The FoxO3 gene and cause-specific mortality.

Area of Science:

• Genetics
• Gerontology
• Epidemiology

Background:

• The FOXO3 gene, specifically the G allele of SNP rs2802292, has been consistently associated with longevity across diverse global populations.
• Understanding the specific mortality risks and causes of death linked to this longevity-associated genotype is crucial for aging research.

Purpose of the Study:

• To quantify the mortality risk associated with the longevity-associated FOXO3 genotype (rs2802292 G allele).
• To identify specific causes of death linked to this allele in older American men of diverse ancestry.

Main Methods:

• A 17-year prospective cohort study of 3584 older Japanese American men (Honolulu Heart Program).
• A 17-year prospective replication study of 1595 white and 1056 black elderly individuals (Health Aging and Body Composition cohort).
• Cox proportional hazards models were used to assess cause-specific mortality (coronary heart disease, cancer, stroke) and all-cause mortality in relation to FOXO3 genotype.

Main Results:

• Carriers of the FOXO3 G allele demonstrated a combined 10% reduction in all-cause mortality risk across Japanese, white, and black populations (HR=0.90).
• This survival advantage was predominantly driven by a 26% lower risk of death from coronary heart disease (CHD) (HR=0.74).
• No other significant cause-specific mortality reductions were observed for G allele carriers.

Conclusions:

• At older ages, carrying the FOXO3 G allele is associated with a significant reduction in overall mortality, primarily due to decreased CHD mortality.
• These findings highlight FOXO3 and its protein product as potential therapeutic targets for aging-related diseases, especially cardiovascular disease.