Список литературы

2658-6533

Научные результаты биомедицинских исследований

2658-6533

10.18413/2658-6533-2023-9-1-0-1

2981

Генетика

Генетические детерминанты уровня половых гормонов у больных эндометриозом

Genetic determinants of sex hormone levels in endometriosis patients

Головченко

Илья Олегович

Golovchenko

Ilya O.

ilyagolovchenko1@yandex.ru

2023

9100

Актуальность: Эндометриоз – это хроническое гормонозависимое воспалительное заболевание, определяемое наличием очагов эндометриальной ткани вне полости матки. Генетические факторы занимают лидирующие позиции в этиопатогенезе данного заболевания. При эндометриозе наблюдается выраженный гормональный дисбаланс в половых гормонах как в очаге поражения, так и в организме больной женщины в целом. Цель исследования: Изучить ассоциации полиморфизма генов половых гормонов с гормональным профилем пациенток с эндометриозом. Материалы и методы: В группу исследования вошли 103 пациентки с эндометриозом, у которых были изучены уровни половых гормонов (фолликулостимулирующий гормон, лютеинизирующий гормон, пролактин, эстрадиол, прогестерон, тестостерон и дегидроэпиандростерон). В работе проведено генотипирование 9 однонуклеотидных полиморфизмов (SNP) GWAS-значимых генов половых гормонов (rs148982377 ZNF789, rs34670419 ZKSCAN5, rs11031002 and rs11031005 FSHB, rs112295236 SLC22A10, rs117585797 ANO2, rs117145500 CHD9, rs727428 SHBG, rs1641549 TP53). Методом линейной регрессии исследованы ассоциации SNPs с уровнем половых гормонов у больных эндометриозом. Результаты: Среди пациенток с эндометриозом уровень эстрадиола в сыворотке крови ассоциирован с полиморфными локусами rs148982377 ZNF789 (β=-0,488 - -0,445, pperm≤0,050) и rs34670419 ZKSCAN5 (β=-0,544 - -0,449, pperm≤0,050), лютеинизирующего гормона – rs117585797 ANO2 (β=0,618 - 0,709, pperm≤0,050), прогестерона – rs117145500 CHD9 (β=0,365 - 0,429, pperm<0,050), пролактина – rs1641549 TP53 (β=-0,306 - -0,218, pperm<0,050), тестостерона – rs148982377 ZNF789 и rs34670419 ZKSCAN5 (β=0,492, pperm=0,050). Заключение: Установлены ассоциации полиморфизма генов-кандидатов с уровнем половых гормонов у пациенток с эндометриозом

Background: Endometriosis is a chronic hormone-dependent inflammatory disease determined by the presence of foci of the endometrial tissue outside the uterine cavity. Genetic factors occupy a leading position in the etiopathogenesis of this disease. With endometriosis, there is a pronounced hormonal imbalance in the sex hormones both in the lesion and in the body of the sick woman as a whole. The aim of the study: To study the associations of polymorphism of sex hormone genes with the hormonal profile of patients with endometriosis. Materials and methods: The study group included 103 patients with endometriosis, in whom the levels of sex hormones (follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, progesterone, testosterone and dehydroepiandrosterone) were studied. The genotyping of 9 single nucleotide polymorphisms (SNP) of GWAS-significant sex hormone genes was carried out (rs148982377 ZNF789, rs34670419 ZKSCAN5, rs11031002 and rs11031005 FSHB, rs112295236 SLC22A10, rs117585797 ANO2, rs117145500 CHD9, rs727428 SHBG, rs1641549 TP53). The associations of SNPs with the level of sex hormones in patients with endometriosis were investigated by linear regression. Results: In patients with endometriosis, the serum estradiol level is associated with polymorphic loci rs148982377 ZNF789 (β=-0.488 - -0.445, pperm≤0.050) and rs34670419 ZKSCAN5 (β=-0.544 - -0.449, pperm≤0.050), luteinizing hormone – rs117585797 ANO2 (β= 0.618 - 0.709, pperm≤0.050), progesterone – rs117145500 CHD9 (β=0.365 - 0.429, pperm<0.050), prolactin – rs1641549 TP53 (β=-0.306 - -0.218, pperm<0.050), testosterone – rs148982377 ZNF789 and rs34670419 ZKSCAN5 (β=0.492, pperm=0.050). Conclusion: Associations of candidate gene polymorphism with the level of sex hormones in patients with endometriosis have been established

