endofocusFOCUS ЭндокринологияFOCUS. Endocrinology2713-01772713-0185ООО "Издательство "Перо"10.62751/2713-0177-2026-7-2-04endofocus-229Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИПолногеномный анализ генетических вариантов, ассоциированных с секрецией энтеропанкреатических гормонов у пациентов с впервые выявленным сахарным диабетом 2 типаGenome wide analysis of genetic variants associated with the secretion of enteropancreatic hormones in patients with newly diagnosed type 2 diabetes mellitushttps://orcid.org/0000-0002-8684-6095ТитоваВ. В.ТitovaV. V.

Титова Виктория Викторовна – ассистент кафедры эндокринологии Института клинической медицины

117997, г. Москва, ул. Островитянова, д. 1

Victoria V. Тitova – assistant at the Department of endocrinology 

1 Ostrovitynova St., Moscow, 117997 

meteora-vica@mail.ruhttps://orcid.org/0000-0001-6385-540XДемидоваТ. Ю.DemidovaT. Yu.

Демидова Татьяна Юльевна – д.м.н., профессор, заслуженный врач РФ

Москва 

Scopus Author ID: 7003771623  

Tatyana Yu. Demidova – Dr. Sci (Med), professor, Honored Doctor of the Russian Federation 

Moscow 

Scopus Author ID: 7003771623 

t.y.demidova@gmail.comhttps://orcid.org/0000-0003-3553-7126БалхияроваЖ. Р.BalkhiyarovaZh. R.

Балхиярова Жанна Радиковна – научный сотрудник, ассистент 

Уфа 

Гилфорд 

Zhanna R. Balkhiyarova – research fellow, assistant 

Ufa 

Guildford 

jane125@yandex.ruhttps://orcid.org/0000-0002-9918-6962ТимашеваЯ. Р.TimashevaYa. R.

Тимашева Янина Римовна – старший научный сотрудник, доцент кафедры 

Уфа 

Yanina R. Timasheva – senior scientist, associate professor 

Ufa 

ianina_t@mail.ruРоссийский национальный исследовательский медицинский университет им. Н.И. Пирогова (Пироговский университет)РоссияPirogov Russian National Research Medical UniversityRussian FederationБашкирский государственный медицинский университетс; Школа биологических наук Университета СурреяВеликобританияBashkir State Medical University; School of Biosciences, University of SurreyUnited KingdomБашкирский государственный медицинский университет; Институт биохимии и генетики – обособленное структурное подразделение Уфимского федерального исследовательского центра Российской академии наукРоссияBashkir State Medical University; Institute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre of the Russian Academy of SciencesRussian Federation20261107202672616Copyright © Титова В.В., Демидова Т.Ю., Балхиярова Ж.Р., Тимашева Я.Р., 20262026Титова В.В., Демидова Т.Ю., Балхиярова Ж.Р., Тимашева Я.Р.Тitova V.V., Demidova T.y., Balkhiyarova Z.R., Timasheva Y.R.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://endofocus.elpub.ru/jour/article/view/229

Цель исследования – изучить ассоциации генетических вариантов, выявленных методом полногеномного генотипирования, с клинико-метаболическими характеристиками пациентов с впервые выявленным сахарным диабетом 2 типа (СД2), включая базальную и постпрандиальную концентрации глюкагоноподобного пептида-1 (ГПП-1) и глюкагона, а также показатель функции β-клеток поджелудочной железы (HOMA-B). Материалы и методы. Проведено полногеномное генотипирование ДНК 100 пациентов с впервые выявленным СД2 с использованием микрочипов Illumina Infinium I Array. Анализ генетических ассоциаций выполнялся с использованием обобщенных линейных моделей (GLM) в рамках аддитивной генетической модели с поправкой на возраст, пол и первые две главные компоненты анализа главных компонент (PCA). Уровни ГПП-1 и глюкагона оценивалась натощак и через 30 мин. после стандартного завтрака, уровень инсулина – натощак и через 120 мин. На основании значений глюкозы и инсулина рассчитывался индекс HOMA-B. Порог полногеномной значимости был установлен на уровне p <5 × 10-8. Результаты. Более 30 генетических вариантов продемонстрировали значимые ассоциации с уровнем ГПП-1 натощак, включая локусы в генах, участвующих в дифференцировке миоцитов и адипоцитов (HDAC9, rs17347800; p = 2,83 × 10-8), ангиогенезе (EFNB2, rs56077446; p = 8,73 × 10-10), транспорте холестерина и ожирении (INSIG2, rs62164898; p = 1,47 × 10-10), переключении между гликолизом и окислительным фосфорилированием (ADCY10, rs73022199; p = 7,16 × 10-9). Для уровня ГПП-1 после стимуляции статистически значимых ассоциаций выявлено не было. Базальная концентрация глюкагона была ассоциирована с локусами AKAP14 (rs141362915; p = 2,22 × 10-10), EGR2 (rs2664317; p = 1,3 × 10-8), CNTN3 (rs676403; p = 8,15 × 10-9), уровень глюкагона через 30 мин. после нагрузки – с генами GPR19 (rs10772590; p = 1,81 × 10-8), псевдогеном KRT8P17 (rs3005547; p = 1,35 × 10-9), регионом AL049634.2‑SIRPB1 (rs3848789; p = 2,56 × 10-8) и SLC45A4 (rs78605132; p = 1,65 × 10-8). Для значений HOMA-B обнаружены ассоциации с неаннотированными локусами AL354984.1 (rs6015149; p = 4,33 × 10-9) и AC034195.1 (rs7624611; p = 2,3 × 10-9). Заключение. Впервые выявлены генетические варианты, ассоциированные с базальным уровнем ГПП-1 у пациентов с впервые диагностированным СД2. Отсутствие значимых ассоциаций для стимулированного уровня ГПП-1 может свидетельствовать о различиях в генетической регуляции базальной и постпрандиальной секреции инкретинов. Различные наборы ассоциированных генов для базального и стимулированного уровней глюкагона подтверждают существование дискретных механизмов генетического контроля этих состояний. Полученные данные расширяют представления о генетической регуляции инкретиновой системы и секреции глюкагона при СД2, что может иметь значение для разработки персонализированных подходов к терапии. 

