Dataset Information

Forkhead box O3 longevity genotype may attenuate the impact of hypertension on risk of intracerebral haemorrhage.

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.

SUBMITTER: Nakagawa K

PROVIDER: S-EPMC9553272 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

Forkhead box O3 longevity genotype may attenuate the impact of hypertension on risk of intracerebral haemorrhage.

Nakagawa Kazuma K Chen Randi R Greenberg Steven M SM Ross G Webster GW Willcox Bradley J BJ Donlon Timothy A TA Allsopp Richard C RC Willcox D Craig DC Morris Brian J BJ Masaki Kamal H KH

Journal of hypertension 20220803 11

<h4>Objective</h4>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).<h4>Methods</h4>From a prospective population-based cohort of Japanese American men from the Kuakini ...[more]

PMID: 35943066

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Project description:Intracerebral haemorrhage in the elderly is a severe manifestation of common forms of cerebral small vessel disease. Nearly 60% of intracerebral haemorrhage survivors will develop clinical manifestations of small vessel disease progression including recurrent haemorrhage, ischaemic stroke, dementia, late-life depression and gait impairment within 5 years. Blood pressure measurements following intracerebral haemorrhage are strongly associated with this risk. However, aggressive blood pressure lowering in the elderly carries substantial risks. In order to determine whether there might be an opportunity to select individuals at the highest risk for small vessel disease progression for aggressive blood pressure reduction, we investigated whether APOE gene variants ɛ2/ɛ4 modify the association between blood pressure and small vessel disease clinical progression after intracerebral haemorrhage. We conducted a single-centre longitudinal study at a tertiary care referral centre (Massachusetts General Hospital in Boston, MA, USA), analysing 716 consecutive survivors of acute intracerebral haemorrhage, enrolled from January 2006 to December 2016. We conducted research interviews at the time of enrolment and obtained APOE genotypes from peripheral venous blood samples. We followed patients longitudinally by means of validated phone-based research encounters, aimed at gathering measurements of systolic and diastolic blood pressure, as well as information on small vessel disease clinical outcomes (including recurrent haemorrhage, incident ischaemic stroke, incident dementia, incident depression and incident gait impairment). APOE ε4 and systolic blood pressure were associated with the risk of recurrent haemorrhage, ischaemic stroke and post-haemorrhage dementia, depression and gait impairment (all P < 0.05). APOE ε4 and systolic blood pressure interacted to increase the risk of recurrent haemorrhage, ischaemic stroke, dementia and gait impairment (all interaction P < 0.05). Among patients with elevated blood pressure following intracerebral haemorrhage (average systolic blood pressure 120-129 mmHg and diastolic blood pressure <80 mmHg) only those with one or more APOE ε4 copies were at increased risk for one or more small vessel disease outcomes (hazard ratio = 1.97, 95% confidence interval 1.17-3.31). Among haemorrhage survivors with hypertension (stage 1 and beyond) APOE genotype also stratified risk for all small vessel disease outcomes. In conclusion, APOE genotype modifies the already strong association of hypertension with multiple small vessel disease clinical outcomes among intracerebral haemorrhage survivors. These data raise the possibility that genetic screening could inform blood pressure treatment goals in this patient population.

Project description:BackgroundFerroptosis is a nonapoptotic cell death process that is characterized by lipid peroxidation and intracellular iron accumulation. As osteoarthritis (OA) progresses, inflammation or iron overload induces ferroptosis of chondrocytes. However, the genes that play a vital role in this process are still poorly studied.MethodsFerroptosis was elicited in the ATDC5 chondrocyte cell line and primary chondrocytes by administration of the proinflammatory cytokines, interleukin (IL)-1β and tumor necrosis factor (TNF)-α, which play key roles in OA. The effect of FOXO3 expression on apoptosis, extracellular matrix (ECM) metabolism, and ferroptosis in ATDC5 cells and primary chondrocytes was verified by western blot, Immunohistochemistry (IMHC), immunofluorescence (IF) and measuring Malondialdehyde (MDA) and Glutathione (GSH) levels. The signal cascades that modulated FOXO3-mediated ferroptosis were identified by using chemical agonists/antagonists and lentivirus. In vivo experiments were performed following destabilization of medial meniscus surgery on 8-week-old C57BL/6 mice and included micro-computed tomography measurements.ResultsIn vitro administration of IL-1β and TNF-α, to ATDC5 cells or primary chondrocytes induced ferroptosis. In addition, the ferroptosis agonist, erastin, and the ferroptosis inhibitor, ferrostatin-1, downregulated or upregulated the protein expression of forkhead box O3 (FOXO3), respectively. This, suggested, for the first time, that FOXO3 may regulate ferroptosis in articular cartilage. Our results further suggested that FOXO3 regulated ECM metabolism via the ferroptosis mechanism in ATDC5 cells and primary chondrocytes. Moreover, a role for the NF-κB/mitogen-activated protein kinase (MAPK) signaling cascade in regulating FOXO3 and ferroptosis was demonstrated. In vivo experiments confirmed the rescue effect of intra-articular injection of a FOXO3-overexpressing lentivirus against erastin-aggravated OA.ConclusionsThe results of our study show that the activation of ferroptosis promotes chondrocyte death and disrupts the ECM both in vivo and in vitro. In addition, FOXO3 can reduce OA progression by inhibiting ferroptosis through the NF-κB/MAPK signaling pathway.The translational potential of this articleThis study highlights the important role of chondrocyte ferroptosis regulated by FOXO3 through the NF-κB/MAPK signaling in the progression of OA. The inhibition of chondrocyte ferroptosis by activating FOXO3 is expected to be a new target for the treatment of OA.

Dataset Information

Forkhead box O3 longevity genotype may attenuate the impact of hypertension on risk of intracerebral haemorrhage.

Objective

Methods

Results

Conclusions

Publications

Forkhead box O3 longevity genotype may attenuate the impact of hypertension on risk of intracerebral haemorrhage.

Similar Datasets

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