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

Science Advances

Volumn 3, Issue 6, 2017, Pages

  Ben Avraham, Danny ^a   Govindaraju, Diddahally R ^a,b   Budagov, Temuri ^a   Fradin, Delphine ^c   Durda, Peter ^d   Liu, Bing ^e   Ott, Sandy ^f   Gutman, Danielle ^g   Sharvit, Lital ^g   Kaplan, Robert ^a   Bougnères, Pierre ^c,h   Reiner, Alex ^i,j   Shuldiner, Alan R ^f,k   Cohen, Pinchas ^e   Barzilai, Nir ^a   Atzmon, Gil ^a,g  

^a ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^b HARVARD UNIVERSITY   (United States)

^c INSERM   (France)

^d UNIVERSITY OF VERMONT COLLEGE OF MEDICINE   (United States)

^e UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^f UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

^g UNIVERSITY OF HAIFA   (Israel)

^h Bicetre Hospital   (France)

ⁱ UNIVERSITY OF WASHINGTON   (United States)

^j USA   (United States)

^k BALTIMORE VA MEDICAL CENTER   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

CHEMICAL ACTIVATION; LYMPHOCYTES; MULTIVARIANT ANALYSIS; REGRESSION ANALYSIS;

DOSE RESPONSE; EXTRACELLULAR SIGNALS; GENETIC POLYMORPHISMS; GROWTH HORMONES; INSULIN-LIKE GROWTH FACTOR 1; MULTIVARIATE REGRESSION ANALYSIS; REGULATED KINASE; SEXUAL DIMORPHISM;

SYNTHESIS GAS MANUFACTURE;

GROWTH HORMONE RECEPTOR; HUMAN GROWTH HORMONE; IGF1 PROTEIN, HUMAN; SOMATOMEDIN C;

BODY HEIGHT; EXON; FEMALE; GENE DELETION; GENETIC ASSOCIATION STUDY; GENETIC POLYMORPHISM; GENETICS; HUMAN; KAPLAN MEIER METHOD; LONGEVITY; MALE; METABOLISM; PHENOTYPE; QUANTITATIVE TRAIT;

BODY HEIGHT; EXONS; FEMALE; GENETIC ASSOCIATION STUDIES; HUMAN GROWTH HORMONE; HUMANS; INSULIN-LIKE GROWTH FACTOR I; KAPLAN-MEIER ESTIMATE; LONGEVITY; MALE; PHENOTYPE; POLYMORPHISM, GENETIC; QUANTITATIVE TRAIT, HERITABLE; RECEPTORS, SOMATOTROPIN; SEQUENCE DELETION;

EID: 85029723998     PISSN: None     EISSN: 23752548     Source Type: Journal    
DOI: 10.1126/sciadv.1602025     Document Type: Article

References (56)

