The Relationship between Obstructive Sleep Apnea and Gln223Arg Polymorphism in Human Leptin Receptor Gene

Year 2017, Volume: 76 Issue: 2, 43 - 50, 27.12.2017

Serkan Kuccukturk , Sebnem Yosunkaya Hacer Kuzu Okur Seyit Ali Kayis Sennur Demirel Hasibe Cingilli Vural

https://doi.org/10.5152/EurJBiol.2017.1708

Abstract

Leptin is derived from an adipocyte and
acts through the leptin receptor (LEPR). Gln223Arg polymorphism of the LEPR
gene is thought to be associated with impaired signaling capacity of LEPR and
with higher mean circulating levels of leptin and obesity; therefore, it may
contribute to the pathogenesis of obstructive sleep apnea syndrome (OSAS). The
aim of this study was to investigate the frequency of distribution of LEPR gene
polymorphism (Gln223Arg) in OSAS patients in relation to polysomnographic
traits and phenotype.

In total, 230 men (152 OSAS patients and 78
controls) were included in the study. All participants were evaluated by
polysomnography in addition to anthropometric, metabolic, and hemodynamic
variables. The relationship between these phenotypes and polymorphism of the
LEPR gene was investigated by PCR-RFLP.

There was no difference between the
genotype frequencies of the Gln223Arg polymorphism in the OSAS and control
groups. However, OSAS patients carrying the R allele (RR and QR genotypes) had
significantly lower Body Mass Index (BMI) than those carrying the Q allele
(QQ). OSAS patients with the RR genotype had a significantly lower diastolic
blood pressure value than those with the QQ and QR genotypes. When all
participants were grouped by blood pressure, the genotype frequency of RR
individuals was more prevalent among normotensive men compared to hypertensive
men.

Gln223Arg
polymorphism of LEPR does not seem to be associated with OSAS. This
polymorphism may, however, predispose the carrier to reduced BMI and blood
pressure. Further studies are needed to unveil the genetic basis of OSAS
pathophysiology.

Keywords

Blood pressure, gln223arg, leptin receptor polymorphism, leptin, obstructive sleep apnea, obstructive sleep apnea