Aim of the study. To study the associations of genetic variants identified by genome-wide genotyping with clinical and metabolic characteristics of patients with newly diagnosed type 2 diabetes mellitus (T2DM), including basal and postprandial glucagon-like peptide-1 (GLP-1) and glucagon levels, as well as a pancreatic β-cell function index (HOMA-B). Material and methods. Genome-wide genotyping of DNA from 100 patients with newly diagnosed T2DM was performed using Illumina Infinium I Array microarrays. Genetic association analysis was performed using generalized linear models (GLMs) within an additive genetic model, adjusted for age, sex, and the first two principal components of a principal component analysis (PCA). GLP-1 and glucagon levels were measured fasting and 30 minutes after a standard breakfast, and insulin levels were measured fasting and 120 minutes after a standard breakfast. The HOMA-B index was calculated based on glucose and insulin values. The genome-wide significance threshold was set at p <5 × 10-8. Results. More than 30 genetic variants showed significant associations with fasting GLP-1 levels, including loci in genes involved in myocyte and adipocyte differentiation (HDAC9, rs17347800; p = 2.83 × 10-8), angiogenesis (EFNB2, rs56077446; p = 8.73 × 10-10), cholesterol transport and obesity (INSIG2, rs62164898; p = 1.47 × 10-10), and the switch between glycolysis and oxidative phosphorylation (ADCY10, rs73022199; p = 7.16 × 10-9). No statistically significant associations were found for post-stimulation GLP-1 levels. Basal glucagon concentration was associated with the loci AKAP14 (rs141362915; p = 2.22 × 10-10), EGR2 (rs2664317; p = 1.3 × 10-8), CNTN3 (rs676403; p = 8.15 × 10-9), glucagon level 30 min after exercise – with the genes GPR19 (rs10772590; p = 1.81 × 10-8), pseudogene KRT8P17 (rs3005547; p = 1.35 × 10-9), region AL049634.2‑SIRPB1 (rs3848789; p = 2.56 × 10-8) and SLC45A4 (rs78605132; p = 1.65 × 10-8). HOMA-B was associated with the unannotated loci AL354984.1 (rs6015149; p = 4.33 × 10-9) and AC034195.1 (rs7624611; p = 2.3 × 10-9). Conclusion. Genetic variants associated with basal GLP-1 levels in patients with newly diagnosed T2DM were identified for the first time. The lack of significant associations for stimulated GLP-1 levels may indicate differences in the genetic regulation of basal and postprandial incretin secretion. Different sets of associated genes for basal and stimulated glucagon levels support the existence of discrete mechanisms of genetic control of these conditions. The obtained data expand our understanding of the genetic regulation of the incretin system and glucagon secretion in T2DM, which may be important for the development of personalized approaches to therapy. 

