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

Abstract

The single nucleotide polymorphism (SNP) rs4130113 of the growth hormone receptor gene (GHR) 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. Rs4130113 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, p = 4.3 x10^-4]. But in individuals with diabetes, CHD, and cancer there was no genotypic difference in lifespan. As expected, normotensive men outlived men with hypertension (p = 0.036). There was no effect, however, of genotypic difference on lifespan in normotensive men (p = 0.11). We found that SNP rs4130113 potentially influenced the binding of transcription factors E2A, MYF, NRSF, TAL1, and TCF12 so as to alter GHR expression. We propose that in individuals with hypertension, longevity-associated genetic variation in GHR 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 GHR live as long as normotensive men.

Keywords: growth hormone receptor; hypertension; longevity; mortality.

Figure 1

Survival curves spanning the period from baseline (1991–1993) to Dec 31, 2019 for subjects with and without hypertension according to genotypes of GHR SNP rs4130113. The survival probabilities were estimated from the Cox proportional hazard model: h(t) = h(t0) * exp(β1*Age + β2*BMI + β3*glucose + β4*hypertension + β5*GHR_AG + β6* (hypertension*GHR_ AG)), by fixing age at 75 years, BMI at the mean, 23.5 kg/m², and glucose at the mean, 113 mg/dL (where β6 is the effect of the interaction of hypertension with GHR genotype on mortality, for AG vs AA/GG, i.e., a heterozygote disadvantage model, giving p(β6) = 0.0004). Survival curves of AG vs. AA/GG for hypertensive subjects and subjects without hypertension (p = 0.0003 and p = 0.14, respectively). In men with hypertension who had the longevity-associated genotype AA and those with the GG genotype, the mortality risk was reduced to a level not significantly different from subjects without hypertension (hypertensive AA/GG vs. normotensive AA/GG: p = 0.20; hypertensive AA/GG vs normotensive AG: p = 0.78).

Figure 2

Mortality risk (hazard ratio), adjusted for age, BMI and glucose, for hypertensive subjects and normotensive subjects according to genotype of GHR SNP rs4130113 in heterozygote disadvantage model, AG vs. AA/GG. It can be seen that in men with hypertension who had a longevity-associated genotype, mortality risk was reduced to normal in that it did not differ significantly from the survival curves of normotensive men.