Dilek KAYA AKYÜZLÜ, Selin ÖZKAN-KOTİLOĞLU, Ece AĞTAŞ ERTAN, Özlem DOĞAN, Berfin KILIMAN, İnci ÖZGÜR İLHAN

Pro-Ghrelin Leu72Met Polimorfizmi ile Açil Ghrelin Düzeyi ve Alkol Kullanım Bozukluğu Arasındaki İlişki: Bir Ön Çalışma

Amaç: Birçok çevresel ve genetik faktör, alkol kullanım bozukluğunun (AKB) gelişimine ve ilerlemesine neden olmaktadır. Beyin-bağırsak ekseninin önemli unsurlarından biri olan ghrelinin, bağımlılığın patofizyolojisinde yer aldığı düşünülmektedir. Bu çalışmanın amacı, GHRL Leu72Met gen polimorfizminin plazma açil ghrelin düzeylerine etkisinin olup olmadığını ilk kez alkol bağımlılarında belirlemektir. Yöntem: Bu çalışmaya 50 alkol bağımlısı erkek ve 50 kontrol dahil edilmiştir. Açil ghrelin düzeyleri ELISA kiti ile ölçülmüştür. GHRL Leu72Met polimorfizmi ise, standart PCR-RFLP yöntemiyle analiz edilmiştir. Bulgular: Açil ghrelin seviyeleri, AKB tanılı hastalarda kontrollere göre anlamlı bir şekilde daha yüksek, Leu72Leu genotipli AKB hastalarında Leu72Met ve Met72Met genotipli hastalara göre daha düşük bulunmuştur. Detoksifikasyondan sonra Leu72Met+Met72Met genotipli AKB hastalarında belirgin bir azalma görülmüştür. Türk erkeklerinde 72Met alelinin varlığı ile AKB riski arasında bir ilişki belirlenmiştir. Sonuç: Bu çalışmada, alkol kullanım bozukluğu olan bireylerde GHRL Leu72Met varyantı ile yüksek açil ghrelin düzeyi arasındaki ilişki ilk kez gösterilmiştir. Türk erkeklerinde, AKB açısından GHRL Leu72 alelinin, Met72 aleli ile kıyaslandığında koruyucu etkiye sahip olduğu söylenebilir. Çalışmaya dahil edilen örneklem büyüklüğü küçük olmasına rağmen, bu çalışmadan elde edilen bulgular GHRL Leu72Met polimorfizminin plazma açil ghrelin ve alkol bağımlılığı üzerinde etkisi olduğunu göstermiştir.

Anahtar Kelimeler:

Alkol Kullanım bozukluğu, GHRL Leu72Met polimorfizmi, açil ghrelin.

Association of Pro-Ghrelin Leu72Met Polymorphism with Acylated Ghrelin Level and Alcohol Use Disorder: A Preliminary Study

Objective: Multiple environmental and genetic factors contribute to the progression of alcohol use disorder (AUD). Ghrelin is one of the important elements of the brain-gut axis that has been believed to involve in the pathophysiology of addiction. This study aimed to determine whether the GHRL Leu72Met gene polymorphism has an effect on the plasma acylated ghrelin levels in alcohol addicts for the first time. Method: A sample of 50 alcohol-dependent men and 50 controls were enrolled in this study. Acylated ghrelin levels were detected by ELISA kit. The GHRL Leu72Met polymorphism was analyzed by the standard PCR-RFLP method. Results: Acylated ghrelin levels were significantly higher in AUD patients than in controls, and were lower in AUD patients with Leu72Leu than those with Leu72Met and Met72Met. After detoxification, a dramatic decrease was seen in AUD patients having Leu72Met+Met72Met. The presence of 72Met allele was also found to be associated with an increased risk of AUD in Turkish men. Conclusion: It was indicated for the first time that the GHRL Leu72Met variant was associated with higher plasma acylated levels in patients with AUD. The GHRL Leu72 allele compared to the Met72 allele seemed to be protective against AUD in Turkish men. Taken together, despite the small number of subjects evaluated, the findings in this study suggested the effect of the GHRL Leu72Met polymorphism on plasma acylated ghrelin levels and alcohol addiction.

Keywords:

