77030, USA. E-mail: Xiaodong.zhou@uth.tmc.edu. Accepted for publication August 8, 2018.
Maureen D. Mayes
From the Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health, Houston, Texas, USA; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai; Department of Rheumatology, Jiangxi People’s Hospital, Nanchang; Department of Rheumatology, Peking University-Shenzhen Hospital, Shenzhen; Life Sciences College, Hubei University, Wuhan, China. Supported by the US National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases 1U01AI09090-01 and NIH P01-052915-01; the Major National Science and Technology Program of China, grant number 2008ZX10002-002; and the Science and Technology Committee of Shanghai Municipality (11410701800). X. Zhou, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; H. Li, MD, PhD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; S. Guo, PhD, Human Genetics Center, Division of Biostatistics, The University of Texas School of Public Health; J. Wang, PhD, State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University; C. Shi, MD, Department of Rheumatology, Jiangxi People’s Hospital; M. Espitia, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; X. Guo, BS, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; Q. Wang, MD, PhD, Department of Rheumatology, Peking University-Shenzhen Hospital; M. Liu, PhD, Life Sciences College, Hubei University; S. Assassi, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; J.D. Reveille, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School; M.D. Mayes, MD, Division of Rheumatology, Department of Internal Medicine, University of Texas McGovern Medical School. Address correspondence to Prof. X. Zhou, Department of Internal Medicine, Division of Rheumatology, The University of Texas Medical School at Houston, 6431 Fannin St., MSB5270, Houston, Texas 77030, USA. E-mail: Xiaodong.zhou@uth.tmc.edu. Accepted for publication August 8, 2018.
Abstract
Objective Findings from previous genome-wide association studies indicated an association of the NOTCH4 gene with systemic sclerosis (SSc). This is a followup study to fine-map exonic variants of NOTCH4 in SSc.
Methods All exons of NOTCH4 were sequenced and analyzed in a total of 1006 patients with SSc and 1004 controls of US white ancestry with the Ion Torrent system. Identified SSc-associated variants were confirmed with Sanger sequencing, and then examined in a Chinese Han cohort consisting of 576 patients with SSc and 574 controls. The NOTCH4 variants were analyzed for association with SSc as a whole and with SSc clinical and autoantibody subtypes with and without the influence of specific HLA-class II alleles that had been previously identified as major genetic factors in SSc.
Results A total of 12 SSc-associated and SSc subtype–associated exonic variants of NOTCH4 were identified in the US cohort. Three of them are nonsynonymous single-nucleotide polymorphisms and 1 is a CTG tandem repeat that encodes for a poly-leucine, all of which are located in the NOTCH4 extracellular domain (NECD). Conditional logistic regression analysis on SSc-associated HLA-class II alleles indicated an independent association of the NOTCH4 variants with SSc autoantibody subtypes. Analysis of the Chinese cohort supported a genetic contribution of NOTCH4 to SSc and its subtypes.
Conclusion Multiple NOTCH4 exonic variants were associated with SSc and/or SSc subtypes. Several of these variants encode nonsynonymous sequence changes occurring in the NECD, which implicates a potentially functional effect of NOTCH4.
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In this issue
The Journal of Rheumatology
Vol. 45, Issue 12
1 Dec 2018
Associations of Multiple NOTCH4 Exonic Variants with Systemic Sclerosis
Xiaodong Zhou, Hongye Li, Shicheng Guo, Jiucun Wang, Chunhua Shi, Maribel Espitia, Xinjian Guo, Qingwen Wang, Mengyuan Liu, Shervin Assassi, John D. Reveille, Maureen D. Mayes
The Journal of Rheumatology Nov 2018, jrheum.180094; DOI: 10.3899/jrheum.180094
Associations of Multiple NOTCH4 Exonic Variants with Systemic Sclerosis
Xiaodong Zhou, Hongye Li, Shicheng Guo, Jiucun Wang, Chunhua Shi, Maribel Espitia, Xinjian Guo, Qingwen Wang, Mengyuan Liu, Shervin Assassi, John D. Reveille, Maureen D. Mayes
The Journal of Rheumatology Nov 2018, jrheum.180094; DOI: 10.3899/jrheum.180094
