Human Genetics

, Volume 129, Issue 4, pp 455–462 | Cite as

Leptin expression and leptin receptor gene polymorphisms in growth hormone deficiency patients

  • Pen-Hua Su
  • Jia-Yuh Chen
  • Ju-Shan Yu
  • Suh-Jen Chen
  • Shun-Fa YangEmail author
Original Investigation


Growth hormone deficiency (GHD) patients have lower weight, height, bone age, insulin-like growth factor 1 (IGF-1) levels, GH levels, fat metabolism and skeletal growth. The association of leptin with GHD characteristics and the effect of gene variants of leptin on GHD are unknown. Our aim was to examine the association of circulating leptin levels and common genetic variants in leptin (LEP) and leptin receptor (LEPR) genes with anthropometric measures, circulating hormone concentrations and GHD. A case control study of 125 GHD cases and 159 control subjects were characterized for bone age, body mass index (BMI), height, weight, leptin, IGF-1, GH and their genotype at the leptin promoter G-2548A, and LEPR variants, K109R and Q223R, at Chung Shan Medical University Hospital. Leptin levels were significantly associated with lower bone age, weight and BMI in GHD patients. Leptin levels were also significantly associated with reduced IGF-1 levels in girls but not boys in both groups. The frequency of LEPR223 [A/G or A/A] genotype was significantly higher than the LEPR223 G/G genotype in the GHD group. The LEPR223 [A/G or A/A] genotype was significantly associated with increased weight and BMI in the control group, but not in the GHD group. In conclusion, the GHD group carried a significantly higher frequency of the LEPR [G/A or A/A] genotype and of the A allele (LEPR223R). The LEPR223R polymorphism affected weight and BMI in control, but not in GHD patients, suggesting that the effect of LEPR223 [A/G or A/A] genotype was counteracted by other factor(s) in GHD patients.


