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The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature.

ABSTRACT: Although both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling were shown to regulate life span in lower organisms, the role of GH signaling in human longevity remains unclear. Because a GH receptor exon 3 deletion (d3-GHR) appears to modulate GH sensitivity in humans, we hypothesized that this polymorphism could play a role in human longevity. We report a linear increased prevalence of d3-GHR homozygosity with age in four independent cohorts of long-lived individuals: 841 participants [567 of the Longevity Genes Project (LGP) (8% increase; P = 0.01), 152 of the Old Order Amish (16% increase; P = 0.02), 61 of the Cardiovascular Health Study (14.2% increase; P = 0.14), and 61 of the French Long-Lived Study (23.5% increase; P = 0.02)]. In addition, mega analysis of males in all cohorts resulted in a significant positive trend with age (26% increase; P = 0.007), suggesting sexual dimorphism for GH action in longevity. Further, on average, LGP d3/d3 homozygotes were 1 inch taller than the wild-type (WT) allele carriers (P = 0.05) and also showed lower serum IGF-1 levels (P = 0.003). Multivariate regression analysis indicated that the presence of d3/d3 genotype adds approximately 10 years to life span. The LGP d3/d3-GHR transformed lymphocytes exhibited superior growth and extracellular signal-regulated kinase activation, to GH treatment relative to WT GHR lymphocytes (P < 0.01), indicating a GH dose response. The d3-GHR variant is a common genetic polymorphism that modulates GH responsiveness throughout the life span and positively affects male longevity.

SUBMITTER: Ben-Avraham D

PROVIDER: S-EPMC5473676 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature.

Ben-Avraham Danny D Govindaraju Diddahally R DR Budagov Temuri T Fradin Delphine D Durda Peter P Liu Bing B Ott Sandy S Gutman Danielle D Sharvit Lital L Kaplan Robert R Bougnères Pierre P Reiner Alex A Shuldiner Alan R AR Cohen Pinchas P Barzilai Nir N Atzmon Gil G

Science advances 20170616 6

Although both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling were shown to regulate life span in lower organisms, the role of GH signaling in human longevity remains unclear. Because a GH receptor exon 3 deletion (<i>d3-GHR</i>) appears to modulate GH sensitivity in humans, we hypothesized that this polymorphism could play a role in human longevity. We report a linear increased prevalence of <i>d3-GHR</i> homozygosity with age in four independent cohorts of long-lived ind ...[more]

PMID: 28630896

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Project description:Objective/purposeThe aryl hydrocarbon receptor (AHR) pathway plays a critical role in the biology of Growth Hormone (GH)-secreting pituitary tumor (somatotropinoma). Germline rs2066853 AHR variant was found to be more frequent among acromegaly patients and associated with a more severe disease with larger invasive somatropinoma, and with resistance to somatostatin analogs treatment in patients living in polluted areas. However, no somatic changes in AHR gene have been reported so far in acromegaly patients. On that basis, the aim of the study was to assess at the somatic level the AHR gene status encompassing exon 10 region, also because of the high rate of variants found in this genomic region.MethodsA cohort of 13 patients aged 20-76 years with biochemical, clinical and histological diagnosis of somatotropinoma was studied. DNA and RNA from pituitary tumor histological samples have been extracted and analyzed by PCR and direct sequencing for AHR gene variants, and compared with corresponding patients' germline DNA as well as normal pituitary tissue as reference control.ResultsA degenerated letter codes in the region corresponding to AHR exon 10 (c.1239-c.2056) was detected in somatotropinomas-derived DNA but not in that of matched germline and pituitary normal tissue. By multiple PCR and sequencing analysis, we observed amplification only before codon 1246 and after codon 1254, confirming the presence of a tumor-restricted somatic deletion in the 5' upstream region of AHR exon 10. Analysis of PCR-amplified cDNA revealed a wildtype sequence of exon 9 and 10 in normal pituitary tissue, and a wildtype sequence of exon 9 and 10 up to codon 1246 and no sequence after the deletion region (c.1246-c.1254) in 6 out of 9 tumor samples. Patients carrying the germline rs2066853 AHR variant showed no somatic LOH at the corresponding genetic locus.ConclusionThis is the first demonstration of a recurrent somatic deletion in the exon 10 of the AHR gene in somatotropinomas. The functional impact of this genetic finding needs to be clarified.

Dataset Information

The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature.

Publications

The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature.

Similar Datasets

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