References

• 1. Guilleminault C, Abad VC. Obstructive sleep apnea syndromes. Med Clin North Am 2004; 88(3): 611-30. 2. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002; 165(9): 1217-39. 3. Drager LF, Togeiro SM, Polotsky VY, Lorenzi-Filho G. Obstructive sleep apnea: a cardiometabolic risk in obesity and the metabolic syndrome. J Am Coll Cardiol 2013; 62(7): 569-76. 4. Sánchez-de-la-Torre M, Campos-Rodriguez F, Barbé F. Obstructive sleep apnoea and cardiovascular disease. Lancet Respir Med 2013; 1(1): 61-72. 5. Frey WC, Pilcher J. Obstructive sleep-related breathing disorders in patients evaluated for bariatric surgery. Obes Surg 2003; 13(5): 676-83. 6. Vgontzas AN, Bixler EO, Chrousos GP. Sleep apnea is a manifestation of the metabolic syndrome. Sleep Med Rev 2005; 9: 211-24. 7. Phillips BG, Kato M, Narkiewicz K, Choe I, Somers VK. Increases in leptin levels, sympathetic drive, and weight gain in obstructive sleep apnea. Am J Physiol Heart Circ Physiol 2000; 279: H234-7. 8. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 1996; 348(9021): 159-61. 9. Wiesner G, Vaz M, Collier G, Seals D, Kaye D, Jennings G, et al. Leptin is released from the human brain: influence of adiposity and gender. J Clin Endocrinol Metab 1999; 84(7): 2270-4. 10. Redline S, Tishler PV. The genetics of sleep apnea. Sleep Med Rev 2000; 4(6): 583-602. 11. Liu YJ, Rocha-Sanchez SM, Liu PY, Long JR, Lu Y, Elze L, et al. Tests of linkage and/or association of the LEPR gene polymorphisms with obesity phenotypes in Caucasian nuclear families. Physiol Genomics 2004; 17(2): 101-6. 12. Tartaglia LA. The leptin receptor. J Biol Chem 1997; 272(10): 6093-6. 13. Mantzoros CS. The role of leptin in human obesity and disease: a review of current evidence. Ann Intern Med 1999; 130(8): 671-80. 14. Ogawa T, Hirose H, Yamamoto Y, Nishikai K, Miyashita K, Nakamura H, et al. Relationships between serum soluble leptin receptor level and serum leptin and adiponectin levels, insulin resistance index, lipid profile, and leptin receptor gene polymorphisms in the Japanese population. Metabolism 2004; 53(7): 879-85. 15. Ragin CC, Dallal C, Okobia M, Modugno F, Chen J, Garte S, et al. Leptin levels and leptin receptor polymorphism frequency in healthy populations. Infect Agent Cancer 2009; 4 Suppl 1: S13. 16. Chiu KC, Chu A, Chuang LM, Saad MF. Association of leptin receptor polymorphism with insulin resistance. Eur J Endocrinol 2004; 150(5): 725-9. 17. Shimizu H, Oh-I S, Okada S, Mori M. Leptin resistance and obesity. Endocr J 2007; 54(1): 17-26. 18. Quinton ND, Lee AJ, Ross RJ, Eastell R, Blakemore AI. A single nucleotide polymorphism (SNP) in the leptin receptor is associated with BMI, fat mass and leptin levels in postmenopausal Caucasian women. Hum Genet 2001; 108(3): 233-6. 19. Yiannakouris N, Yannakoulia M, Melistas L, Chan JL, Klimis-Zacas D, Mantzoros CS. 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 2001; 86(9): 4434-9. 20. Hastuti P, Zukhrufia I, Padwaswari MH, Nuraini A, Sadewa AH. Polymorphism in leptin receptor gene was associated with obesity in Yogyakarta, Indonesia. Egypt J Med Hum Genet 2016; 17(3): 271-6. 21. Lv D, Tan L, Wu Y, Cao C, Deng Z. Leptin and leptin receptor gene polymorphisms in obstructive sleep apnea: a HuGE review and meta-analysis. Sleep Breath 2015; 19(3): 1073-8. 22. Schiza SE, Mermigkis C, Bouloukaki I. Leptin and leptin receptor gene polymorphisms and obstructive sleep apnea syndrome: is there an association? Sleep Breath 2015; 19(3): 1079-80. 23. Izci B, Ardic S, Firat H, Sahin A, Altinors M, Karacan I. Reliability and validity studies of the Turkish version of the Epworth Sleepiness Scale. Sleep Breath 2008; 12(2): 161-8. 24. Hommel G. A stagewise rejective multiple test procedure based on a modified Bonferroni test. Biometrika 1988; 75(2): 383-6. 25. World Health Organization. International association for the study of obesity, international obesity task force. The Asia-Pacific perspective: redefining obesity and its treatment 2000: 15-21. 