Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
권호 표지
DOI QR코드

DOI QR Code

Analysis of cytosine adenine repeat polymorphism of the IGF-I promoter gene in children with idiopathic short stature

특발성 저신장증 환자에서 IGF-I 프로모터 cytosine-adenine repeat 유전자 다형성의 분석

  • Moon, Jae Hoon (Department of Pediatrics, College of Medicine, Inje University) ;
  • Chung, Woo Yeong (Department of Pediatrics, College of Medicine, Inje University)
  • 문재훈 (인제대학교 의과대학 소아과학교실) ;
  • 정우영 (인제대학교 의과대학 소아과학교실)
  • Received : 2008.06.02
  • Accepted : 2009.01.13
  • Published : 2009.03.15
Download PDF
⟨ Previous Next ⟩

Abstract

Purpose : A polymorphism in the IGF-I gene promoter region is known to be associated with serum IGF-I levels, birth weight, and body length, suggesting that IGF-I gene polymorphism might influence postnatal growth. The present study aimed to investigate the role of this polymorphic cytosine-adenine (CA) repeat of the IGF-I gene in children with idiopathic short stature. Methods : The study involved 131 children (72 boys and 59 girls) diagnosed with idiopathic short stature, aged 715 years. Genomic DNA was extracted from anticoagulated peripheral whole blood. The primers were designed to cover the promoter region containing the polymorphic CA repeat. Data were analyzed using GeneMapper software. The correlations between age and serum IGF-I levels were analyzed using Spearmans correlation coefficient. Results : The CA repeat sequences ranged from 15 to 22, with 19 CA repeats the most common with an allele frequency of 40.6%. Homozygous for 19 CA repeat was 13.0%, heterozygous for 19 CA repeat was 56.5%, and 19 CA non-carrier was 30.5%. The three different genotype groups showed no significant differences in height, body weight and body mass index, and serum IGF-I levels. The serum IGF-I level and age according to the IGF-I genotypes were significantly correlated in the entire group, 19 CA repeat carrier group, and the non-carrier group. The three groups also showed no significant differences in the first year responsiveness to GH treatment. Conclusion : There were no significant different correlations between 19 CA repeat polymorphism and serum IGF-I levels according to genotype. Our results suggest that the IGF-I 19 CA repeat gene polymorphism is not functional in children with idiopathic short stature.

목 적 : 특발성 저신장증 환자에서 IGF-I 유전자 다형성의 역할에 대한 연구는 아직 보고되지 않았다. 저자들은 한국인 특발성 저신장증 환자를 대상으로 IGF-I 프로모터 CA repeat 유전자 다형성에 대한 분석을 실시하였다. 방 법 : 신장 계측에 의해 2007년에 제작된 한국 소아 발육 표준 신장표에 의거하여 나이와 성별에 따른 신장백분위수가 3백분위수 미만인 131명을 대상으로 하였다. 성장호르몬 치료의 분석은 최소한 6개월 이상 성장호르몬 치료를 받은 37명을 대상으로 실시하였다. 유전자형의 분석은 유전자 염기서열분석을 통하여 실시하였다. CA repeat 횟수에 따른 대립유전자의 분포를 조사하였고, 이를 바탕으로 유전자형을 분석하였다. CA repeat의 heterozygous의 분석은 Gene Mapper software를 이용하였다. 혈청 IGF-I 농도는 RIA방법으로 측정하였다. 결 과 : 국인 특발성 저신장증 환자에서의 CA repeat의 분포는 15부터 22까지였으며, 19 repeat가 40.6%의 빈도로 가장 높았다. 유전자형에 따른 분포는 131명 중 17명(13.0%)이 19 CA repeat homozygous 였으며, 74명(56.5%)은 heterozygous, 40명(30.5%)은 19 CA repeat noncarrier 였다. 유전자형에 따른 키, 체중, BMI는 세군 모두에서 유의한 차이가 없었다. 유전자형에 따른 혈청 IGF-I 농도는 19 CA repeat noncarrier군에서 $435.67{\pm}160.29$ ng/mL로, 19 CA homozygous 군에서의 $435.60{\pm}131.51$ ng/mL, 19 CA heterozygous 군에서의 $473.76{\pm}185.01$ ng/mL과 유의한 차이가 없었다. 나이와 혈청 IGF-I 농도와의 상관관계를 분석한 결과 세군 모두에서 유의한 양의 상관관계를 보였다(P<0.01). 유전자형에 따른 첫 1년 동안의 성장호르몬 치료 효과를 분석한 결과 성장호르몬 치료 후 12개월로 환산한 성장속도는 19 CA homozygote군에서 $7.6{\pm}3.4$ Cm, 19 CA heterozygote군에서 $7.9{\pm}2.6$ cm 그리고 19 CA noncarrier군에서 $7.7{\pm}2.8$ cm로 세군 사이에 유의한 차이가 없었다(P>0.05). 성장호르몬 치료 전후의 신장표준편차점수 차이도 19 CA homozygote군에서 $0.6{\pm}0.2$, 19 CA heterozygote군에서 $0.5{\pm}0.4$ 그리고 19 CA noncarrier군에서 $0.5{\pm}0.4$로 세군 사이에 유의한 차이가 없었다(P>0.05). 결 론 : 특발성 저신장증 환자에서의 IGF-I 프로모터 CA repeat 유전자 다형성의 분포는 15부터 22까지였으며, 19 repeat가 40.6%의 빈도로 가장 높았다. 키, 체중, BMI 그리고 혈중 IGF-I농도는 유전자형에 따라 유의한 차이가 없었다. 유전자형에 관계없이 나이와 혈중 IGF-I 농도 사이에는 모든 군에서 유의한 양의 상관관계를 나타내었다. 유전자형에 따른 첫 1년간의 성장호르몬 치료 효과도 유전자형에 따라 유의한 차이가 없었다. 그러므로 특발성 저신장증 환자에서는 IGF-I 유전자 다형성은 기능적 역할을 하지 못한다고 생각한다.

