Kazuma Nakagawa1,2,3, Randi Chen1, Steven M Greenberg4, G Webster Ross3,5,6,7, Bradley J Willcox1,7, Timothy A Donlon1,8, Richard C Allsopp9, D Craig Willcox1,10, Brian J Morris1,7,11, Kamal H Masaki1,7. 1. Department of Research, Kuakini Medical Center. 2. Neuroscience Institute, The Queen's Medical Center. 3. Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii. 4. Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston, Massachusetts. 5. Pacific Health Research and Education Institute. 6. Veterans Affairs Pacific Islands Healthcare Systems. 7. Department of Geriatric Medicine. 8. Department of Cell and Molecular Biology. 9. Department of Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA. 10. Department of Human Welfare, Okinawa International University, Ginowan, Okinawa, Japan. 11. School of Medical Sciences, University of Sydney, Sydney, New South Wales, Australia.
Abstract
OBJECTIVE: Since the G allele of forkhead box O3 ( FOXO3 ) single nucleotide polymorphism (SNP) rs2802292 is associated with resilience and longevity, ostensibly by mitigating the adverse effects of chronic cardiometabolic stress on mortality, our aim was to determine the association between the FOXO3 SNP rs2802292 genotype and risk of hypertension-mediated intracerebral haemorrhage (ICH). METHODS: From a prospective population-based cohort of Japanese American men from the Kuakini Honolulu Heart Program (KHHP), age-adjusted prevalence of ICH by hypertension was assessed for the whole cohort after stratifying by FOXO3 genotype. Cox regression models, adjusted for age, cardiovascular risk factors and, FOXO3 and APOE genotypes, were utilized to determine relative risk of hypertension's effect on ICH. All models were created for the whole cohort and stratified by FOXO3 G -allele carriage vs. TT genotype. RESULTS: Among 6469 men free of baseline stroke, FOXO3 G -allele carriage was seen in 3009 (46.5%) participants. Overall, 183 participants developed ICH over the 34-year follow-up period. Age-adjusted ICH incidence was 0.90 vs. 1.32 per 1000 person-years follow-up in those without and with hypertension, respectively ( P = 0.002). After stratifying by FOXO3 genotype, this association was no longer significant in G allele carriers. In the whole cohort, hypertension was an independent predictor of ICH (relative risk [RR] = 1.70, 95% confidence interval [CI] 1.25, 2.32; P = 0.0007). In stratified analyses, hypertension remained an independent predictor of ICH among the FOXO3 TT -genotype group (RR = 2.02, 95% CI 1.33, 3.07; P = 0.001), but not in FOXO3 G -allele carriers (RR = 1.39, 95% CI 0.88, 2.19; P = 0.15). CONCLUSIONS: The longevity-associated FOXO3 G allele may attenuate the impact of hypertension on ICH risk.
OBJECTIVE: Since the G allele of forkhead box O3 ( FOXO3 ) single nucleotide polymorphism (SNP) rs2802292 is associated with resilience and longevity, ostensibly by mitigating the adverse effects of chronic cardiometabolic stress on mortality, our aim was to determine the association between the FOXO3 SNP rs2802292 genotype and risk of hypertension-mediated intracerebral haemorrhage (ICH). METHODS: From a prospective population-based cohort of Japanese American men from the Kuakini Honolulu Heart Program (KHHP), age-adjusted prevalence of ICH by hypertension was assessed for the whole cohort after stratifying by FOXO3 genotype. Cox regression models, adjusted for age, cardiovascular risk factors and, FOXO3 and APOE genotypes, were utilized to determine relative risk of hypertension's effect on ICH. All models were created for the whole cohort and stratified by FOXO3 G -allele carriage vs. TT genotype. RESULTS: Among 6469 men free of baseline stroke, FOXO3 G -allele carriage was seen in 3009 (46.5%) participants. Overall, 183 participants developed ICH over the 34-year follow-up period. Age-adjusted ICH incidence was 0.90 vs. 1.32 per 1000 person-years follow-up in those without and with hypertension, respectively ( P = 0.002). After stratifying by FOXO3 genotype, this association was no longer significant in G allele carriers. In the whole cohort, hypertension was an independent predictor of ICH (relative risk [RR] = 1.70, 95% confidence interval [CI] 1.25, 2.32; P = 0.0007). In stratified analyses, hypertension remained an independent predictor of ICH among the FOXO3 TT -genotype group (RR = 2.02, 95% CI 1.33, 3.07; P = 0.001), but not in FOXO3 G -allele carriers (RR = 1.39, 95% CI 0.88, 2.19; P = 0.15). CONCLUSIONS: The longevity-associated FOXO3 G allele may attenuate the impact of hypertension on ICH risk.
Authors: A Kagan; B R Harris; W Winkelstein; K G Johnson; H Kato; S L Syme; G G Rhoads; M L Gay; M Z Nichaman; H B Hamilton; J Tillotson Journal: J Chronic Dis Date: 1974-09
Authors: Daniel Woo; Laura R Sauerbeck; Brett M Kissela; Jane C Khoury; Jerzy P Szaflarski; James Gebel; Rakesh Shukla; Arthur M Pancioli; Edward C Jauch; Anil G Menon; Ranjan Deka; Janice A Carrozzella; Charles J Moomaw; Robert N Fontaine; Joseph P Broderick Journal: Stroke Date: 2002-05 Impact factor: 7.914
Authors: Sandro Marini; Katherine Crawford; Andrea Morotti; Myung J Lee; Alessandro Pezzini; Charles J Moomaw; Matthew L Flaherty; Joan Montaner; Jaume Roquer; Jordi Jimenez-Conde; Eva Giralt-Steinhauer; Roberto Elosua; Elisa Cuadrado-Godia; Carolina Soriano-Tarraga; Agnieszka Slowik; Jeremiasz M Jagiella; Joanna Pera; Andrzej Urbanik; Alexander Pichler; Björn M Hansen; Jacob L McCauley; David L Tirschwell; Magdy Selim; Devin L Brown; Scott L Silliman; Bradford B Worrall; James F Meschia; Chelsea S Kidwell; Fernando D Testai; Steven J Kittner; Helena Schmidt; Christian Enzinger; Ian J Deary; Kristiina Rannikmae; Neshika Samarasekera; Rustam Al-Shahi Salman; Catherine L Sudlow; Catharina J M Klijn; Koen M van Nieuwenhuizen; Israel Fernandez-Cadenas; Pilar Delgado; Bo Norrving; Arne Lindgren; Joshua N Goldstein; Anand Viswanathan; Steven M Greenberg; Guido J Falcone; Alessandro Biffi; Carl D Langefeld; Daniel Woo; Jonathan Rosand; Christopher D Anderson Journal: JAMA Neurol Date: 2019-04-01 Impact factor: 18.302
Authors: Shannon M Fernando; Danial Qureshi; Robert Talarico; Peter Tanuseputro; Dar Dowlatshahi; Manish M Sood; Eric E Smith; Michael D Hill; Victoria A McCredie; Damon C Scales; Shane W English; Bram Rochwerg; Kwadwo Kyeremanteng Journal: Stroke Date: 2021-03-09 Impact factor: 7.914