2658-6533Научные результаты биомедицинских исследований2658-653310.18413/2658-6533-2023-9-3-0-33163Генетика<strong>Анализ полиморфных вариантов генов рецепторов серотонина и гамма-аминомасляной кислоты у больных сахарным диабетом 2 типа</strong><strong>Analysis of polymorphic variants of serotonin and gamma-aminobutyric acid receptor genes in patients with type 2 diabetes mellitus</strong>КочетоваОльга ВладимировнаKochetovaOlga V.Olga_mk78@mail.ruАвзалетдиноваДиана ШамилевнаAvsaleydinivaDiana Sh.ecolab_203@mail.ruКорытинаГульназ ФаритовнаKorytinaGulnaz F.guly_kory@mail.ruВиктороваТатьяна ВикторовнаViktorovaTatiana V.vict@mail.ru20239300

Актуальность:&nbsp;СД2 одно из наиболее распространенных заболеваний 21 века. СД2 имеет многофакторную природу, в его этиологии ведущую роль играют такие факторы, как возраст и ожирение, а также генетическая предрасположенность, обусловленная полиморфизмом ряда генов. Цель исследования:&nbsp;Анализ полиморфных вариантов генов рецепторов серотонина HTRD rs674386, HTR1F rs56398417, HTR2A rs6313, HTR3A rs1062613, HTR2C rs6318, гена рецептора гамма-аминомасляной кислоты GABRA2 rs279845, среди больных СД2, проживающих в РБ. Материалы и методы:&nbsp;Образцы ДНК включали группу больных СД2&nbsp;691 человек и контроль 1096 человек. Исследование полиморфных маркеров проводили с использованием полимеразной цепной реакции (ПЦР) TaqMan. Результаты:&nbsp;В результате изучения 6 полиморфных локусов генов нейротрансмиттерной системы были выявлены протективные маркеры, включающие генотипы CT и СС полиморфного локуса rs1062613 гена HTR3A (OR=0,73, Pcor_FDR=0,0007) и генотипы риска GC и CC полиморфного локуса rs6318 гена HTR2C (OR=2,21, Pcor_FDR=0,0045) среди женщин, генотип СС является рисковым и среди мужчин (OR=4,05, Pcor_FDR=0,0045). Мультилокусный анализ комбинаций генотипов и аллелей выявил пять сочетаний повышенного и пониженного риска развития СД2. Наиболее значимая ассоциация была выявлена для комбинации HTR3A rs1062613 аллель C+HTR2A rs6313 аллель A+HTRD rs674386 аллель А+HTR1F rs55639841 генотип СС (OR=1,74, Pcor_FDR=0,0004). Проведенный анализ ROC кривых показал, что исследуемые локусы HTRD rs674386, HTR1F rs56398417, HTR3A rs1062613, GABRA2 rs279845 и такие переменные как пол, возраст обследуемых и уровень ИМТ, включенные в построение модели расчета риска, могут предсказывать развитие СД2 с чувствительностью 79,0% и специфичностью 75,0%, площадь под кривой AUC составила 83,40% (95% CI 83,50-87,40). Заключение:&nbsp;Полученные результаты могут свидетельствует о высоком уровне прогностической значимости полиморфных вариантов генов нейротрасмиттерной системы в оценке предрасположенности к риску СД2.