Growth Hormone Growth Hormone Deficiency Growth Hormone Level Growth Hormone Deficiency Patient LEPR Polymorphism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Ajuwon KM, Kuske JL, Ragland D, Adeola O, Hancock DL, Anderson DB, Spurlock ME (2003) The regulation of IGF-1 by leptin in the pig is tissue specific and independent of changes in growth hormone. J Nutr Biochem 14:522–530PubMedCrossRefGoogle Scholar
  2. Ben Ali S, Kallel A, Ftouhi B, Sediri Y, Feki M, Slimane H, Jemaa R, Kaabachi N (2009a) Association of G-2548A LEP polymorphism with plasma leptin levels in Tunisian obese patients. Clin Biochem 42:584–588PubMedCrossRefGoogle Scholar
  3. Ben Ali S, Kallel A, Sediri Y, Ftouhi B, Feki M, Slimene H, Jemaa R, Kaabachi N (2009b) LEPR p.Q223R polymorphism influences plasma leptin levels and body mass index in Tunisian obese patients. Arch Med Res 40:186–190PubMedCrossRefGoogle Scholar
  4. Beuschlein F, Hancke K, Petrick M, Gobel H, Honegger J, Reincke M (2005) Growth hormone receptor mRNA expression in non-functioning and somatotroph pituitary adenomas: implications for growth hormone substitution therapy? Exp Clin Endocrinol Diabetes 113:214–218PubMedCrossRefGoogle Scholar
  5. Bideci A, Cinaz P, Hasanoglu A, Tumer L (2002) Leptin, insulin-like growth factor (IGF)-I and IGF binding protein-3 levels in children with constitutional delay of growth. J Pediatr Endocrinol Metab 15:41–46PubMedGoogle Scholar
  6. Bogarin R, Steinbok P (2009) Growth hormone treatment and risk of recurrence or progression of brain tumors in children: a review. Childs Nerv Syst 25:273–279PubMedCrossRefGoogle Scholar
  7. Buzi F, Mella P, Pilotta A, Prandi E, Lanfranchi F, Carapella T (2007) Growth hormone receptor polymorphisms. Endocr Dev 11:28–35PubMedCrossRefGoogle Scholar
  8. Chagnon YC, Wilmore JH, Borecki IB, Gagnon J, Perusse L, Chagnon M, Collier GR, Leon AS, Skinner JS, Rao DC, Bouchard C (2000) Associations between the leptin receptor gene and adiposity in middle-aged Caucasian males from the HERITAGE family study. J Clin Endocrinol Metab 85:29–34PubMedCrossRefGoogle Scholar
  9. Conceicao FL, Jorgensen JO, Vahl N, Norrelund H, Christiansen JS (2000) Evidence-based approach to growth hormone replacement therapy in adults, with special emphasis on body composition. J Pediatr Endocrinol Metab 13(Suppl 6):1353–1358PubMedGoogle Scholar
  10. Dagogo-Jack S, Franklin SC, Vijayan A, Liu J, Askari H, Miller SB (1998) Recombinant human insulin-like growth factor-I (IGF-I) therapy decreases plasma leptin concentration in patients with chronic renal insufficiency. Int J Obes Relat Metab Disord 22:1110–1115PubMedCrossRefGoogle Scholar
  11. De A Barretto ES, Gill MS, De Freitas ME, Magalhaes MM, Souza AH, Aguiar-Oliveira MH, Clayton PE (1999) Serum leptin and body composition in children with familial GH deficiency (GHD) due to a mutation in the growth hormone-releasing hormone (GHRH) receptor. Clin Endocrinol (Oxf) 51:559–564CrossRefGoogle Scholar
  12. Federico G, Street ME, Maghnie M, Caruso-Nicoletti M, Loche S, Bertelloni S, Cianfarani S (2006) Assessment of serum IGF-I concentrations in the diagnosis of isolated childhood-onset GH deficiency: a proposal of the Italian Society for Pediatric Endocrinology and Diabetes (SIEDP/ISPED). J Endocrinol Invest 29:732–737PubMedGoogle Scholar
  13. Fofanova OV, Evgrafov OV, Polyakov AV, Poltaraus AB, Peterkova VA, Dedov II (2003) A novel IVS2-2A>T splicing mutation in the GH-1 gene in familial isolated growth hormone deficiency type II in the spectrum of other splicing mutations in the Russian population. J Clin Endocrinol Metab 88:820–826PubMedCrossRefGoogle Scholar
  14. Franek E, Nowak J, Safranow K, Adler G, Binczak-Kuleta A, Ciechanowicz A, Wiecek A (2010) G(-2548)A leptin gene polymorphism in obese subjects is associated with serum leptin concentration and bone mass. Pol Arch Med Wewn 120:175–180PubMedGoogle Scholar
  15. Furusawa T, Naka I, Yamauchi T, Natsuhara K, Kimura R, Nakazawa M, Ishida T, Inaoka T, Matsumura Y, Ataka Y, Nishida N, Tsuchiya N, Ohtsuka R, Ohashi J (2010) The Q223R polymorphism in LEPR is associated with obesity in Pacific Islanders. Hum Genet 127:287–294Google Scholar
  16. Giordano M, Godi M, Mellone S, Petri A, Vivenza D, Tiradani L, Carlomagno Y, Ferrante D, Arrigo T, Corneli G, Bellone S, Giacopelli F, Santoro C, Bona G, Momigliano-Richiardi P (2008) A functional common polymorphism in the vitamin D-responsive element of the GH1 promoter contributes to isolated growth hormone deficiency. J Clin Endocrinol Metab 93:1005–1012PubMedCrossRefGoogle Scholar
  17. Haghshenas Z, Sotoudeh K, Karamifar H, Karamizadeh Z, Amirhakimi G (2009) The role of insulin like growth factor (IGF)-1 and IGF-binding protein-3 in diagnosis of growth hormone deficiency in short stature children. Indian J Pediatr 76:699–703PubMedCrossRefGoogle Scholar
  18. Heo M, Leibel RL, Fontaine KR, Boyer BB, Chung WK, Koulu M, Karvonen MK, Pesonen U, Rissanen A, Laakso M, Uusitupa MI, Chagnon Y, Bouchard C, Donohoue PA, Burns TL, Shuldiner AR, Silver K, Andersen RE, Pedersen O, Echwald S, Sorensen TI, Behn P, Permutt MA, Jacobs KB, Elston RC, Hoffman DJ, Gropp E, Allison DB (2002) A meta-analytic investigation of linkage and association of common leptin receptor (LEPR) polymorphisms with body mass index and waist circumference. Int J Obes Relat Metab Disord 26:640–646PubMedCrossRefGoogle Scholar