эндометриозполовые гормоныполиморфизмассоциации

endometriosissex hormonespolymorphismassociations

Список литературы

Адамян ЛВ, Арсланян КН, Логинова ОН, и др. Иммунологические аспекты эндометриоза: обзор литературы. Лечащий Врач. 2020;4:37. DOI: https://doi.org/10.26295/OS.2020.29.10.007

Shafrir AL, Farland LV, Shah DK, et al. Risk for and consequences of endometriosis: A critical epidemiologic review. Best Practice and Research in Clinical Obstetrics and Gynaecology. 2018;51:1-15. DOI: https://doi.org/10.1016/j.bpobgyn.2018.06.001

Zondervan KT, Becker CM, Missmer SA. Endometriosis. New England Journal of Medicine. 2020;382(13):1244-1256. DOI: https://doi.org/10.1056/NEJMra1810764

Bulun SE, Yilmaz BD, Sison C, et al. Endometriosis. Endocrine Reviews. 2019;40:1048-1079. DOI: https://doi.org/10.1210/er.2018-00242

Foster WG, Leonardi M. Endometriosis – novel approaches and controversies debated. Reproduction and Fertility. 2021;2:C39-C41. DOI: https://doi.org/10.1530/RAF-21-0097

Dinsdale N, Nepomnaschy P, Crespi B. The evolutionary biology of endometriosis. Evolution, Medicine and Public Health. 2021;9(1):174-191. DOI: https://doi.org/10.1093/emph/eoab008

Adewuyi EO, Sapkota Y, International Endogene Consortium Iec, et al. Shared molecular genetic mechanisms underlie endometriosis and migraine comorbidity. Genes. 2020;11(3):268. DOI: https://doi.org/10.3390/genes11030268

Sapkota Y, Steinthorsdottir V, Morris AP, et al. Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nature Communications. 2017;8:15539. DOI: https://doi.org/10.1038/ncomms15539

Dinsdale NL, Crespi BJ. Endometriosis and polycystic ovary syndrome are diametric disorders. Evolutionary Applications. 2021;14(7):1693-1715. DOI: https://doi.org/10.1111/eva.13244

Головченко ИО, Пономаренко ИВ, Чурносов МИ. Современные данные об этиопатогенезе и факторах риска развития эндометриоза. Российский вестник акушера-гинеколога. 2021;21(5):41‑48. DOI: https://doi.org/10.17116/rosakush20212105141

Saha R, Pettersson HJ, Svedberg P, et al. Heritability of endometriosis. Fertility and Sterility. 2015;104(4):947-952. DOI: https://doi.org/10.1016/j.fertnstert.2015.06.035

Lee SH, Harold D, Nyholt DR, et al. Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer’s disease, multiple sclerosis and endometriosis. Human Molecular Genetics. 2012;22(4):832-841. DOI: https://doi.org/10.1093/hmg/dds491

Пономаренко ИВ, Полоников АВ, Верзилина ИН, и др. Молекулярно-генетические детерминанты развития эндометриоза. Вопросы гинекологии, акушерства и перинатологии. 2019;18(1):82-86. DOI: https://doi.org/10.20953/1726-1678-2019-1-82-86

Пономаренко ИВ, Полоников АВ, Верзилина ИН, и др. Полиморфизм гена UGT2B4 как фактор развития эндометриоза. Вопросы гинекологии, акушерства и перинатологии. 2019;18(3):15-20. DOI: https://doi.org/10.20953/1726-1678-2019-3-15-20

McGrath IM, Mortlock S, Montgomery GW. Genetic regulation of physiological reproductive lifespan and female fertility. International Journal of Molecular Sciences. 2021;22(5):2556. DOI: https://doi.org/10.3390/ijms22052556

Головченко ИО, Пономаренко ИВ, Чурносов МИ. Генетические факторы развития эндометриоза. (Данные полногеномных исследований). Российский вестник акушера-гинеколога. 2022;22(3):30‑36. DOI: https://doi.org/10.17116/rosakush20222203130

Радзинский ВЕ, Алтухова ОБ. