Association of growth hormone receptor gene variant with longevity in men is due to amelioration of increased mortality risk from hypertension.

The single nucleotide polymorphism (SNP) of the growth hormone receptor gene () is associated with longevity. Here we explored whether longevity-associated genotypes protect against mortality in all individuals, or only in individuals with aging-related diseases. genotypes were tested for association with mortality in 3,557 elderly American men of Japanese ancestry. At baseline (1991-1993), 1,000 had diabetes, 730 had coronary heart disease (CHD), 1,901 had hypertension, 485 had cancer, and 919 lacked these diseases. The men were followed from baseline until Dec 31, 2019 or death (mean 10.8 ± 6.5 SD years, range 0.01-28.8 years; 99.0% deceased by that date). In a heterozygote disadvantage model, longevity-associated genotypes were associated with significantly lower mortality risk in individuals having hypertension (covariate-adjusted hazard ratio [HR] 0.83 [95% CI: 0.76-0.93, = 4.3 x10]. But in individuals with diabetes, CHD, and cancer there was no genotypic difference in lifespan. As expected, normotensive men outlived men with hypertension ( = 0.036). There was no effect, however, of genotypic difference on lifespan in normotensive men ( = 0.11). We found that SNP potentially influenced the binding of transcription factors E2A, MYF, NRSF, TAL1, and TCF12 so as to alter expression. We propose that in individuals with hypertension, longevity-associated genetic variation in enhances cell resilience mechanisms to help protect against cellular stress caused by hypertension. As a result, hypertension-affected men who possess the longevity-associated genetic variant of live as long as normotensive men.