Fulden Sarac, Afig Berdeli, Özen K. Basoglu, Sumru Savas, Merve Atan, Fehmi Akcicek

Lack of Association of Insulin Receptor Substrate Gene Polymorphisms with Obstructive Sleep Apnea Syndrome

Sleep apnea syndrome is associated with increased prevalence of diabetes and has recently shown to be associated with insulin resistance. The aim of the present study was to investigate the relationships between insulin resistance, insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2) gene polymorphisms and obstructive sleep apnea syndrome (OSAS). The study population consisted of 56 consecutive patients with OSAS and 26 subjects without OSAS were enrolled in the study. Genotyping of IRS-1 and IRS-2 were amplified by polymerase chain reaction (PCR). Insulin resistance was estimated using the homeostasis model assessment (HOMA). In OSAS patients, 2 (3.6%) had G972R gene polymorphism and 54 (96.4%) had no nucleotide substitution in IRS-1 gene whereas in the control group, there was no nucleotide substitution in IRS-1 gene (p>0.05). Besides, 47 OSAS patients (84.0%) had no nucleotide substitution, 3 (5.3%) had G1057D heterozygous, 1 (1.8%) had P1033P heterozygous, 3 (5.3%) had P1033P homozygous and 2 (3.6%) had P1033P heterozygous/G1057D heterozygous polymorphisms in IRS-2 gene. In the control subjects, 21 (80.8%) had no nucleotide substitution, 3 (11.5%) had P1033P homozygous and 2 (7.7%) had P1033P heterozygous polymorphisms in IRS-2 gene (p>0.05). There was no significant difference between two groups in terms of fasting glucose and HOMA-IR. It was observed that IRS-1 and IRS-2 gene polymorphisms didnt increase risk for OSAS. Besides, there was no association between IRS-1 and IRS-2 polymorphisms and HOMA in OSAS.

Keywords:

Obstructive sleep apnea syndrome, insulin receptor substrate-1 gene polymorphism, insulin receptor substrate-2 gene polymorphism,

PDF

___

Ronksley PE, Hemmelgarn BR, Heitman SJ, Flemons WW, Ghali WA, Manns B, Faris P, Tsai WH. Excessive daytime sleepiness is associated with increased health care utilization among patients referred for assessment of OSA. Sleep. 2011;34(3):363-70.
Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet. 2009;373(9657):82-93.
Riha RL, McNicholas WT. The genetic and cardiovascular aspects of obstructive sleep apnoea/hypopnoea syndrome. Eur Respir J. 2009;33(2):233-6.
Kent BD, Ryan S, McNicholas WT. The genetics of obstructive sleep apnoea. Curr Opin Pulm Med. 2010;16(6):536-42.
Reichmuth KJ, Austin D, Skatrud JB, Young T. Association of sleep apnea and type II diabetes: a population-based study. Am J Respir Crit Care Med.2005;172(2):1590-5.
Botros N, Concato J, Mohsenin V, Selim B, Doctor K, Yaggi HK. Obstructive sleep apnea as a risk factor for type 2 diabetes. Am J Med. 2009;122(12):1122-7.
Polotsky VY, Patil SP, Savransky V, Laffan A, Fonti S, Frame LA, Steele KE, Schweizter MA, Clark JM, Torbenson MS, Schwartz AR. Obstructive sleep apnea, insulin resistance, and steatohepatitis in severe obesity. Am J Respir Crit Care Med. 2009;179(3):228-4.
Hribal ML, Federici M, Porzio O, Lauro D, Borboni P, Accili D, Lauro R, Sesti G. The Gly-->Arg972 amino acid polymorphism in insulin receptor substrate-1 affects glucose metabolism in skeletal muscle cells. J Clin Endocrinol Metab. 2000;85(5):2004-13.
Ura S, Araki E, Kishikawa H, Shirotani T, Todaka M, Isami S, Shimoda S, Yoshimura R, Matsuda K, Motoyoshi S, Miyamura N, Kahn CR, Shichiri M. Molecular scanning of the insulin receptor substrate-1 (IRS-1) gene in Japanese patients with NIDDM: identification of five novel polymorphisms. Diabetologia. 1996;39(5):600-8.
Laakso M, Malkki M, Kekäläinen P, Kuusisto J, Deeb SS. Insulin receptor substrate-1 variants in non-insulin-dependent diabetes. J Clin Invest. 1994;94(3):1141-6.
Porzio O, Federici M, Hribal ML, Lauro D, Accili D, Lauro R, Borboni P, Sesti G. The Gly972-->Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. J Clin Invest. 1999;104(3):357-64.
Mammarella S, Romano F, Di Valerio A, Creati B, Esposito DL, Palmirotta R, Capani F, Vitullo P, Volpe G, Battista P, Della Loggia F, Mariani-Costantini R, Cama A. Interaction between the G1057D variant of IRS-2 and overweight in the pathogenesis of type 2 diabetes. Hum Mol Genet. 2000;9(17):2517-21.
Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991;14(6):540-5.
Rechtschaffen A, Kales A. A Manual of Standardized Terminology, Techniques and Scoring for Sleep Stages of Human Subjects. Los Angeles, Brain Information Service/Brain Research Institute, University of California, 1968.
Iber C, Ancoli-Israel S, Chesson AL, Quan SF for the American Academy of Sleep Medicine. The AASM manual 2007 for the scoring of sleep and associated events: rules, terminology and technical specifications. Westchester, Illinois: American Academy of Sleep Medicine, 2007.
American Academy of Sleep Medicine. International classification of sleep disorders, 2nd edition: Diagnostic and coding manual. Westchester, Illinois: American Academy of Sleep Medicine, 2005.
Baroni MG, Arca M, Sentinelli F, Buzzetti R, Capici F, Lovari S, Vitale M, Romeo S, Di Mario U. The G972R variant of the insulin receptor substrate-1 (IRS-1) gene, body fat distribution and insulin-resistance. Diabetologia. 2001;44(3):367-72.
Lautier C, El Mkadem SA, Renard E, Brun JF, Gris JC, Bringer J, Grigorescu F. Complex haplotypes of IRS2 gene are associated with severe obesityand reveal heterogeneity in the effect of Gly1057Asp mutation. Hum Genet. 2003;113(1):34-43.
Mohn A, Marcovecchio M, Chiarelli F. Validity of HOMA-IR as index of insulin resistance in obesity. J Pediatr. 2006;148(4):565-6.
Schwab RJ. Genetic determinants of upper airway structures that predispose to obstructive sleep apnea. Respir Physiol Neurobiol. 2005;147(2-3):289-98.
White MF. The insulin signalling system and the IRS proteins. Diabetologia. 1997;40 Suppl 2:S2-17.
Sesti G, Federici M, Hribal ML, Lauro D, Sbraccia P, Lauro R. Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. FASEB J. 2001;15(12):2099-111.
Sun XJ, Wang LM, Zhang Y, Yenush L, Myers MG, Glasheen E, Lane WS, Pierce JH, White MF. Role of IRS-2 in insulin and cytokine signalling. Nature. 1995;377 ( 6545):173-7.
Lavan BE, Lane WS, Lienhard GE. The 60-kDa phosphotyrosine protein in insulintreated adipocytes is a new member of the insulin receptor substrate family. J Biol Chem. 1997;272(17):11439-43.
Lavan BE, Fantin VR, Chang ET, Lane WS, Keller SR, Lienhard GE. A novel 160kDa phosphotyrosine protein in insulin-treated embryonic kidney cells is a new member of the insulin receptor substrate family. J Biol Chem. 1997;272(34): 21403-7. Ogus C, Ket S, Bilgen T, Keser I, Cilli A, Gocmen AY, Tosun O, Gumuslu S. Insertion/deletion polymorphism and serum activity of the angiotensin-converting enzyme in Turkish patients with obstructive sleep apnea syndrome. Biochem Genet. 2010;48(5-6):516-23.
Yakut T, Karkucak M, Ursavas A, Gulten T, Burgazlioglu B, Gorukmez O, Karadag M. Lack of association of ACE gene I/D polymorphism with obstructive sleep apnea syndrome in Turkish patients. Genet Mol Res. 2010;9(2):734-8.
Bayazit YA, Erdal ME, Yilmaz M, Ciftci TU, Soylemez F, Gokdoğan T, Kokturk O, Kemaloglu YK, Koybasioglu A. Insulin receptor substrate gene polymorphism is associated with obstructive sleep apnea syndrome in men. Laryngoscope. 2006;116(11):1962-5.
Laukkanen O, Pihlajamäki J, Lindström J, Eriksson J, Valle TT, Hämäläinen H, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Tuomilehto J, Uusitupa M, Laakso M; Finnish Diabetes Prevention Study Group. Common polymorphisms in the genes regulating the early insulin signalling pathway: effects on weight change and the conversion from impaired glucose tolerance to type 2 diabetes. The Finnish Diabetes Prevention Study. Diabetologia. 2004;47(5):871-7.
Hoffstein V, Oliver Z. Pulmonary function and sleep apnea. Sleep Breath. 2003;7(4):159-65.
Ip MS, Lam B, Ng MM, Lam WK, Tsang KW, Lam KS. Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med. 2002;165(5):670-6.
Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NFkappaB, Nat Med. 2005;11(2):183-90.
Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science. 2001;293(5535):1673-7.
Morton NM. Obesity and corticosteroids: 11beta-hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease. Mol Cell Endocrinol. 2010;316(2):154-64.
Ip MS, Lam KS, Ho C, Tsang KW, Lam W. Serum leptin and vascular risk factors in obstructive sleep apnea. Chest. 2000;118(3):580-6.
Magalang UJ, Cruff JP, Rajappan R, Hunter MG, Patel T, Marsh CB, Raman SV, Parinandi NL. Intermittent hypoxia suppresses adiponectin secretion by adipocytes. Exp Clin Endocrinol Diabetes. 2009;117(3):129-34.
Sesti G. Insulin receptor substrate polymorphisms and type 2 diabetes mellitus. Pharmacogenomics 2000;1(3):343-57.