Association with Longevity of Phosphatidylinositol 3-Kinase Regulatory Subunit 1 Gene Variants Stems from Protection against Mortality Risk in Men with Cardiovascular Disease

Introduction: Genetic variation in the phosphatidylinositol 3-kinase reregulatory subunit 1 gene (PIK3R1) is associated with longevity.

Objective: The aim of the study was to determine whether cardiovascular disease (CVD) affects this association.

Methods: We performed a longitudinal study of longevity-associated PIK3R1 single-nucleotide polymorphism rs7709243 genotype by CVD status in 3,584 elderly American men of Japanese ancestry.

Results: At baseline (1991-1993), 2,254 subjects had CVD and 1,314 did not. The follow-up until Dec 31, 2019 found that overall, men with a CVD had higher mortality than men without a CVD (p = 1.7 × 10-5). However, survival curves of CVD subjects differed according to PIK3R1 genotype. Those with longevity-associated PIK3R1 TT/CC had survival curves similar to those of subjects without a CVD (p = 0.11 for TT/CC, and p = 0.054 for TC), whereas survival curves for CVD subjects with the CT genotype were significantly attenuated compared with survival curves of subjects without a CVD (p = 0.0000012 compared with TT/CC, and p = 0.0000028 compared with TC). Men without CVD showed no association of longevity-associated genotype with life span (p = 0.58). Compared to subjects without any CVD, hazard ratios for mortality risk were 1.26 (95% CI, 1.14-1.39; p = 0.0000043) for CT subject with CVD and 1.07 (95% CI 0.99-1.17; p = 0.097) for CC/TT subjects with CVD. There was no genotypic effect on life span for 1,007 subjects with diabetes and 486 with cancer.

Conclusion: Our study provides novel insights into the basis for PIK3R1 as a longevity gene. We suggest that the PIK3R1 longevity genotype attenuates mortality risk in at-risk individuals by protection against cellular stress caused by CVD.