Background:&nbsp;Type 2 diabetes mellitus (T2DM) is an expanding global health problem of the 21st century. There has been a global increase in the number of patients with T2DM. It has established a strong association of obesity and age with T2DM. The aim of the study:&nbsp;To analyze polymorphic variants of the serotonin receptor genes HTRD rs674386, HTR1F rs56398417, HTR2A rs6313, HTR3A rs1062613, HTR2C rs6318, the gamma-aminobutyric acid receptor gene GABRA2 rs279845, in patients with type 2 diabetes living in the Republic of Bashkortostan. Materials and methods:&nbsp;DNA samples included a group of patients with T2DM &ndash; 691 individuals and control &ndash; 1096 individuals. The study of polymorphic markers was carried out using the polymerase chain reaction (PCR) TaqMan. Results:&nbsp;As a result of the study of 6 polymorphic loci of the genes of the neurotransmitter system, protective markers were identified, including the CT and CC genotypes of the rs1062613 polymorphic locus of the HTR3A gene (OR=0.73, Pcor_FDR=0.0007) and the GC and CC risk genotypes of the rs6318 polymorphic locus of the HTR2C gene (OR=2.21, Pcor_FDR =0.0045) among women, the CC genotype is also at risk among men (R=4.05, Pcor_FDR=0.0045). Multilocus analysis of combinations of genotypes and alleles revealed five combinations of increased and decreased risk of developing T2DM. The most significant association was found for the combination of HTR3A rs1062613 allele C + HTR2A rs6313 allele A + HTRD rs674386 allele A + HTR1F rs55639841 CC genotype (OR=1.74, Pcor_FDR=0.0004). The analysis of ROC curves showed that the studied loci HTRD rs674386, HTR1F rs56398417, HTR3A rs1062613, GABRA2 rs279845 and variables such as gender, age of the subjects and the level of BMI included in the construction of the risk calculation model can predict the development of T2DM with a sensitivity of 79.0% and a specificity of 75.0%, the area under the AUC curve was 83.40% (95% CI 83.50-87.40). Conclusion:&nbsp;The results obtained may indicate a high level of prognostic significance of polymorphic variants of the genes of the neurotransmitter system in the formation of predisposition to T2DM.

сахарный диабет 2 типанейротрасмиттерная системарецепторы серотонинарецептор гамма-аминомасляной кислотыtype 2 diabetes mellitusneurotransmitter systemserotonin receptorsgamma-aminobutyric acid receptorСписок литературыДедов ИИ, Шестакова МВ, Майоров АЮ, редакторы. Алгоритмы специализированной медицинской помощи больным сахарным диабетом. 10-й выпуск.&nbsp;М.; 2021. DOI: https://doi.org/10.14341/DM12802Cataldo Bascu&ntilde;an LR, Lyons C, Bennet H, et al. Serotonergic regulation of insulin secretion. Acta Physiologica. 2019;225(1):e13101. DOI: https://doi.org/10.1111/apha.13101Choi WG, Choi W, Oh TJ, et al. Inhibiting serotonin signaling through HTR2B in visceral adipose tissue improves obesity-related insulin resistance. Journal of Clinical Investigation. 2021;131(23):e145331. DOI: https://doi.org/10.1172/JCI145331Georgescu T, Lyons D, Heisler LK. Role of serotonin in body weight, insulin secretion and glycaemic control. Journal of Neuroendocrinology. 2021;33(4):e12960. DOI: https://doi.org/10.1111/jne.12960Bennet H, Balhuizen A, Medina A, et al. Altered serotonin (5-HT) 1D and 2A receptor expression may contribute to defective insulin and glucagon secretion in human type 2 diabetes. Peptides. 2015;71:113-120. DOI: https://doi.org/10.1016/j.peptides.2015.07.008Kring SI, Werge T, Holst C, et al. Polymorphisms of serotonin receptor 2A and 2C genes and COMT in relation to obesity and type 2 diabetes. PLoS ONE. 2009;4(8):e6696. DOI: https://doi.org/10.1371/journal.pone.0006696Iordanidou M, Tavridou A, Vasiliadis MV, et al. The-759C/T polymorphism of the 5-HT2C receptor is associated with type 2 diabetes in male and female Caucasians. Pharmacogenetics and Genomics. 