Lack of association of the HSD11B1 gene polymorphisms with obesity and other traits of metabolic syndrome in children and adolescents
Abstract
Introduction. Obesity and its related disorders, clustered into metabolic syndrome (MetS), are increasingly diagnosed in children and adolescents. Clinical features, which define MetS are also encountered in patients with glucocorticoid excess. Since no evident hypercortisolaemia was detected in obesity and MetS, investigations turned to the local modulators of cortisol action. 11b-hydroxysteroid dehydrogenase type 1, encoded by HSD11B1 gene, controls tissue availability of cortisol by its regeneration from inert cortisone. Changes in HSD11B1 expression and enzyme activity may be influenced by its sequence variants and seem implicated in MetS pathogenesis. Our study was designed to evaluate plausible association of the HSD11B1 polymorphisms with early-onset obesity and features of MetS in Polish children and adolescents.
Material and methods. The study comprised of 258 obese children (136 females), aged 12.3 ± 3.6 years, with excessive body mass lasting 7.1 ± 3.8 years. Anthropometric and blood pressure measurements, baseline biochemical analyses and oral glucose tolerance test were performed in all participants. Genotyping of the HSD11B1 variants rs12086634, rs846910, rs4844880, and rs3753519 was conducted in obese youth and compared with 568 lean blood donors.
Results. Mean relative body mass index in obese cohort was 164.7 ± 27.1%. Hypertension was detected in 12.4%, impaired fasting glucose in 8.9%, impaired glucose tolerance in 10.8%, diabetes in 2.7%, and dyslipidemia in 31.4% children and adolescents. None of the studied HSD11B1 polymorphisms displayed significant difference in frequency between obese and lean individuals. MetS was diagnosed in 27.6% of 203 patients with obesity aged 10–18 years. Further genotype-stratified analyses of relationship between HSD11B1 variants and particular features of MetS did not confirm increased susceptibility to develop early-onset hyperglycaemia, dyslipidaemia and hypertension in carriers of specific genotypes at rs4844880, rs846910, rs3753519, and rs12086634 (p ≥ 0.05 in all tests).
Conclusion. Our study does not support the implication of the HSD11B1 polymorphisms in early-onset obesity and other features of MetS.
Keywords: childhood obesityHSD11B1 genepolymorphismcortisolmetabolic syndrome
References
- Garanty-Bogacka B, Syrenicz M, Rać M, et al. Association between serum osteocalcin, adiposity and metabolic risk in obese children and adolescents. Endokrynol Pol. 2013; 64(5): 346–352.
- Alberti KG, Zimmet P, Shaw J. Metabolic syndrome--a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med. 2006; 23(5): 469–480.
- Ferraù F, Korbonits M. Metabolic comorbidities in Cushing's syndrome. Eur J Endocrinol. 2015; 173(4): M133–M157.
- Pisarczyk-Wiza D, Zozulińska-Ziółkiewicz D. Glikokortykosteroidy a zaburzenia metabolizmu glukozy. Diabetologia Kliniczna. 2015; 4(3): 110–116.
- Incollingo Rodriguez AC, Epel ES, White ML, et al. Hypothalamic-pituitary-adrenal axis dysregulation and cortisol activity in obesity: A systematic review. Psychoneuroendocrinology. 2015; 62: 301–318.
- Tomlinson JW, Walker EA, Bujalska IJ, et al. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004; 25(5): 831–866.
- Ricketts ML, Verhaeg JM, Bujalska I, et al. Immunohistochemical localization of type 1 11beta-hydroxysteroid dehydrogenase in human tissues. J Clin Endocrinol Metab. 1998; 83(4): 1325–1335.
- Masuzaki H, Paterson J, Shinyama H, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science. 2001; 294(5549): 2166–2170.
- Kotelevtsev Y, Holmes MC, Burchell A, et al. 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. Proc Natl Acad Sci U S A. 1997; 94(26): 14924–14929.
- Alberts P, Engblom L, Edling N, et al. Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice. Diabetologia. 2002; 45(11): 1528–1532.
- Desbriere R, Vuaroqueaux V, Achard V, et al. 11beta-hydroxysteroid dehydrogenase type 1 mRNA is increased in both visceral and subcutaneous adipose tissue of obese patients. Obesity (Silver Spring). 2006; 14(5): 794–798.
- Michailidou Z, Jensen MD, Dumesic DA, et al. Omental 11beta-hydroxysteroid dehydrogenase 1 correlates with fat cell size independently of obesity. Obesity (Silver Spring). 2007; 15(5): 1155–1163.
- Veilleux A, Rhéaume C, Daris M, et al. Omental adipose tissue type 1 11 beta-hydroxysteroid dehydrogenase oxoreductase activity, body fat distribution, and metabolic alterations in women. J Clin Endocrinol Metab. 2009; 94(9): 3550–3557.
- Draper N, Walker EA, Bujalska IJ, et al. Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. Nat Genet. 2003; 34(4): 434–439.
- Gambineri A, Tomassoni F, Munarini A, et al. A combination of polymorphisms in HSD11B1 associates with in vivo 11{beta}-HSD1 activity and metabolic syndrome in women with and without polycystic ovary syndrome. Eur J Endocrinol. 2011; 165(2): 283–292.
- Malavasi ELV, Kelly V, Nath N, et al. Functional effects of polymorphisms in the human gene encoding 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1): a sequence variant at the translation start of 11 beta-HSD1 alters enzyme levels. Endocrinology. 2010; 151(1): 195–202.
- Feldman K, Szappanos A, Butz H, et al. The rs4844880 polymorphism in the promoter region of the HSD11B1 gene associates with bone mineral density in healthy and postmenopausal osteoporotic women. Steroids. 2012; 77(13): 1345–1351.
- Nair S, Lee YH, Lindsay RS, et al. 11beta-Hydroxysteroid dehydrogenase Type 1: genetic polymorphisms are associated with Type 2 diabetes in Pima Indians independently of obesity and expression in adipocyte and muscle. Diabetologia. 2004; 47(6): 1088–1095.
- Moon SS, Lee YS, Kim JG, et al. Relationship of 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase gene polymorphisms with metabolic syndrome and type 2 diabetes. Endocr J. 2011; 58(11): 949–959.
- Olza J, Gil-Campos M, Leis R, et al. A gene variant of 11β-hydroxysteroid dehydrogenase type 1 is associated with obesity in children. Int J Obes (Lond). 2012; 36(12): 1558–1563.
- Gelernter-Yaniv L, Feng N, Sebring NG, et al. Associations between a polymorphism in the 11 beta hydroxysteroid dehydrogenase type I gene and body composition. Int J Obes Relat Metab Disord. 2003; 27(8): 983–986.
- Duran-Gonzalez J, Ortiz I, Gonzales E, et al. Association study of candidate gene polymorphisms and obesity in a young Mexican-American population from South Texas. Arch Med Res. 2011; 42(6): 523–531.
- Ruan LiLi, Xu J, Wang CL, et al. Variants of 11β-hydroxysteroid dehydrogenase (HSD11B) gene type 1 and 2 in Chinese obese adolescents. J Endocrinol Invest. 2014; 37(6): 565–573.
- Smit P, Dekker MJ, de Jong FJ, et al. Lack of Association of the 11beta-hydroxysteroid dehydrogenase type 1 gene 83,557insA and hexose-6-phosphate dehydrogenase gene R453Q polymorphisms with body composition, adrenal androgen production, blood pressure, glucose metabolism, and dementia. J Clin Endocrinol Metab. 2007; 92(1): 359–362.
- Kułaga Z, Litwin M, Tkaczyk M, et al. Polish 2010 growth references for school-aged children and adolescents. Eur J Pediatr. 2011; 170(5): 599–609.
- Cole TJ, Freeman JV, Preece MA. Body mass index reference curves for the UK, 1990. Arch Dis Child. 1995; 73(1): 25–29.
- Kułaga Z, Litwin M, Zajączkowska MM, et al. Porównanie wartości obwodów talii i bioder dzieci i młodzieży polskiej w wieku 7–18 lat z wartościami referencyjnymi dla oceny ryzyka sercowo-naczyniowego — wyniki wstępne projektu badawczego OLAF (PL0080). Standardy Medyczne/Pediatria. 2008; 5: 473–485.
- Kułaga Z, Litwin M, Gajda A, et al. Rozkłady wartości ciśnienia krwi w populacji referencyjnej dzieci i młodzieży w wieku szkolnym. Standardy Medyczne/Pediatria. 2010; 7: 100–111.
- Zeitler P, Fu J, Tandon N, et al. International Society for Pediatric and Adolescent Diabetes. ISPAD Clinical Practice Consensus Guidelines 2014. Type 2 diabetes in the child and adolescent. Pediatr Diabetes. 2014; 15 Suppl 20: 26–46.
- Zimmet P, Alberti KG, Kaufman F, et al. IDF Consensus Group. The metabolic syndrome in children and adolescents - an IDF consensus report. Pediatr Diabetes. 2007; 8(5): 299–306.
- Gandhi K, Adhikari P, Basu A, et al. Association between a 11β-hydroxysteroid dehydrogenase type 1 gene polymorphism and metabolic syndrome in a South Indian population. Metab Syndr Relat Disord. 2013; 11(6): 397–402.
- Dujic T, Bego T, Mlinar B, et al. Association between 11beta-hydroxysteroid dehydrogenase type 1 gene polymorphisms and metabolic syndrome in Bosnian population. Biochem Med (Zagreb). 2012; 22(1): 76–85.
- Turek LV, Leite N, Rodrigues Souza RL, et al. Gender-dependent association of HSD11B1 single nucleotide polymorphisms with glucose and HDL-C levels. Genet Mol Biol. 2014; 37(3): 490–495.
- Rosmond R. Association studies of genetic polymorphisms in central obesity: a critical review. Int J Obes Relat Metab Disord. 2003; 27(10): 1141–1151.
- Robitaille J, Brouillette C, Houde A, et al. Molecular screening of the 11beta-HSD1 gene in men characterized by the metabolic syndrome. Obes Res. 2004; 12(10): 1570–1575.
- Miyamoto Y, Morisaki H, Yamanaka I, et al. Association study of 11beta-hydroxysteroid dehydrogenase type 1 gene polymorphisms and metabolic syndrome in urban Japanese cohort. Diabetes Res Clin Pract. 2009; 85(2): 132–138.
- Hejduk P, Sakowicz A, Pietrucha T. Association between ins4436A in 11β-hydroxysteroid dehydrogenase type 1 gene and essential hypertension in Polish population. Postepy Hig Med Dosw (Online). 2015; 69: 1245–1250.
- Fichna M, Żurawek M, Gryczyńska M, et al. Polymorphic variants of the HSD11B1 gene may be involved in adverse metabolic effects of glucocorticoid replacement therapy in Addison's disease. Eur J Intern Med. 2016; 31: 99–104.
- Molnár Á, Kövesdi A, Szücs N, et al. Polymorphisms of the GR and HSD11B1 genes influence body mass index and weight gain during hormone replacement treatment in patients with Addison's disease. Clin Endocrinol (Oxf). 2016; 85(2): 180–188.