сахарный диабет 2 типаполногеномное генотипированиеGWASглюкагоноподобный пептид-1глюкагонHOMA-Bгенетические вариантыtype 2 diabetesgenome-wide genotypingGWASglucagon-like peptide-1glucagonHOMA-Bgenetic variantsReferencesDuncan, B. B., Magliano, D. J., & Boyko, E. J. (2025). IDF Diabetes Atlas 11th edition 2025: global prevalence and projections for 2050. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 41(1), 7–9. https://doi.org/10.1093/ndt/gfaf177Duncan, B. B., Magliano, D. J., & Boyko, E. J. (2025). IDF Diabetes Atlas 11th edition 2025: global prevalence and projections for 2050. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 41(1), 7–9. https://doi.org/10.1093/ndt/gfaf177Suzuki, K., Hatzikotoulas, K., Southam, L., Taylor, H. J., Yin, X., Lorenz, K. M., et al. (2024). Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. Nature, 627(8003), 347–357. https://doi.org/10.1038/s41586-024-07019-6Suzuki, K., Hatzikotoulas, K., Southam, L., Taylor, H. J., Yin, X., Lorenz, K. M., et al. (2024). Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. Nature, 627(8003), 347–357. https://doi.org/10.1038/s41586-024-07019-6Torekov, S. S., Ma, L., Grarup, N., Hartmann, B., Hainerová, I. A., Kielgast, U., et al. (2011). Homozygous carriers of the G allele of rs4664447 of the glucagon gene (GCG) are characterised by decreased fasting and stimulated levels of insulin, glucagon and glucagon-like peptide (GLP)-1. Diabetologia, 54(11), 2820–2831. https://doi.org/10.1007/s00125-011-2265-7Torekov, S. S., Ma, L., Grarup, N., Hartmann, B., Hainerová, I. A., Kielgast, U., et al. (2011). Homozygous carriers of the G allele of rs4664447 of the glucagon gene (GCG) are characterised by decreased fasting and stimulated levels of insulin, glucagon and glucagon-like peptide (GLP)-1. Diabetologia, 54(11), 2820–2831. https://doi.org/10.1007/s00125-011-2265-7Böhm, A., Wagner, R., Machicao, F., Holst, J. J., Gallwitz, B., Stefan, N., et al. (2017). DPP4 gene variation affects GLP-1 secretion, insulin secretion, and glucose tolerance in humans with high body adiposity. PloS one, 12(7), e0181880. https://doi.org/10.1371/journal.pone.0181880Böhm, A., Wagner, R., Machicao, F., Holst, J. J., Gallwitz, B., Stefan, N., et al. (2017). DPP4 gene variation affects GLP-1 secretion, insulin secretion, and glucose tolerance in humans with high body adiposity. PloS one, 12(7), e0181880. https://doi.org/10.1371/journal.pone.0181880Mahajan, A., Taliun, D., Thurner, M., Robertson, N. R., Torres, J. M., Rayner, N. W., et al. (2018). Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nature genetics, 50(11), 1505–1513. https://doi.org/10.1038/s41588-018-0241-6Mahajan, A., Taliun, D., Thurner, M., Robertson, N. R., Torres, J. M., Rayner, N. W., et al. (2018). Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nature genetics, 50(11), 1505–1513. https://doi.org/10.1038/s41588-018-0241-6Дедов И.И., Шестакова М.В., Сухарева О.Ю., Мокрышева Н.Г., Андреева Е.Н., Безлепкина О.Б., и др. Алгоритмы специализированной медицинской помощи больным сахарным диабетом / Под редакцией И.И. Дедова, М.В. Шестаковой, О.Ю. Сухаревой. 12-й выпуск. Сахарный диабет. 2025;28(5S):1-175. [Dedov I., Shestakova M., Sukhareva O., Mokrysheva N., Andreeva E., Bezlepkina O., et al. Standards of Specialized Diabetes Care / Edited by Dedov I.I., Shestakova M.V., Sukhareva O.Yu. 12th Edition. Diabetes mellitus. 2025;28(5S):1-175. (In Russ.) (In Russ.)] https://doi.org/10.14341/DM20255SДедов И.И., Шестакова М.В., Сухарева О.Ю., Мокрышева Н.Г., Андреева Е.Н., Безлепкина О.Б., и др. Алгоритмы специализированной медицинской помощи больным сахарным диабетом / Под редакцией И.И. Дедова, М.В. Шестаковой, О.Ю. Сухаревой. 12-й выпуск. Сахарный диабет. 2025;28(5S):1-175. [Dedov I., Shestakova M., Sukhareva O., Mokrysheva N., Andreeva E., Bezlepkina O., et al. Standards of Specialized Diabetes Care / Edited by Dedov I.I., Shestakova M.V., Sukhareva O.Yu. 12th Edition. Diabetes mellitus. 