Keywords

References

  1. Rosenfeld RG. The molecular basis of idiopathic short stature. Growth Horm IGF Res 2005;15:3-5 https://doi.org/10.1016/j.ghir.2005.06.014
  2. Attie KM. Genetic studies in idiopathic short stature. Curr Opin Pediatr 2000;12:400-4 https://doi.org/10.1097/00008480-200008000-00021
  3. Lopez-Bermejo A, Buckway CK, Rosenfeld RG. Genetic defects of the growth hormone-insulin-like growth factor axis. Trends Endocrinol Metab 2000;11:39-49 https://doi.org/10.1016/S1043-2760(99)00226-X
  4. Carlsson LM, Attie KM, Compton PG, Vitangcol RV, Merimee TJ. Reduced concentration of serum growth hormone- binding protein in children with idiopathic short stature. National Cooperative Growth Study. J Clin Endocrinol Metab 1994;78:1325-30 https://doi.org/10.1210/jc.78.6.1325
  5. Mauras N, Carlsson LM, Murphy S, Merimee TJ. Growth hormone-binding protein levels: studies of children with short stature. Metabolism 1994;43:357-9 https://doi.org/10.1016/0026-0495(94)90104-X
  6. Selva KA, Buckway CK, Sexton G, Pratt KL, Tjoeng E, Guevara-Aguirre J, et al. Reproducibility in patterns of IGF generation with special reference to idiopathic short stature. Horm Res 2003;60:237-46 https://doi.org/10.1159/000074038
  7. Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y, Liu JL, et al. Circulating levels of IGF-I directly regulate bone growth and density. J Clin Invest 2002;110:771-81
  8. Lupu F, Terwilliger JD, Lee K, Segre GV, Efstratiadis A. Roles of growth hormone and insulin-like growth factor I in mouse postnatal growth. Dev Biol 2001;229:141-62 https://doi.org/10.1006/dbio.2000.9975
  9. Arends N, Johnston L, Hokken-Koelega A, van Duijn C, de Ridder M, Savage M, et al. Polymorphism in the IGF-I gene: Clinical relevance for short children born small for gestational age (SGA). J Clin Endocrinol Metab 2002;87: 2720-4 https://doi.org/10.1210/jc.87.6.2720
  10. Frayling TM, Hattersley AT, McCarthy A, Holly J, Mitchell SM, Gloyn AL, et al. A putative functional polymorphism in the IGF-I gene: association studies with type 2 diabetes, adult height, glucose tolerance, and fetal growth in U.K. populations. Diabetes 2002;51:2313-6 https://doi.org/10.2337/diabetes.51.7.2313
  11. Adamo ML. Regulation of insulin-like growth factor I gene expression. Implications for normal and pathological growth. Diabetes Rev 1995;3:2-27
  12. Rotwein P. Structure, evolution, expression and regulation of insulin-like growth factors I and II. Growth Factors 1991;5:3-18 https://doi.org/10.3109/08977199109000267
  13. Vaessen N, Heutink P, Janssen JA, Witteman JC, Testers L, Hofman A, et al. A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction. Diabetes 2001;50;637-42 https://doi.org/10.2337/diabetes.50.3.637
  14. Rosen CJ, Kurland ES, Vereault D, Adler RA, Rackoff PJ, Craig WY, et al. Association between serum insulin growth factor-I (IGF-I) and a simple sequence repeat in IGF-I gene: implications for genetic studies of bone mineral density. J Clin Endocrinol Metab 1998;83:2286-90 https://doi.org/10.1210/jc.83.7.2286
  15. Johnston LB, Dahlgren J, Leger J, Gelander L, Savage MO, Czernichow P, et al. Association between insulin-like growth factor I (IGF-I) polymorphisms, circulating IGF-I, and pre- and postnatal growth in two European small for gestational age populations. J Clin Endocrinol Metab 2003;88:4805-10 https://doi.org/10.1210/jc.2003-030563
  16. Rietveld I, Janssen JA, van Rossum EF, Houwing-Duistermaat JJ, Rivadeneira F, Hofman A, et al. A polymorphic CA repeat in the IGF-I gene is associated with gender-specific differences in body height, but has no effect on the secular trend in body height. Clin Endoclinol (Oxf) 2004;61:195-203 https://doi.org/10.1111/j.1365-2265.2004.02078.x
  17. Allen NE, Davey GK, Key TJ, Zhang S, Narod SA. Serum insulin-like growth factor I (IGF-I) concentration in men is not associated with cytosine-adenosine repeat polymorphism of the IGF-I gene. Cancer Epidemiol Biomarkers Prev 2002; 11:319-20