1. M. Barbieri, M. Bonafè, C. Franceschi, G. Paolisso, Insulin/IGF-I-signaling pathway: An evolutionarily conserved mechanism of longevity from yeast to humans. Am. J. Physiol. 285, E1064–E1071 (2003).
2. Q. Fu, X. Yu, C. W. Callaway, R. H. Lane, R. A. McKnight, Epigenetics: Intrauterine growth retardation (IUGR) modifies the histone code along the rat hepatic IGF-1 gene. FASEB J. 23, 2438–2449 (2009).
3. A. M. Oberbauer, The regulation of IGF-1 gene transcription and splicing during development and aging. Front. Endocrinol. 4, 39 (2013).
4. J. Yang, M. Anzo, P. Cohen, Control of aging and longevity by IGF-I signaling. Exp. Gerontol. 40, 867–872 (2005).
5. A. Bartke, Healthspan and longevity can be extended by suppression of growth hormone signaling. Mamm. Genome 27, 289–299 (2016).
6. Y. Suh, G. Atzmon, M.-O. Cho, D. Hwang, B. Liu, D. J. Leahy, N. Barzilai, P. Cohen, Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc. Natl. Acad. Sci. U.S.A. 105, 3438–3442 (2008).
7. J. Guevara-Aguirre, P. Balasubramanian, M. Guevara-Aguirre, M. Wei, F. Madia, C.-W. Cheng, D. Hwang, A. Martin-Montalvo, J. Saavedra, S. Ingles, R. de Cabo, P. Cohen, V. D. Longo, Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci. Transl. Med. 3, 70ra13 (2011).
8. S. Milman, G. Atzmon, D. M. Huffman, J. Wan, J. P. Crandall, P. Cohen, N. Barzilai, Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity. Aging Cell 13, 769–771 (2014).
9. A. Besson, S. Salemi, S. Gallati, A. Jenal, R. Horn, P. S. Mullis, P. E. Mullis, Reduced longevity in untreated patients with isolated growth hormone deficiency. J. Clin. Endocrinol. Metab. 88, 3664–3667 (2003).
10. C. Höybye, J. S. Christiansen, Growth hormone replacement in adults—Current standards and new perspectives. Best Pract. Res. Clin. Endocrinol. Metab. 29, 115–123 (2015).
11. A. Bartke, Pleiotropic effects of growth hormone signaling in aging. Trends Endocrinol. Metab. 22, 437–442 (2011).
12. E. van der Spoel, S. W. Jansen, A. A. Akintola, B. E. Ballieux, C. M. Cobbaert, P. E. Slagboom, G. J. Blauw, R. G. J. Westendorp, H. Pijl, F. Roelfsema, D. van Heemst, Growth hormone secretion is diminished and tightly controlled in humans enriched for familial longevity. Aging Cell 15, 1126–1131 (2016).
13. P. J. Godowski, D. W. Leung, L. R. Meacham, J. P. Galgani, R. Hellmiss, R. Keret, P. S. Rotwein, J. S. Parks, Z. Laron, W. I. Wood, Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron-type dwarfism. Proc. Natl. Acad. Sci. U.S.A. 86, 8083–8087 (1989).
14. A. A. Palizban, M. Radmansorry, M. Bozorgzad, Exon 3-deleted and full-length growth hormone receptor polymorphism frequencies in an Iranian population. Res. Pharm. Sci. 9, 489–494 (2014).
15. J. Pantel, K. Machinis, M.-L. Sobrier, P. Duquesnoy, M. Goossens, S. Amselem, Species-specific alternative splice mimicry at the growth hormone receptor locus revealed by the lineage of retroelements during primate evolution. J. Biol. Chem. 275, 18664–18669 (2000).
16. C. Dos Santos, L. Essioux, C. Teinturier, M. Tauber, V. Goffin, P. Bougnères, A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat. Genet. 36, 720–724 (2004).
