Yoichiro Otaki1, Tetsu Watanabe2, Junya Sato1, Yuta Kobayashi1, Tomonori Aono1, Yuji Saito1, Jun Goto1, Hiroki Takahashi1, Takanori Arimoto1, Hidenori Sato3, Tsuneo Konta4, Yoshiyuki Ueno5, Masafumi Watanabe1. 1. Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan. 2. Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan. tewatana@med.id.yamagata-u.ac.jp. 3. Genome Informatics Unit, Institute for Promotion of Medical Science Research, Faculty of Medicine, Yamagata University, Yamagata, Japan. 4. Department of Public Health and Hygiene, Yamagata University School of Medicine, Yamagata, Japan. 5. Global Center of Excellence Program Study Group, Yamagata University School of Medicine, Yamagata, Japan.
Abstract
BACKGROUND: Nephronophthisis (NPHP) 4 gene encoding nephrocystin-4, which contributes to end-stage renal disease in children and young adults, is involved in the development of the heart and kidneys. Cardiorenal syndrome (CRS), which consists of bidirectional dysfunction of the heart and kidneys, is a risk factor for cardiovascular events. Single-nucleotide polymorphisms (SNPs) within the NPHP4 gene are reportedly associated with kidney function, even in adults. However, the association of NPHP4 gene variability with CRS and cardiovascular events remains unknown. METHODS AND RESULTS: This prospective cohort study included 2946 subjects who participated in a community-based health study with a 16-year follow-up period. We genotyped 11 SNPs within the NPHP4 gene whose minor allele frequency was greater than 0.1 in the Japanese population. The SNP rs12058375 was significantly associated with CRS and cardiovascular events. Multivariate logistic analysis demonstrated a significant association between the homozygous A-allele of rs12058375 with the presence of CRS. Haplotype analysis identified the haplotype with the A-allele of rs12058375 as an increased susceptibility factor for CRS. Kaplan-Meier analysis demonstrated that homozygous A-allele carriers of rs12058375 had the greatest risk of developing cardiovascular events among the NPHP4 variants. Multivariate Cox proportional hazard regression analysis revealed that the homozygous A-allele and heterozygous carriers of rs12058375 were associated with cardiovascular events after adjusting for confounding factors. The net reclassification index and integrated discrimination index were significantly improved by the addition of rs12058375 as a cardiovascular risk factor. CONCLUSION: Genetic variations in the NPHP4 gene were associated with CRS and cardiovascular events in the general population, suggesting that it may facilitate the early identification of high-risk subjects with CRS and cardiovascular events.
BACKGROUND: Nephronophthisis (NPHP) 4 gene encoding nephrocystin-4, which contributes to end-stage renal disease in children and young adults, is involved in the development of the heart and kidneys. Cardiorenal syndrome (CRS), which consists of bidirectional dysfunction of the heart and kidneys, is a risk factor for cardiovascular events. Single-nucleotide polymorphisms (SNPs) within the NPHP4 gene are reportedly associated with kidney function, even in adults. However, the association of NPHP4 gene variability with CRS and cardiovascular events remains unknown. METHODS AND RESULTS: This prospective cohort study included 2946 subjects who participated in a community-based health study with a 16-year follow-up period. We genotyped 11 SNPs within the NPHP4 gene whose minor allele frequency was greater than 0.1 in the Japanese population. The SNP rs12058375 was significantly associated with CRS and cardiovascular events. Multivariate logistic analysis demonstrated a significant association between the homozygous A-allele of rs12058375 with the presence of CRS. Haplotype analysis identified the haplotype with the A-allele of rs12058375 as an increased susceptibility factor for CRS. Kaplan-Meier analysis demonstrated that homozygous A-allele carriers of rs12058375 had the greatest risk of developing cardiovascular events among the NPHP4 variants. Multivariate Cox proportional hazard regression analysis revealed that the homozygous A-allele and heterozygous carriers of rs12058375 were associated with cardiovascular events after adjusting for confounding factors. The net reclassification index and integrated discrimination index were significantly improved by the addition of rs12058375 as a cardiovascular risk factor. CONCLUSION: Genetic variations in the NPHP4 gene were associated with CRS and cardiovascular events in the general population, suggesting that it may facilitate the early identification of high-risk subjects with CRS and cardiovascular events.
Authors: Alexander G Bick; James P Pirruccello; Gabriel K Griffin; Namrata Gupta; Stacey Gabriel; Danish Saleheen; Peter Libby; Sekar Kathiresan; Pradeep Natarajan Journal: Circulation Date: 2019-11-11 Impact factor: 29.690
Authors: Donald M Lloyd-Jones; Martin G Larson; Eric P Leip; Alexa Beiser; Ralph B D'Agostino; William B Kannel; Joanne M Murabito; Ramachandran S Vasan; Emelia J Benjamin; Daniel Levy Journal: Circulation Date: 2002-12-10 Impact factor: 29.690
Authors: Caroline S Fox; Qiong Yang; L Adrienne Cupples; Chao-Yu Guo; Martin G Larson; Eric P Leip; Peter W F Wilson; Daniel Levy Journal: J Am Soc Nephrol Date: 2004-09 Impact factor: 10.121