Alcohol use disorder, GHRL Leu72Met polymorphism, acylated ghrelin.,

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1.Kamat PK, Mallonee CJ, George AK, Tyagi SC, Tyagi N. Homocysteine, Alcoholism, and Its Potential Epigenetic Mechanism. Alcohol Clin Exp Res 2016; 40 (12): 2474-2481.
2. Farokhnia M, Faulkner ML, Piacentino D, Lee MR, Leggio L. Ghrelin: From a gut hormone to a potential therapeutic target for alcohol use disorder. Physiol Behav 2019; 204: 49-57.
3. Koutouratsas T, Kalli T, Karamanolis G, Gazouli M. Contribution of ghrelin to functional gastrointestinal disorders' pathogenesis. World J Gastroenterol 2019; 25: 539-551.
4. Vestlund J, Winsa-Jörnulf J, Hovey D, Lundström S, Lichtenstein P, et al. Ghrelin and aggressive behaviours-Evidence from preclinical and human genetic studies. Psychoneuroendocrinol 2019; 104: 80-88.
5. Arias AJ, Sewell RA. Pharmacogenetically driven treatments for alcoholism: are we there yet?. CNS Drugs 2012; 26: 461-476.
6. D’Addario C, Shchetynsky K, Pucci M, Cifani C, Gunnar A, et al. Genetic variation and epigenetic modification of the prodynorphin gene in peripheral blood cells in alcoholism. Prog Neuropsychopharmacol Biol Psychiatry 2017; 76: 195-203.
7. Klimkiewicz A, Mach A, Jakubczyk A, Klimkiewicz J, Wnorowska A, et al. COMT and BDNF gene Variants Help to Predict Alcohol Consumption in Alcohol-dependent Patients. J Addict Med 2017; 11: 114-118.
8. Landgren S, Jerlhag E, Zetterberg H, Gonzalez-Quintela A, Campos J, et al. Association of pro-ghrelin and GHS-R1A gene polymorphisms and haplotypes with heavy alcohol use and body mass. Alcohol Clin Exp Res 2008; 32: 2054-2061. doi:10.1111/j.1530-0277.2008.00793.x
9. Suchankova P, Yan J, Schwandt ML, Stangl BL, Jerlhag E, et al. The Leu72Met Polymorphism of the Prepro-ghrelin Gene is Associatedwith AlcoholConsumption and Subjective Responses to Alcohol: Preliminary Findings. Alcohol Alcohol 2017; 52: 425-430.
10. Leggio L, Ferrulli A, Cardone S, Nesci A, Miceli A, et al. Ghrelin system in alcohol-dependent subjects: role of plasma ghrelin levels in alcohol drinking and craving. Addict Biol 2012; 17: 452-464.
11. Wurst FM, Rasmussen DD, Hillemacher T, Kraus T, Ramskogler K, et al. Alcoholism, craving, and hormones: The role of leptin, ghrelin, prolactin and pro-opiomelanocortin system in modulating ethanol intake. Alcohol Clin Exp Res 2007; 31: 1963-1967.
12. Badaoui A, De Saeger C, Duchemin J, Gihousse D, de Timary P, Stärkel P. Alcohol dependence is associated with reduced plasma and fundic ghrelin levels. Eur J Clin Invest 2008; 38: 397-403.
13. Ukkola O, Ravussin E, Jacobson P, Pérusse L, Rankinen T, et al. Role of ghrelin polymorphisms in obesity based on three different studies. Obes Res 2002; 10: 782-791.
14. Seim I, Collet C, Herington AC, Chopin LK. Revised genomic structure of human ghrelin gene and identification of novel exons, alternative splice variants and natural antisense transcripts. BMC Genomics 2007; 8: 298.
15. Li YY, Lu XZ, Yang XX, Wang H, Geng HY, et al. GHRL Gene Leu72Met Polymorphism and Type 2 Diabetes Mellitus: A Meta-Analysis Involving 8,194 Participants. Front Endocrinol (Lausanne) 2019; 10: 559.
16. Huang R, Tian S, Cai R, Sun J, Shen Y, Wang S. Ethnicity-Specific Association Between Ghrelin Leu72Met Polymorphism and Type 2 Diabetes Mellitus Susceptibility: An Updated Meta-Analysis. Front Genet 2018; 9: 541.
17. Monteleone P, Tortorella A, Castaldo E, Di Filippo C, Maj M. The Leu72Met polymorphism of the ghrelin gene is significantly associated with binge eating disorder. Psychiatr Genet 2007; 17: 13-16.
18. Ando T, Komaki G, Naruo T, Okabe K, Takii M, et al. Possible role of preproghrelin gene polymorphisms in susceptibility to bulimia nervosa. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 929-934.
19. Ando T, Ichimaru Y, Konjiki F, Shoji M, Komaki G. Variations in the preproghrelin gene correlate with higher body mass index, fat mass, and body dissatisfaction in young Japanese women. Am J Clin Nutr 2007; 86: 25-32.
20. Holst B, Schwartz TW. Ghrelin receptor mutations - too little height and too much hunger. J Clin Invest 2006; 116: 637-641.
21. Landgren S, Jerlhag E, Hallman J, Oreland L, Lissner L, et al. Genetic variation of the ghrelin signaling system in females with severe alcohol dependence. Alcohol Clin Exp Res 2010; 34: 1519-1524.
22. Kuzuya M, Ando F, Iguchi A, Shimokata H. Preproghrelin Leu72Met variant contributes to overweight in middle-aged men of a Japanese large cohort. Int J Obes (Lond) 2006; 30: 1609-1614.
23. del Giudice EM, Santoro N, Cirillo G, Raimondo P, Grandone A, et al. Molecular screening of the ghrelin gene in Italian obese children: the Leu72Met variant is associated with an earlier onset of obesity. Int J Obes Relat Metab Disord 2004; 28: 447-450. doi:10.1038/sj.ijo.0802572
24. Korbonits M, Gueorguiev M, O’Grady E, Lecoeur C, Swan DC, et al. A variation in the ghrelin gene increases weight and decreases insulin secretion in tall, obese children. J Clin Endocrinol Metab 2002; 87: 4005-4008.