17. A. A. L. Jorge, F. G. Marchisotti, L. R. Montenegro, L. R. Carvalho, B. B. Mendonca, I. J. P. Arnhold, Growth hormone (GH) pharmacogenetics: Influence of GH receptor exon 3 retention or deletion on first-year growth response and final height in patients with severe GH deficiency. J. Clin. Endocrinol. Metab. 91, 1076–1080 (2006).
18. G. Binder, F. Baur, R. Schweizer, M. B. Ranke, The d3-growth hormone (GH) receptor polymorphism is associated with increased responsiveness to GH in Turner syndrome and short small-for-gestational-age children. J. Clin. Endocrinol. Metab. 91, 659–664 (2006).
19. L. Audi, C. Esteban, A. Carrascosa, R. Espadero, A. Pérez-Arroyo, R. Arjona, M. Clemente, H. Wollmann, L. Fryklund, L. A. Parodi; Spanish SGA Study Group, Exon 3-deleted/full-length growth hormone receptor polymorphism genotype frequencies in Spanish short small-for-gestational-age (SGA) children and adolescents (n = 247) and in an adult control population (n = 289) show increased fl/fl in short SGA. J. Clin. Endocrinol. Metab. 91, 5038–5043 (2006).
20. A. G. Renehan, M. Solomon, M. Zwahlen, R. Morjaria, A. Whatmore, L. Audi, G. Binder, W. Blum, P. Bougnères, C. Dos Santos, A. Carrascosa, A. Hokken-Koelega, A. Jorge, P. E. Mullis, M. Tauber, L. Patel, P. E. Clayton, Growth hormone receptor polymorphism and growth hormone therapy response in children: A Bayesian meta-analysis. Am. J. Epidemiol. 175, 867–877 (2012).
21. M. J. E. Wassenaar, O. M. Dekkers, A. M. Pereira, J. M. Wit, J. W. Smit, N. R. Biermasz, J. A. Romijn, Impact of the exon 3-deleted growth hormone (GH) receptor polymorphism on baseline height and the growth response to recombinant human GH therapy in GH-deficient (GHD) and non-GHD children with short stature: A systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 94, 3721–3730 (2009).
22. M. Zoledziewska, C. Sidore, C. W. K. Chiang, S. Sanna, A. Mulas, M. Steri, F. Busonero, J. H. Marcus, M. Marongiu, A. Maschio, D. O. Del Vecchyo, M. Floris, A. Meloni, A. Delitala, M. P. Concas, F. Murgia, G. Biino, S. Vaccargiu, R. Nagaraja, K. E. Lohmueller; UK10K Consortium, N. J. Timpson, N. Soranzo, I. Tachmazidou, G. Dedoussis, E. Zeggini; Understanding Society Scientific Group, S. Uzzau, C. Jones, R. Lyons, A. Angius, G. R. Abecasis, J. Novembre, D. Schlessinger, F. Cucca, Height-reducing variants and selection for short stature in Sardinia. Nat. Genet. 47, 1352–1356 (2015).
23. M. B. Lanktree, Y. Guo, M. Murtaza, J. T. Glessner, S. D. Bailey, N. C. Onland-Moret, G. Lettre, H. Ongen, R. Rajagopalan, T. Johnson, H. Shen, C. P. Nelson, N. Klopp, J. Baumert, S. Padmanabhan, N. Pankratz, J. S. Pankow, S. Shah, K. Taylor, J. Barnard, B. J. Peters, C. M. Maloney, M. T. Lobmeyer, A. Stanton, M. H. Zafarmand, S. P. R. Romaine, A. Mehta, E. P. A. van Iperen, Y. Gong, T. S. Price, E. N. Smith, C. E. Kim, Y. R. Li, F. W. Asselbergs, L. D. Atwood, K. M. Bailey, D. Bhatt, F. Bauer, E. R. Behr, T. Bhangale, J. M. A. Boer, B. O. Boehm, J. P. Bradfield, M. Brown, P. S. Braund, P. R. Burton, C. Carty, H. R. Chandrupatla, W. Chen, J. Connell, C. Dalgeorgou, A. de Boer, F. Drenos, C. C. Elbers, J. C. Fang, C. S. Fox, E. C. Frackelton, B. Fuchs, C. E. Furlong, Q. Gibson, C. Gieger, A. Goel, D. E. Grobbee, C. Hastie, P. J. Howard, G.-H. Huang, W. C. Johnson, Q. Li, M. E. Kleber, B. E. K. Klein, R. Klein, C. Kooperberg, B. Ky, A. Lacroix, P. Lanken, M. Lathrop, M. Li, V. Marshall, O. Melander, F. D. Mentch, N. J. Meyer, K. L. Monda, A. Montpetit, G. Murugesan, K. Nakayama, D. Nondahl, A. Onipinla, S. Rafelt, S. J. Newhouse, F. G. Otieno, S. R. Patel, M. E. Putt, S. Rodriguez, R. N. Safa, D. B. Sawyer, P. J. Schreiner, C. Simpson, S. Sivapalaratnam, S. R. Srinivasan, C. Suver, G. Swergold, N. K. Sweitzer, K. A. Thomas, B. Thorand, N. J. Timpson, S. Tischfield, M. Tobin, M. Tomaszewski, W. M. M. Verschuren, C. Wallace, B. Winkelmann, H. Zhang, D. Zheng, L. Zhang, J. M. Zmuda, R. Clarke, A. J. Balmforth, J. Danesh, I. N. Day, N. J. Schork, P. I. W. de Bakker, C. Delles, D. Duggan, A. D. Hingorani, J. N. Hirschhorn, M. H. Hofker, S. E. Humphries, M. Kivimaki, D. A. Lawlor, K. Kottke-Marchant, J. L. Mega, B. D. Mitchell, D. A. Morrow, J. Palmen, S. Redline, D. C. Shields, A. R. Shuldiner, P. M. Sleiman, G. D. Smith, M. Farrall, Y. Jamshidi, D. C. Christiani, J. P. Casas, A. S. Hall, P. A. Doevendans, J. D. Christie, G. S. Berenson, S. S. Murray, T. Illig, G. W. Dorn II, T. P. Cappola, E. Boerwinkle, P. Sever, D. J. Rader, M. P. Reilly, M. Caulfield, P. J. Talmud, E. Topol, J. C. Engert, K. Wang, A. Dominiczak, A. Hamsten, S. P. Curtis, R. L. Silverstein, L. A. Lange, M. S. Sabatine, M. Trip, D. Saleheen, J. F. Peden, K. J. Cruickshanks, W. März, J. R. O’Connell, O. H. Klungel, C. Wijmenga, A. H. Maitland-van der Zee, E. E. Schadt, J. A. Johnson, G. P. Jarvik, G. J. Papanicolaou; Hugh Watkins on behalf of PROCARDIS, S. F. A. Grant, P. B. Munroe, K. E. North, N. J. Samani, W. Koenig, T. R. Gaunt, S. S. Anand, Y. T. van der Schouw; Meena Kumari on behalf of the Whitehall II Study and the WHII 50K Group, N. Soranzo, G. A. Fitzgerald, A. Reiner, R. A. Hegele, H. Hakonarson, B. J. Keating, Meta-analysis of dense genecentric association studies reveals common and uncommon variants associated with height. Am. J. Hum. Genet. 88, 6–18 (2011).
24. P. Bougnères, The exon-3 deletion of the growth hormone receptor (GHR) gene still has a limited impact in clinical endocrinology. J. Clin. Endocrinol. Metab. 95, 56–59 (2010).
25. J. Pantel, J. Grulich-Henn, M. Bettendorf, C. J. Strasburger, U. Heinrich, S. Amselem, Heterozygous nonsense mutation in exon 3 of the growth hormone receptor (GHR) in severe GH insensitivity (Laron syndrome) and the issue of the origin and function of the GHRd3 isoform. J. Clin. Endocrinol. Metab. 88, 1705–1710 (2003).
26. R. J. Strawbridge, L. Kärvestedt, C. Li, S. Efendic, C. G. Östenson, H. F. Gu, K. Brismar, GHR exon 3 polymorphism: Association with type 2 diabetes mellitus and metabolic disorder. Growth Horm. IGF Res. 17, 392–398 (2007).
27. M. Ouni, A.-L. Castell, A. Linglart, P. Bougnères, Genetic and epigenetic modulation of growth hormone sensitivity studied with the IGF-1 generation test. J. Clin. Endocrinol. Metab. 100, E919–E925 (2015).
28. P. C. Tapia, RhoA, Rho kinase, JAK2, and STAT3 may be the intracellular determinants of longevity implicated in the progeric influence of obesity: Insulin, IGF-1, and leptin may all conspire to promote stem cell exhaustion. Med. Hypotheses 66, 570–576 (2006).
29. M. Rincon, R. Muzumdar, G. Atzmon, N. Barzilai, The paradox of the insulin/IGF-1 signaling pathway in longevity. Mech. Ageing Dev. 125, 397–403 (2004).
30. S. W. Park, S.-T. Lee, Y. B. Sohn, S. H. Kim, S.-Y. Cho, A.-r. Ko, S.-T. Ji, J.-Y. Kwon, S. Yeau, K.-H. Paik, J.-W. Kim, D.-K. Jin, A polymorphism in the growth hormone receptor is associated with height in children with Prader-Willi syndrome. Am. J. Med. Genet. A 155A, 2970–2973 (2011).
31. R. Tacutu, T. Craig, A. Budovsky, D. Wuttke, G. Lehmann, D. Taranukha, J. Costa, V. E. Fraifeld, J. P. de Magalhães, Human Ageing Genomic Resources: Integrated databases and tools for the biology and genetics of ageing. Nucleic Acids Res. 41, D1027–D1033 (2013).
32. V. D. Longo, C. E. Finch, Evolutionary medicine: From dwarf model systems to healthy centenarians? Science 299, 1342–1346 (2003).
33. C. Finch, The Biology of Human Longevity: Inflammation, Nutrition, and Aging in the Evolution of Lifespans (Academic Press, 2007).
34. P. Anversa, Aging and longevity: The IGF-1 enigma. Circ. Res. 97, 411–414 (2005).
35. A. Bartke, Can growth hormone (GH) accelerate aging? Evidence from GH-transgenic mice. Neuroendocrinology 78, 210–216 (2003).
36. M. Bonafè, M. Barbieri, F. Marchegiani, F. Olivieri, E. Ragno, C. Giampieri, E. Mugianesi, M. Centurelli, C. Franceschi, G. Paolisso, Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: Cues for an evolutionarily conserved mechanism of life span control. J. Clin. Endocrinol. Metab. 88, 3299–3304 (2003).
37. E. van der Spoel, M. P. Rozing, J. J. Houwing-Duistermaat, P. E. Slagboom, M. Beekman, A. J. M. de Craen, R. G. J. Westendorp, D. van Heemst, Association analysis of insulin-like growth factor-1 axis parameters with survival and functional status in nonagenarians of the Leiden Longevity Study. Aging 7, 956–963 (2015).
38. A. J. Brooks, M. J. Waters, The growth hormone receptor: Mechanism of activation and clinical implications. Nat. Rev. Endocrinol. 6, 515–525 (2010).
39. C. Giavoli, E. Ferrante, E. Profka, L. Olgiati, S. Bergamaschi, C. L. Ronchi, E. Verrua, M. Filopanti, E. Passeri, L. Montefusco, A. G. Lania, S. Corbetta, M. Arosio, B. Ambrosi, A. Spada, P. Beck-Peccoz, Influence of the d3GH receptor polymorphism on the metabolic and biochemical phenotype of GH-deficient adults at baseline and during short- and long-term recombinant human GH replacement therapy. Eur. J. Endocrinol. 163, 361–368 (2010).
40. R. S. Jallad, E. B. Trarbach, F. H. Duarte, A. A. L Jorge, M. D. Bronstein, Influence of growth hormone receptor (GHR) exon 3 and -202A/C IGFBP-3 genetic polymorphisms on clinical and biochemical features and therapeutic outcome of patients with acromegaly. Pituitary 18, 666–673 (2015).
41. C. A. M. Glad, L. M. S. Carlsson, O. Melander, P. Almgren, L. Sjöström, S. Nilsson, I. Larsson, P.-A. Svensson, G. Johannsson, The GH receptor exon 3 deleted/full-length polymorphism is associated with central adiposity in the general population. Eur. J. Endocrinol. 172, 123–128 (2015).