  18. Yu H, Li BD, Smith M, Shi R, Berkel HJ, Kato I. Polymorphic CA repeats in the IGF-I gene and breast cancer. Breast Cancer Res Treat 2001;70:117-22 https://doi.org/10.1023/A:1012947027213
  19. Ko MJ, Hwang TG, Lee JN, Chung WY. Analysis of cytosine adenine(CA) repeat polymorphism of the IGF-I gene and influence on serum IGF-I levels in healthy children and adolescents. Korean J Pediatr 2006;49:1340-7
  20. Stewart CE, Rotwein P. Growth, differentiation, and survival: multiple physiological functions for insulin-like growth factors. Physiol Rev 1996;76:1005-26
  21. Robson H, Siebler T, Shalet SM, Williams GR. Interactions between GH, IGF-I, glucocorticoids, and thyroid hormones during skeletal growth. Pediatr Res 2002;52:137-47
  22. Woods KA, Dastot F, Preece MA, Clark AJ, Postel-Vinay MC, Chatelain PG, et al. Phenotype: genotype relationships in growth hormone insensitivity syndrome. J Clin Endoclinol Metab 1997;82:3529-35 https://doi.org/10.1210/jc.82.11.3529
  23. Goddard AD, Covello R, Luoh SM, Clackson T, Attie KM, Gesundheit N, et al. Mutations of the growth hormone receptor in children with idiopathic short stature. The Growth Hormone Insensitivity Study Group. N Engl J Med 1995; 333:1093-8 https://doi.org/10.1056/NEJM199510263331701
  24. Clayton PE, Freeth JS, Norman MR. Congenital growth hormone insensitivity syndromes and their relevance to idiopathic short stature. Clin Endocrinol (Oxf) 1999;50:275-83
  25. Sanchez J, Perera E, Baumbach L, Cleveland WW. Growth hormone receptor gene mutations in children with idiopathic short stature. J Clin Endocrinol Metab 1998;83:4079-83 https://doi.org/10.1210/jc.83.11.4079
  26. Bonioli E, Taro M, Rosa CL, Citana A, Bertorelli R, Morcaldi G, et al. Heterozygous mutations of growth hormone receptor gene in children with idiopathic short stature. Growth Horm IGF Res 2005;15:405-10 https://doi.org/10.1016/j.ghir.2005.08.004
  27. Sakurai T, Iida K, Takahashi Y, Kaji H, Takakuwa S, Sumita R, et al. A novel heterozygous T51I mutation of growth hormone receptor is not associated with short stature. Growth Horm IGF Res 2002;12:411-7 https://doi.org/10.1016/S1096-6374(02)00082-5
  28. Hujeirat Y, Hess O, Shalev S, Tenenbaum-Rakover Y. Growth hormone receptor sequence changes do not play a role in determining height in children with idiopathic short stature. Horm Res 2006;65:210-6
  29. Jorge AA, Marchisotti FG, Montenegro LR, Carvalho LR, Mendonca BB, Arnhold IJ. 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 Endoclinol Metab 2006;91:1076-80 https://doi.org/10.1210/jc.2005-2005
  30. Binder G, Baur F, Schweizer R, Ranke MB. 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 Endoclinol Metab 2006;91:659-64 https://doi.org/10.1210/jc.2005-1581
  31. Carrascosa A, Esteban C, Espadero R, Fernandez-Cancio M, Andaluz P, Clemente M, et al. The d3/fl-growth hormone (GH) receptor polymorphism does not influence the effect of GH treatment (66 µg/kg per day) or the spontaneous growth in short non-GH-deficient small-for-gestational-age children: results from a two-year controlled prospective study in 170 Spanish patients. J Clin Endoclinol Metab 2006;91: 3281-6 https://doi.org/10.1210/jc.2006-0685
  32. Brissenden JE, Ullrich A, Francke U. Human chromosomal mapping of genes for insulin-like growth factors I and II and epidermal growth factor. Nature 1984;310:781-4 https://doi.org/10.1038/310781a0
  33. Foyt HL, LeRoith D, Roberts CT Jr. Differential association of insulin-like growth factor I mRNA variants with polysomes in vivo. J Biol Chem 1991;266:7300-5
  34. Yang H, Adamo ML, Koval AP, McGuinness MC, Ben-Hur H, Yang Y, et al. Alternative leader sequences in insulin-like growth factor I mRNAs modulate translational efficiency and encode multiple signal peptides. Mol Endocrinol 1995;9:1380- 95 https://doi.org/10.1210/me.9.10.1380
  35. Mittanck DW, Kim SW, Rotwein P. Essential promoter elements are located within the 5' untranslated region of human insulin-like growth factor-I exon I. Mol Cell Endocrinol 1997; 126:153-63 https://doi.org/10.1016/S0303-7207(96)03979-2