2025;28(5S):1-175. (In Russ.) (In Russ.)] https://doi.org/10.14341/DM20255SSong Y, Manson JE, Tinker L, Howard BV, Kuller LH, Nathan L, Rifai N, Liu S (2007) Insulin sensitivity and insulin secretion determined by homeostasis model assessment and risk of diabetes in a multiethnic cohort of women: the Women’s Health Initiative Observational Study. Diabetes Care 30(7):1747–1752. https://doi.org/10.2337/dc07-0358Song Y, Manson JE, Tinker L, Howard BV, Kuller LH, Nathan L, Rifai N, Liu S (2007) Insulin sensitivity and insulin secretion determined by homeostasis model assessment and risk of diabetes in a multiethnic cohort of women: the Women’s Health Initiative Observational Study. Diabetes Care 30(7):1747–1752. https://doi.org/10.2337/dc07-0358Levey, A. S., Stevens, L. A., Schmid, C. H., Zhang, Y. L., Castro, A. F., 3rd, Feldman, H. I., et al., & CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) (2009). A new equation to estimate glomerular filtration rate. Annals of internal medicine, 150(9), 604–612. https://doi.org/10.7326/0003-4819-150-9-200905050-00006Levey, A. S., Stevens, L. A., Schmid, C. H., Zhang, Y. L., Castro, A. F., 3rd, Feldman, H. I., et al., & CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) (2009). A new equation to estimate glomerular filtration rate. Annals of internal medicine, 150(9), 604–612. https://doi.org/10.7326/0003-4819-150-9-200905050-00006Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A., Bender, D., et al. (2007). PLINK: a tool set for whole-genome association and population-based linkage analyses. American journal of human genetics, 81(3), 559–575. https://doi.org/10.1086/519795Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A., Bender, D., et al. (2007). PLINK: a tool set for whole-genome association and population-based linkage analyses. American journal of human genetics, 81(3), 559–575. https://doi.org/10.1086/519795Chang, C.C.; Chow, C.C.; Tellier, L.C.; Vattikuti, S.; Purcell, S.M.; Lee, J.J. Second-generation PLINK: rising to the challenge of larger and richer datasets, GigaScience, Volume 4, Issue 1, December 2015, s13742–015–0047–8, https://doi.org/10.1186/s13742-015-0047-8Chang, C.C.; Chow, C.C.; Tellier, L.C.; Vattikuti, S.; Purcell, S.M.; Lee, J.J. Second-generation PLINK: rising to the challenge of larger and richer datasets, GigaScience, Volume 4, Issue 1, December 2015, s13742–015–0047–8, https://doi.org/10.1186/s13742-015-0047-8Boughton, A. P., Welch, R. P., Flickinger, M., VandeHaar, P., Taliun, D., Abecasis, G. R., Boehnke, M. (2021). LocusZoom.js: interactive and embeddable visualization of genetic association study results. Bioinformatics (Oxford, England), 37(18), 3017–3018. https://doi.org/10.1093/bioinformatics/btab186Boughton, A. P., Welch, R. P., Flickinger, M., VandeHaar, P., Taliun, D., Abecasis, G. R., Boehnke, M. (2021). LocusZoom.js: interactive and embeddable visualization of genetic association study results. Bioinformatics (Oxford, England), 37(18), 3017–3018. https://doi.org/10.1093/bioinformatics/btab186Casper, J., Speir, M. L., Raney, B. J., Perez, G., Nassar, L. R., Lee, C. M., et al. (2026). The UCSC Genome Browser database: 2026 update. Nucleic acids research, 54(D1), D1331–D1335. https://doi.org/10.1093/nar/gkaf1250Casper, J., Speir, M. L., Raney, B. J., Perez, G., Nassar, L. R., Lee, C. M., et al. (2026). The UCSC Genome Browser database: 2026 update. Nucleic acids research, 54(D1), D1331–D1335. https://doi.org/10.1093/nar/gkaf1250Dyer, S. C., Austine-Orimoloye, O., Azov, A. G., Barba, M., Barnes, I., Barrera-Enriquez, V. P., et al. (2025). Ensembl 2025. Nucleic acids research, 53(D1), D948–D957. https://doi.org/10.1093/nar/gkae1071Dyer, S. C., Austine-Orimoloye, O., Azov, A. G., Barba, M., Barnes, I., Barrera-Enriquez, V. P., et al. (2025). Ensembl 2025. Nucleic acids research, 53(D1), D948–D957. https://doi.org/10.1093/nar/gkae1071Fairley, S., Lowy-Gallego, E., Perry, E., & Flicek, P. (2020). The International Genome Sample Resource (IGSR) collection of open human genomic variation resources. Nucleic acids research, 48(D1), D941–D947. https://doi.org/10.1093/nar/gkz836Fairley, S., Lowy-Gallego, E., Perry, E., & Flicek, P. (2020). The International Genome Sample Resource (IGSR) collection of open human genomic variation resources. Nucleic acids research, 48(D1), D941–D947. https://doi.org/10.1093/nar/gkz836Hu, S., Cho, E. H., & Lee, J. Y. (2020). Histone Deacetylase 9: Its Role in the Pathogenesis of Diabetes and Other Chronic Diseases. Diabetes & metabolism journal, 44(2), 234–244. https://doi.org/10.4093/dmj.2019.0243Hu, S., Cho, E. H., & Lee, J. Y. (2020). Histone Deacetylase 9: Its Role in the Pathogenesis of Diabetes and Other Chronic Diseases. Diabetes & metabolism journal, 44(2), 234–244. https://doi.org/10.4093/dmj.2019.0243Caporali, A., Meloni, M., Nailor, A. Mitić, T., Shantikumar, S., Riu, F., et