Research Paper Volume 13, Issue 11 pp 14745—14767
Association of growth hormone receptor gene variant with longevity in men is due to amelioration of increased mortality risk from hypertension
- 1 Department of Research, Kuakini Medical Center, Honolulu, HI 96817, USA
- 2 Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA
- 3 Department of Pathology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA
- 4 Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96817, USA
- 5 Department of Human Welfare, Okinawa International University, Ginowan, Okinawa 901-2701, Japan
- 6 Institute for Biogenesis Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96822, USA
- 7 School of Medical Sciences, University of Sydney, Sydney, New South Wales 2006, Australia
Received: March 19, 2021 Accepted: May 20, 2021 Published: June 1, 2021https://doi.org/10.18632/aging.203133
How to Cite
Copyright: © 2021 Donlon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.