2008;18(2):153-159. DOI: https://doi.org/10.1097/FPC.0b013e3282f4ae93Kwon YJ, Hong KW, Park BJ, et al. Serotonin receptor 3B polymorphisms are associated with type 2 diabetes: The Korean Genome and Epidemiology Study. Diabetes Research and Clinical Practice. 2019;153:76-85. DOI: https://doi.org/10.1016/j.diabres.2019.05.032Asadzadeh A, Seyedhosseini GH, Sholehvar F, et al. Investigation of the Association between 5-Hydroxytryptamine Transporter Gene-Linked Polymorphic Region with Type 2 Diabetes Mellitus, Obesity and Biochemical Profiles of Serum in Iranian Population. Avicenna Journal of Medical Biotechnology. 2019;11(3):239-244.Gajos JM, Russell MA, Cleveland HH, et al. Romantic Partner Alcohol Misuse Interacts with GABRA2 Genotype to Predict Frequency of Drunkenness in Young Adulthood. Journal of Contemporary Criminal Justice. 2019;35(1):7-20. DOI: https://doi.org/10.1177/1043986218810578Al-Kuraishy HM, Hussian NR, Al-Naimi MS, et al. The Potential Role of Pancreatic &gamma;-Aminobutyric Acid (GABA) in Diabetes Mellitus: A Critical Reappraisal. International Journal of Preventive Medicine. 2021;12:19. DOI: https://doi.org/10.4103/ijpvm.IJPVM_278_19Al Safar HS, Cordell HJ, Jafer O, et al. A genome‐wide search for type 2 diabetes susceptibility genes in an extended Arab family. Annals of Human Genetics. 2013;77(6):488-503. DOI: https://doi.org/10.1111/ahg.12036Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics. 2007;81(3):559-75. DOI: https://doi.org/10.1086/519795Jahn K, Kurz B, Sinke C, et al. Serotonin system-associated genetic and epigenetic changes in pedophilia and child sexual offending. Journal of Psychiatric Research. 2021;145:60-69. DOI: https://doi.org/10.1016/j.jpsychires.2021.11.042Suchanecka A, Chmielowiec J, Chmielowiec K, et al. Serotonin Receptor HTR3A Gene Polymorphisms rs1985242 and rs1062613, E-Cigarette Use and Personality. International Journal of Environmental Research and Public Health. 2022;19(8):4746. DOI: https://doi.org/10.3390/ijerph19084746Ledermann K, Hasler G, Jenewein J, et al. 5&#39;UTR polymorphism in the serotonergic receptor HTR3A gene is differently associated with striatal Dopamine D2/D3 receptor availability in the right putamen in Fibromyalgia patients and healthy controls-Preliminary evidence. Synapse. 2020;74(5):e22147. DOI: https://doi.org/10.1002/syn.22147Manfredi L, Accoto A, Couyoumdjian A, et al. A Systematic Review of Genetic Polymorphisms Associated with Binge Eating Disorder. Nutrients. 2021;13(3):848. DOI: https://doi.org/10.3390/nu13030848Levchenko A, Vyalova NM, Nurgaliev T, et al. NRG1, PIP4K2A, and HTR2C as Potential Candidate Biomarker Genes for Several Clinical Subphenotypes of Depression and Bipolar Disorder. Frontiers in Genetics. 2020;11:936. DOI: https://doi.org/10.3389/fgene.2020.00936Drago A, Serretti A. Focus on HTR2C: A possible suggestion for genetic studies of complex disorders. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. 2009;150(5):601-637. DOI: https://doi.org/10.1002/ajmg.b.30864Bah J, Westberg L, Baghaei F, et al. Further exploration of the possible influence of polymorphisms in HTR2C and 5HTT on body weight. Metabolism. 2010;59(8):1156-1163. DOI: https://doi.org/10.1016/j.metabol.2009.11.007Santos-J&uacute;nior AD, Henriques TB, de Mello MP, et al. Pharmacogenetics of Risperidone and Cardiovascular Risk in Children and Adolescents. International Journal of Endocrinology. 2016;2016:5872423. DOI: https://doi.org/10.1155/2016/5872423Schlomer GL, Cleveland HH, Deutsch AR, et al. Developmental Change in Adolescent Delinquency: Modeling Time-Varying Effects of a Preventative Intervention and GABRA2 Halpotype Linked to Alcohol Use. Journal of Youth and Adolescence. 2019;48(1):71-85. DOI: https://doi.org/10.1007/s10964-018-0929-zKim J, Park A. A systematic review: Candidate gene and environment interaction on alcohol use and misuse among adolescents and young adults. American Journal on Addictions. 2018;10:10.1111/ajad.12755. DOI: https://doi.org/10.1111/ajad.12755