al. p75NTR-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte–endothelial crosstalk in diabetes after limb ischaemia. Nat Commun 6, 8024 (2015). https://doi.org/10.1038/ncomms9024Caporali, A., Meloni, M., Nailor, A. Mitić, T., Shantikumar, S., Riu, F., et al. p75NTR-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte–endothelial crosstalk in diabetes after limb ischaemia. Nat Commun 6, 8024 (2015). https://doi.org/10.1038/ncomms9024Andreasen, C. H., Mogensen, M. S., Borch-Johnsen, K., Sandbaek, A., Lauritzen, T., Sørensen, T. I., Hansen, L., Almind, K., Jørgensen, T., Pedersen, O., & Hansen, T. (2008). Non-replication of genome-wide based associations between common variants in INSIG2 and PFKP and obesity in studies of 18,014 Danes. PloS one, 3(8), e2872. https://doi.org/10.1371/journal.pone.0002872Andreasen, C. H., Mogensen, M. S., Borch-Johnsen, K., Sandbaek, A., Lauritzen, T., Sørensen, T. I., Hansen, L., Almind, K., Jørgensen, T., Pedersen, O., & Hansen, T. (2008). Non-replication of genome-wide based associations between common variants in INSIG2 and PFKP and obesity in studies of 18,014 Danes. PloS one, 3(8), e2872. https://doi.org/10.1371/journal.pone.0002872Franks, P. W., Jablonski, K. A., Delahanty, L. M., McAteer, J. B., Kahn, S. E., Knowler, W. C., Florez, J. C., & Diabetes Prevention Program Research Group (2008). Assessing gene-treatment interactions at the FTO and INSIG2 loci on obesity-related traits in the Diabetes Prevention Program. Diabetologia, 51(12), 2214–2223. https://doi.org/10.1007/s00125-008-1158-xFranks, P. W., Jablonski, K. A., Delahanty, L. M., McAteer, J. B., Kahn, S. E., Knowler, W. C., Florez, J. C., & Diabetes Prevention Program Research Group (2008). Assessing gene-treatment interactions at the FTO and INSIG2 loci on obesity-related traits in the Diabetes Prevention Program. Diabetologia, 51(12), 2214–2223. https://doi.org/10.1007/s00125-008-1158-xChang, J. C., Go, S., Gilglioni, E. H., Duijst, S., Panneman, D. M., Rodenburg, R. J., Li, H. L., Huang, H. L., Levin, L. R., Buck, J., Verhoeven, A. J., & Oude Elferink, R. P. J. (2021). Soluble adenylyl cyclase regulates the cytosolic NADH/NAD+ redox state and the bioenergetic switch between glycolysis and oxidative phosphorylation. Biochimica et biophysica acta. Bioenergetics, 1862(4), 148367. https://doi.org/10.1016/j.bbabio.2020.148367Chang, J. C., Go, S., Gilglioni, E. H., Duijst, S., Panneman, D. M., Rodenburg, R. J., Li, H. L., Huang, H. L., Levin, L. R., Buck, J., Verhoeven, A. J., & Oude Elferink, R. P. J. (2021). Soluble adenylyl cyclase regulates the cytosolic NADH/NAD+ redox state and the bioenergetic switch between glycolysis and oxidative phosphorylation. Biochimica et biophysica acta. Bioenergetics, 1862(4), 148367. https://doi.org/10.1016/j.bbabio.2020.148367Chaves, G., Stanley, J., & Pourmand, N. (2019). Mutant Huntingtin Affects Diabetes and Alzheimer's Markers in Human and Cell Models of Huntington's Disease. Cells, 8(9), 962. https://doi.org/10.3390/cells8090962Chaves, G., Stanley, J., & Pourmand, N. (2019). Mutant Huntingtin Affects Diabetes and Alzheimer's Markers in Human and Cell Models of Huntington's Disease. Cells, 8(9), 962. https://doi.org/10.3390/cells8090962Kultgen, P. L., Byrd, S. K., Ostrowski, L. E., & Milgram, S. L. (2002). Characterization of an A-kinase anchoring protein in human ciliary axonemes. Molecular biology of the cell, 13(12), 4156–4166. https://doi.org/10.1091/mbc.e02-07-0391Kultgen, P. L., Byrd, S. K., Ostrowski, L. E., & Milgram, S. L. (2002). Characterization of an A-kinase anchoring protein in human ciliary axonemes. Molecular biology of the cell, 13(12), 4156–4166. https://doi.org/10.1091/mbc.e02-07-0391Okamura, T., Yamamoto, K., & Fujio, K. (2018). Early Growth Response Gene 2-Expressing CD4+LAG3+ Regulatory T Cells: The Therapeutic Potential for Treating Autoimmune Diseases. Frontiers in immunology, 9, 340. https://doi.org/10.3389/fimmu.2018.00340Okamura, T., Yamamoto, K., & Fujio, K. (2018). Early Growth Response Gene 2-Expressing CD4+LAG3+ Regulatory T Cells: The Therapeutic Potential for Treating Autoimmune Diseases. Frontiers in immunology, 9, 340. https://doi.org/10.3389/fimmu.2018.00340Tyler, E. J., Gutierrez Del Arroyo, A., Hughes, B. K., Wallis, R., Garbe, J. C., Stampfer, M. R., Koh, J., Lowe, R., Philpott, M. P., & Bishop, C. L. (2021). Early growth response 2 (EGR2) is a novel regulator