42. T. Alfred, Y. Ben-Shlomo, R. Cooper, R. Hardy, C. Cooper, I. J. Deary, T. R. Gaunt, D. Gunnell, S. E. Harris, M. Kumari, R. M. Martin, A. A. Sayer, J. M. Starr, D. Kuh, I. N. M. Day; HALCyon Study Team, A multi-cohort study of polymorphisms in the GH/IGF axis and physical capability: The HALCyon programme. PLOS ONE 7, e29883 (2012).
43. L. Perice, N. Barzilai, J. Verghese, E. F. Weiss, R. Holtzer, P. Cohen, S. Milman, Lower circulating insulin-like growth factor-I is associated with better cognition in females with exceptional longevity without compromise to muscle mass and function. Aging 8, 2414–2424 (2016).
44. R. K. Junnila, S. Duran-Ortiz, O. Suer, E. G. Sustarsic, D. E. Berryman, E. O. List, J. J. Kopchick, Disruption of the GH receptor gene in adult mice increases maximal lifespan in females. Endocrinology 157, 4502–4513 (2016).
45. P. A. Parsons, Antagonistic pleiotropy and the stress theory of aging. Biogerontology 8, 613–617 (2007).
46. A. Rajwani, V. Ezzat, J. Smith, N. Y. Yuldasheva, E. R. Duncan, M. Gage, R. M. Cubbon, M. B. Kahn, H. Imrie, A. Abbas, H. Viswambharan, A. Aziz, P. Sukumar, A. Vidal-Puig, J. K. Sethi, S. Xuan, A. M. Shah, P. J. Grant, K. E. Porter, M. T. Kearney, S. B. Wheatcroft, Increasing circulating IGFBP1 levels improves insulin sensitivity, promotes nitric oxide production, lowers blood pressure, and protects against atherosclerosis. Diabetes 61, 915–924 (2012).
47. C. H. Waddington, The Strategy of Genes (George Allen & Unwin, 1957).
48. J. M. Lancaster, M. E. Carney, P. A. Futreal, BRCA 1 and 2–A genetic link to familial breast and ovarian cancer. Medscape Womens Health 2, 7 (1997).
49. G. Atzmon, I. Gabriely, W. Greiner, D. Davidson, C. Schechter, N. Barzilai, Plasma HDL levels highly correlate with cognitive function in exceptional longevity. J. Gerontol., Ser. A 57, M712–M715 (2002).
50. G. Atzmon, C. Schechter, W. Greiner, D. Davidson, G. Rennert, N. Barzilai, Clinical phenotype of families with longevity. J. Am. Geriatr. Soc. 52, 274–277 (2004).
51. N. Barzilai, G. Atzmon, C. Schechter, E. J. Schaefer, A. L. Cupples, R. Lipton, S. Cheng, A. R. Shuldiner, Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA 290, 2030–2040 (2003).
52. G. Atzmon, M. Rincon, C. B. Schechter, A. R. Shuldiner, R. B. Lipton, A. Bergman, N. Barzilai, Lipoprotein genotype and conserved pathway for exceptional longevity in humans. PLOS Biol. 4, e113 (2006).
53. J. Verghese, R. B. Lipton, C. B. Hall, G. Kuslansky, M. J. Katz, H. Buschke, Abnormality of gait as a predictor of non-Alzheimer’s dementia. N. Engl. J. Med. 347, 1761–1768 (2002).
54. L. P. Fried, N. O. Borhani, P. Enright, C. D. Furberg, J. M. Gardin, R. A. Kronmal, L. H. Kuller, T. A. Manolio, M. B. Mittelmark, A. Newman, D. H. O’Leary, B. Psaty, P. Rautaharju, R. P. Tracy, P. G. Weiler, The Cardiovascular Health Study: Design and rationale. Ann. Epidemiol. 1, 263–276 (1991).
55. J. Wan, G. Atzmon, D. Hwang, N. Barzlai, J. Kratzsch, P. Cohen, Growth hormone receptor (GHR) exon 3 polymorphism status detection by dual-enzyme-linked immunosorbent assay (ELISA). J. Clin. Endocrinol. Metab. 98, E77–E81 (2013).
56. J. R. O’Connell, D. E. Weeks, PedCheck: A program for identification of genotype incompatibilities in linkage analysis. Am. J. Hum. Genet. 63, 259–266 (1998).