  19. Houseknecht KL, Portocarrero CP, Ji S, Lemenager R, Spurlock ME (2000) Growth hormone regulates leptin gene expression in bovine adipose tissue: correlation with adipose IGF-1 expression. J Endocrinol 164:51–57PubMedCrossRefGoogle Scholar
  20. Jung CH, Lee WY, Rhee EJ, Kim SY, Oh KW, Yun EJ, Kim SW (2006) Serum ghrelin and leptin levels in adult growth hormone deficiency syndrome. Arch Med Res 37:612–618PubMedCrossRefGoogle Scholar
  21. Katsumata N, Matsuo S, Sato N, Tanaka T (2001) A novel and de novo splice-donor site mutation in intron 3 of the GH-1 gene in a patient with isolated growth hormone deficiency. Growth Horm IGF Res 11:378–383PubMedCrossRefGoogle Scholar
  22. Liu CL, Chang YC, Cheng SP, Chern SR, Yang TL, Lee JJ, Guo IC, Chen CP (2007) The roles of serum leptin concentration and polymorphism in leptin receptor gene at codon 109 in breast cancer. Oncology 72:75–81PubMedCrossRefGoogle Scholar
  23. Margetic S, Gazzola C, Pegg GG, Hill RA (2002) Leptin: a review of its peripheral actions and interactions. Int J Obes Relat Metab Disord 26:1407–1433PubMedCrossRefGoogle Scholar
  24. Marzullo P, Buckway C, Pratt KL, Colao A, Guevara-Aguirre J, Rosenfeld RG (2002) Leptin concentrations in GH deficiency: the effect of GH insensitivity. J Clin Endocrinol Metab 87:540–545PubMedCrossRefGoogle Scholar
  25. Mazzanti L, Tamburrino F, Bergamaschi R, Scarano E, Montanari F, Torella M, Ballarini E, Cicognani A (2009) Developmental syndromes: growth hormone deficiency and treatment. Endocr Dev 14:114–134PubMedCrossRefGoogle Scholar
  26. Meyer S, Schaefer S, Stolk L, Arp P, Uitterlinden AG, Plockinger U, Stalla GK, Tuschy U, Weber MM, Weise A, Pfutzner A, Kann PH (2009) Association of the exon 3 deleted/full-length GHR polymorphism with recombinant growth hormone dose in growth hormone-deficient adults. Pharmacogenomics 10:1599–1608PubMedCrossRefGoogle Scholar
  27. Mitchell H, Dattani MT, Nanduri V, Hindmarsh PC, Preece MA, Brook CG (1999) Failure of IGF-I and IGFBP-3 to diagnose growth hormone insufficiency. Arch Dis Child 80:443–447PubMedCrossRefGoogle Scholar
  28. Morris DL, Rui L (2009) Recent advances in understanding leptin signaling and leptin resistance. Am J Physiol Endocrinol Metab 297:E1247–E1259PubMedCrossRefGoogle Scholar
  29. Ozata M, Ozdemir IC, Licinio J (1999) Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab 84:3686–3695PubMedCrossRefGoogle Scholar
  30. Ozbey N, Algun E, Turgut AS, Orhan Y, Sencer E, Molvalilar S (2000) Serum lipid and leptin concentrations in hypopituitary patients with growth hormone deficiency. Int J Obes Relat Metab Disord 24:619–626PubMedCrossRefGoogle Scholar
  31. Randeva HS, Murray RD, Lewandowski KC, O’Callaghan CJ, Horn R, O’Hare P, Brabant G, Hillhouse EW, Shalet SM (2002) Differential effects of GH replacement on the components of the leptin system in GH-deficient individuals. J Clin Endocrinol Metab 87:798–804PubMedCrossRefGoogle Scholar
  32. Rosenbloom AL (2008) Insulin-like growth factor-I (rhIGF-I) therapy of short stature. J Pediatr Endocrinol Metab 21:301–315PubMedGoogle Scholar
  33. Shimon I (2003) Growth hormone replacement for adult growth hormone deficiency. Expert Opin Pharmacother 4:1977–1983PubMedCrossRefGoogle Scholar
  34. Stein RI, Legault L, Daneman D, Weksberg R, Hamilton J (2004) Growth hormone deficiency in Costello syndrome. Am J Med Genet A 129A:166–170PubMedCrossRefGoogle Scholar
  35. Su PH, Wang SL, Chen JY, Chen SJ, Ke JC (2008) A study of anthropomorphic and biochemical characteristics in girls with central precocious puberty and thelarche variant. J Pediatr Endocrinol Metab 21:213–220PubMedGoogle Scholar
  36. van der Klaauw AA, van der Straaten T, Baak-Pablo R, Biermasz NR, Guchelaar HJ, Pereira AM, Smit JW, Romijn JA (2008) Influence of the d3-growth hormone (GH) receptor isoform on short-term and long-term treatment response to GH replacement in GH-deficient adults. J Clin Endocrinol Metab 93:2828–2834PubMedCrossRefGoogle Scholar
  37. Wassenaar MJ, Dekkers OM, Pereira AM, Wit JM, Smit JW, Biermasz NR, Romijn JA (2009) 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 94:3721–3730PubMedCrossRefGoogle Scholar
  38. Woods K (2007) Genetic defects of the growth-hormone–IGF axis associated with growth hormone insensitivity. Endocr Dev 11:6–15PubMedCrossRefGoogle Scholar
  39. Yadav S, Krishnamurthy S (2007) Insulin like growth factors and growth hormone deficiency. Indian Pediatr 44:349–353PubMedGoogle Scholar
  40. Yiannakouris N, Yannakoulia M, Melistas L, Chan JL, Klimis-Zacas D, Mantzoros CS (2001) The Q223R polymorphism of the leptin receptor gene is significantly associated with obesity and predicts a small percentage of body weight and body composition variability. J Clin Endocrinol Metab 86:4434–4439PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Pen-Hua Su
    • 1
    • 2
  • Jia-Yuh Chen
    • 1
    • 2
  • Ju-Shan Yu
    • 1
  • Suh-Jen Chen
    • 1
  • Shun-Fa Yang
    • 1
    • 3
    • 4
    Email author
  1. 1.Division of Genetics, Department of PediatricsChung Shan Medical University HospitalTaichungTaiwan
  2. 2.School of MedicineChung Shan Medical UniversityTaichungTaiwan
  3. 3.Institute of MedicineChung Shan Medical UniversityTaichungTaiwan
  4. 4.Department of Medical ResearchChung Shan Medical University HospitalTaichungTaiwan

Personalised recommendations