of the senescence programme. Aging cell, 20(3), e13318. https://doi.org/10.1111/acel.13318Tyler, E. J., Gutierrez Del Arroyo, A., Hughes, B. K., Wallis, R., Garbe, J. C., Stampfer, M. R., Koh, J., Lowe, R., Philpott, M. P., & Bishop, C. L. (2021). Early growth response 2 (EGR2) is a novel regulator of the senescence programme. Aging cell, 20(3), e13318. https://doi.org/10.1111/acel.13318Zhou, J., Xie, Z., Cui, P., Su, Q., Zhang, Y., Luo, L., Li, Z., Ye, L., Liang, H., & Huang, J. (2020). SLC1A1, SLC16A9, and CNTN3 Are Potential Biomarkers for the Occurrence of Colorectal Cancer. BioMed research international, 2020, 1204605. https://doi.org/10.1155/2020/1204605Zhou, J., Xie, Z., Cui, P., Su, Q., Zhang, Y., Luo, L., Li, Z., Ye, L., Liang, H., & Huang, J. (2020). SLC1A1, SLC16A9, and CNTN3 Are Potential Biomarkers for the Occurrence of Colorectal Cancer. BioMed research international, 2020, 1204605. https://doi.org/10.1155/2020/1204605Gaikwad, S., Larionov, S., Wang, Y., Dannenberg, H., Matozaki, T., Monsonego, A., Thal, D. R., & Neumann, H. (2009). Signal regulatory protein-beta1: a microglial modulator of phagocytosis in Alzheimer's disease. The American journal of pathology, 175(6), 2528–2539. https://doi.org/10.2353/ajpath.2009.090147Gaikwad, S., Larionov, S., Wang, Y., Dannenberg, H., Matozaki, T., Monsonego, A., Thal, D. R., & Neumann, H. (2009). Signal regulatory protein-beta1: a microglial modulator of phagocytosis in Alzheimer's disease. The American journal of pathology, 175(6), 2528–2539. https://doi.org/10.2353/ajpath.2009.090147Middleton, S. J., Markússon, S., Åkerlund, M., Deme, J. C., Tseng, M., Li, W., Zuberi, S. R., Kuteyi, G., Sarkies, P., Baskozos, G., Perez-Sanchez, J., Farah, A., Hébert, H. L., Toikumo, S., Yu, Z., Maxwell, S., Dong, Y. Y., Kessler, B. M., Kranzler, H. R., Linley, J. E., … Bennett, D. L. (2025). SLC45A4 is a pain gene encoding a neuronal polyamine transporter. Nature, 646(8084), 404–412. https://doi.org/10.1038/s41586-025-09326-yMiddleton, S. J., Markússon, S., Åkerlund, M., Deme, J. C., Tseng, M., Li, W., Zuberi, S. R., Kuteyi, G., Sarkies, P., Baskozos, G., Perez-Sanchez, J., Farah, A., Hébert, H. L., Toikumo, S., Yu, Z., Maxwell, S., Dong, Y. Y., Kessler, B. M., Kranzler, H. R., Linley, J. E., … Bennett, D. L. (2025). SLC45A4 is a pain gene encoding a neuronal polyamine transporter. Nature, 646(8084), 404–412. https://doi.org/10.1038/s41586-025-09326-yChen, W., Huang, F., Huang, J., Li, Y., Peng, J., Zhuang, Y., Huang, X., Lu, L., Zhu, Z., & Zhang, S. (2021). SLC45A4 promotes glycolysis and prevents AMPK/ULK1-induced autophagy in TP53 mutant pancreatic ductal adenocarcinoma. The journal of gene medicine, 23(9), e3364. https://doi.org/10.1002/jgm.3364Chen, W., Huang, F., Huang, J., Li, Y., Peng, J., Zhuang, Y., Huang, X., Lu, L., Zhu, Z., & Zhang, S. (2021). SLC45A4 promotes glycolysis and prevents AMPK/ULK1-induced autophagy in TP53 mutant pancreatic ductal adenocarcinoma. The journal of gene medicine, 23(9), e3364. https://doi.org/10.1002/jgm.3364Gosmain, Y., Lefai, E., Ryser, S., Roques, M., & Vidal, H. (2004). Sterol regulatory element-binding protein-1 mediates the effect of insulin on hexokinase II gene expression in human muscle cells. Diabetes, 53(2), 321–329. https://doi.org/10.2337/diabetes.53.2.321Gosmain, Y., Lefai, E., Ryser, S., Roques, M., & Vidal, H. (2004). Sterol regulatory element-binding protein-1 mediates the effect of insulin on hexokinase II gene expression in human muscle cells. Diabetes, 53(2), 321–329. https://doi.org/10.2337/diabetes.53.2.321Yazdanpanah, M., Sayed-Tabatabaei, F. A., Hofman, A., Aulchenko, Y. S., Oostra, B. A., Stricker, B. H., Pols, H. A., Lamberts, S. W., Witteman, J. C., Janssen, J. A., & van Duijn, C. M. (2006). The alpha-adducin gene is associated with macrovascular complications and mortality in patients with type 2 diabetes. Diabetes, 55(10), 2922–2927. https://doi.org/10.2337/db06-0302Yazdanpanah, M., Sayed-Tabatabaei, F. A., Hofman, A., Aulchenko, Y. S., Oostra, B. A., Stricker, B. H., Pols, H. A., Lamberts, S. W., Witteman, J. C., Janssen, J. A., & van Duijn, C. M. (2006). The alpha-adducin gene is associated with macrovascular complications and mortality in patients with type 2 diabetes. Diabetes, 55(10), 2922–2927. https://doi.org/10.2337/db06-0302Chen, K., Fu, C., Chen, C., Liu, L., Ren, H., Han, Y., Yang, J., He, D., Zhou, L., Yang, Z., Zhang, L., Jose, P. A., & Zeng, C. (2014). Role