26. Iber C, Ancoli-Israel S, Chesson A, Quan S. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications. Westchester, Illinois: American Academy of Sleep Medicine, 2007. 27. Anonymous. TURKHAYGEN-I (106G005) In Vitro Conservation and Preliminary Molecular Identification of Some Turkish Domestic Animal Genetic Resources-I. Koban E (Ed.). Tür ve Irkların DNA İşaretleri ile Moleküler Tanımlanması Çalışma Paketi I. Çalıştay. ODTÜ, Ankara. 2007. [Online] Available at: http://www.turkhaygen.gov.tr/doc/egitim_ODTU.pdf. Accessed (12.12.2017). 28. Guizar-Mendoza JM, Amador-Licona N, Flores-Martinez SE, Lopez-Cardona MG, Ahuatzin-Tremary R, Sanchez-Corona J. Association analysis of the Gln223Arg polymorphism in the human leptin receptor gene, and traits related to obesity in Mexican adolescents. J Hum Hypertens 2005; 19(5): 341-6. 29. R-DevelopmentCoreTeam. R: A language and environment for statistical computing. R Foundation for Statistical Computing. Vienna, Austria. 2010 http://www.R-project.org. 30. Hanaoka M, Yu X, Urushihata K, Ota M, Fujimoto K, Kubo K. Leptin and leptin receptor gene polymorphisms in obstructive sleep apnea syndrome. Chest 2008; 133(1): 79-85. 31. Huang R, Huang XZ, Li M, Xiao Y, Zhang J. An investigation of the relationship between Lepr gene Gln223Arg polymorphism and obstructive sleep apnea hypopnea syndrome. Zhonghua Jie He He Hu Xi Za Zhi 2003; 26(9): 517-21. 32. Li Z, Wu W, Gu L, Zhao T, Qin G. Lack of association variants of leptin and leptin receptor gene and OSAHS in Chinese Han population. Sleep Biol Rhythms 2016; 14(1): 37-46. 33. Popko K, Gorska E, Wasik M, Stoklosa A, Plywaczewski R, Winiarska M, et al. Frequency of distribution of leptin receptor gene polymorphism in obstructive sleep apnea patients. J Physiol Pharmacol 2007; 58 Suppl 5: 551-61. 34. Stefan N, Vozarova B, Del Parigi A, Ossowski V, Thompson DB, Hanson RL, et al. The Gln223Arg polymorphism of the leptin receptor in Pima Indians: influence on energy expenditure, physical activity and lipid metabolism. Int J Obes Relat Metab Disord 2002; 26: 1629-32. 35. Gotoda T, Manning BS, Goldstone AP, Imrie H, Evans AL, Strosberg AD, et al. Leptin receptor gene variation and obesity: lack of association in a white British male population. Hum Mol Genet 1997; 6(6): 869-76. 36. Mergen H, Karaaslan C, Mergen M, Deniz Ozsoy E, Ozata M. LEPR, ADBR3, IRS-1 and 5-HTT genes polymorphisms do not associate with obesity. Endocr J 2007; 54(1): 89-94. 37. Ben Ali S, Kallel A, Sediri Y, Ftouhi B, Feki M, Slimene H, et al. LEPR p.Q223R Polymorphism influences plasma leptin levels and body mass index in Tunisian obese patients. Arch Med Res 2009; 40(3): 186-90. 38. Chagnon YC, Chung WK, Perusse L, Chagnon M, Leibel RL, Bouchard C. Linkages and associations between the leptin receptor (LEPR) gene and human body composition in the Quebec Family Study. Int J Obes Relat Metab Disord 1999; 23(3): 278-86. 39. Wauters M, Mertens I, Chagnon M, Rankinen T, Considine RV, Chagnon YC, et al. Polymorphisms in the leptin receptor gene, body composition and fat distribution in overweight and obese women. Int J Obes Relat Metab Disord 2001; 25(5): 714-20. 40. Heo M, Leibel RL, Boyer BB, Chung WK, Koulu M, Karvonen MK, et al. Pooling analysis of genetic data: the association of leptin receptor (LEPR) polymorphisms with variables related to human adiposity. Genetics 2001; 159(3): 1163-78. 41. Rosmond R, Chagnon YC, Holm G, Chagnon M, Perusse L, Lindell K, et al. Hypertension in obesity and the leptin receptor gene locus. J Clin Endocrinol Metab 2000; 85(9): 3126-31. 42. Oliveira Rd, Cerda A, Genvigir FDV, Sampaio MF, Armaganijan D, Bernik MMS et al. Leptin receptor gene polymorphisms are associated with adiposity and metabolic alterations in Brazilian individuals. Arq Bras Endocrinol Metabol 2013; 57: 677-84. 43. Gu P, Jiang W, Chen M, Lu B, Shao J, Du H et al. Association of leptin receptor gene polymorphisms and essential hypertension in a Chinese population. J Endocrinol Invest 2012; 35: 859-65.