of GRK4 in the regulation of arterial AT1 receptor in hypertension. Hypertension (Dallas, Tex. : 1979), 63(2), 289–296. https://doi.org/10.1161/HYPERTENSIONAHA.113.01766Chen, K., Fu, C., Chen, C., Liu, L., Ren, H., Han, Y., Yang, J., He, D., Zhou, L., Yang, Z., Zhang, L., Jose, P. A., & Zeng, C. (2014). Role of GRK4 in the regulation of arterial AT1 receptor in hypertension. Hypertension (Dallas, Tex. : 1979), 63(2), 289–296. https://doi.org/10.1161/HYPERTENSIONAHA.113.01766Qingkai, Y., Changqing, Y. GRK4 variant influences the antihypertensive effect and target organ protection of losartan. Int J Clin Exp Med 2019;12(11):12854-12860.Qingkai, Y., Changqing, Y. GRK4 variant influences the antihypertensive effect and target organ protection of losartan. Int J Clin Exp Med 2019;12(11):12854-12860.Du, B., Jia, X., Tian, W., Yan, X., Wang, N., Cai, D., et al. (2021). Associations of SUCNR1, GRK4, CAMK1D gene polymorphisms and the susceptibility of type 2 diabetes mellitus and essential hypertension in a northern Chinese Han population. Journal of Diabetes and Its Complications, 35(1), 107752. https://doi.org/10.1016/j.jdiacomp.2020.107752Du, B., Jia, X., Tian, W., Yan, X., Wang, N., Cai, D., et al. (2021). Associations of SUCNR1, GRK4, CAMK1D gene polymorphisms and the susceptibility of type 2 diabetes mellitus and essential hypertension in a northern Chinese Han population. Journal of Diabetes and Its Complications, 35(1), 107752. https://doi.org/10.1016/j.jdiacomp.2020.107752Avemaria, F., Carrera, P., Lapolla, A., Sartore, G., Chilelli, N. C., Paleari, R., Ambrosi, A., Ferrari, M., & Mosca, A. (2015). Possible role of fructosamine 3-kinase genotyping for the management of diabetic patients. Clinical Chemistry and Laboratory Medicine (CCLM), 53(9). https://doi.org/10.1515/cclm-2015-0207Avemaria, F., Carrera, P., Lapolla, A., Sartore, G., Chilelli, N. C., Paleari, R., Ambrosi, A., Ferrari, M., & Mosca, A. (2015). Possible role of fructosamine 3-kinase genotyping for the management of diabetic patients. Clinical Chemistry and Laboratory Medicine (CCLM), 53(9). https://doi.org/10.1515/cclm-2015-0207Alderawi, A., Caramori, G., Baker, E. H., Hitchings, A. W., Rahman, I., Rossios, C., et al. (2020). FN3K expression in COPD: a potential comorbidity factor for cardiovascular disease. BMJ open respiratory research, 7(1), e000714. https://doi.org/10.1136/bmjresp-2020-000714Alderawi, A., Caramori, G., Baker, E. H., Hitchings, A. W., Rahman, I., Rossios, C., et al. (2020). FN3K expression in COPD: a potential comorbidity factor for cardiovascular disease. BMJ open respiratory research, 7(1), e000714. https://doi.org/10.1136/bmjresp-2020-000714Szwergold, B. S. (2007). Fructosamine-6-phosphates are deglycated by phosphorylation to fructosamine-3,6-bisphosphates catalyzed by fructosamine-3-kinase (FN3K) and/or fructosamine-3-kinase-related-protein (FN3KRP). Medical Hypotheses, 68(1), 37–45. https://doi.org/10.1016/j.mehy.2006.06.030Szwergold, B. S. (2007). Fructosamine-6-phosphates are deglycated by phosphorylation to fructosamine-3,6-bisphosphates catalyzed by fructosamine-3-kinase (FN3K) and/or fructosamine-3-kinase-related-protein (FN3KRP). Medical Hypotheses, 68(1), 37–45. https://doi.org/10.1016/j.mehy.2006.06.030Viscarra, J. A., Wang, Y., Nguyen, H. P., Choi, Y. G., & Sul, H. S. (2020). Histone demethylase JMJD1C is phosphorylated by mTOR to activate de novo lipogenesis. Nature communications, 11(1), 796. https://doi.org/10.1038/s41467-020-14617-1Viscarra, J. A., Wang, Y., Nguyen, H. P., Choi, Y. G., & Sul, H. S. (2020). Histone demethylase JMJD1C is phosphorylated by mTOR to activate de novo lipogenesis. Nature communications, 11(1), 796. https://doi.org/10.1038/s41467-020-14617-1Ding, E. L., Song, Y., Malik, V. S., & Liu, S. (2006). Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA, 295(11), 1288–1299. https://doi.org/10.1001/jama.295.11.1288Ding, E. L., Song, Y., Malik, V. S., & Liu, S. (2006). Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA, 295(11), 1288–1299. https://doi.org/10.1001/jama.295.11.1288Lempiäinen, J. K., Niskanen, E. A., Vuoti, K. M., Lampinen, R. E., Göös, H., Varjosalo, M., & Palvimo, J. J. (2017). Agonist-specific Protein Interactomes of Glucocorticoid and Androgen Receptor as Revealed by Proximity Mapping. Molecular & cellular proteomics : MCP, 16(8), 1462–1474. https://doi.org/10.1074/mcp.M117.067488Lempiäinen, J. K., Niskanen, E. A., Vuoti, K. M., Lampinen, R. E., Göös, H., Varjosalo, M., & Palvimo, J. J. (2017). Agonist-specific Protein Interactomes of Glucocorticoid and Androgen Receptor as Revealed by Proximity Mapping. Molecular & cellular proteomics : MCP, 16(8), 1462–1474. https://doi.org/10.1074/mcp.M117.067488Regard, J. B., Scheek, S., Borbiev, T., Lanahan, A. A., Schneider, A., Demetriades, A. M., et al. (2004). Verge: a novel vascular early response gene. The Journal of neuroscience : the official journal of the Society for Neuroscience, 24(16), 4092–4103. https://doi.org/10.1523/JNEUROSCI.4252-03.2004Regard, J. B., Scheek, S., Borbiev, T., Lanahan, A. A., Schneider, A., Demetriades, A. M., et al. (2004). Verge: a novel vascular early response gene. The Journal of neuroscience : the official journal of the Society for Neuroscience, 24(16), 4092–4103. https://doi.org/10.1523/JNEUROSCI.4252-03.2004Watcharanurak, P., Mutirangura, A., Aksornkitti, V., Bhummaphan, N., & Puttipanyalears, C. (2024). The high FKBP1A expression in WBCs as a potential screening biomarker for pancreatic cancer. Scientific reports, 14(1), 7888. https://doi.org/10.1038/s41598-024-58324-zWatcharanurak, P., Mutirangura, A., Aksornkitti, V., Bhummaphan, N., & Puttipanyalears, C. (2024). The high FKBP1A expression in WBCs as a potential screening biomarker for pancreatic cancer. Scientific reports, 14(1), 7888. https://doi.org/10.1038/s41598-024-58324-zPiccio, L., Vermi, W., Boles, K. S., Fuchs, A., Strader, C. A., Facchetti, F., et al. (2005). Adhesion of human T cells to antigen-presenting cells through SIRPbeta2-CD47 interaction costimulates T-cell proliferation. Blood, 105(6), 2421–2427. https://doi.org/10.1182/blood-2004-07-2823Piccio, L., Vermi, W., Boles, K. S., Fuchs, A., Strader, C. A., Facchetti, F., et al. (2005). Adhesion of human T cells to antigen-presenting cells through SIRPbeta2-CD47 interaction costimulates T-cell proliferation. Blood, 105(6), 2421–2427. https://doi.org/10.1182/blood-2004-07-2823Dupuis, J., Langenberg, C., Prokopenko, I., Saxena, R., Soranzo, N., Jackson, A. U., et al. (2010). New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nature genetics, 42(2), 105–116. https://doi.org/10.1038/ng.520Dupuis, J., Langenberg, C., Prokopenko, I., Saxena, R., Soranzo, N., Jackson, A. U., et al. (2010). New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nature genetics, 42(2), 105–116. https://doi.org/10.1038/ng.520Wang, R., Xu, D., Liu, R., Zhao, L., Hu, L., & Wu, P. (2017). Microsatellite and Single Nucleotide Polymorphisms in the Insulin-Like Growth Factor 1 Promoter with Insulin Sensitivity and Insulin Secretion. Medical science monitor : international medical journal of experimental and clinical research, 23, 3722–3736. https://doi.org/10.12659/msm.902956Wang, R., Xu, D., Liu, R., Zhao, L., Hu, L., & Wu, P. (2017). Microsatellite and Single Nucleotide Polymorphisms in the Insulin-Like Growth Factor 1 Promoter with Insulin Sensitivity and Insulin Secretion. Medical science monitor : international medical journal of experimental and clinical research, 23, 3722–3736. https://doi.org/10.12659/msm.902956Almgren, P., Lindqvist, A., Krus, U., Hakaste, L., Ottosson-Laakso, E., Asplund, O., et al. (2017). Genetic determinants of circulating GIP and GLP-1 concentrations. JCI insight, 2(21), e93306. https://doi.org/10.1172/jci.insight.93306Almgren, P., Lindqvist, A., Krus, U., Hakaste, L., Ottosson-Laakso, E., Asplund, O., et al. (2017). Genetic determinants of circulating GIP and GLP-1 concentrations. JCI insight, 2(21), e93306. https://doi.org/10.1172/jci.insight.93306Jonsson, A., Ladenvall, C., Ahluwalia, T. S., Kravic, J., Krus, U., Taneera, J., Isomaa, B., Tuomi, T., Renström, E., Groop, L., & Lyssenko, V. (2013). Effects of common genetic variants associated with type 2 diabetes and glycemic traits on α- and β-cell function and insulin action in humans. Diabetes, 62(8), 2978–2983. https://doi.org/10.2337/db12-1627Jonsson, A., Ladenvall, C., Ahluwalia, T. S., Kravic, J., Krus, U., Taneera, J., Isomaa, B., Tuomi, T., Renström, E., Groop, L., & Lyssenko, V. (2013). Effects of common genetic variants associated with type 2 diabetes and glycemic traits on α- and β-cell function and insulin action in humans. Diabetes, 62(8), 2978–2983. https://doi.org/10.2337/db12-1627

The authors declare that there are no conflicts of interest present.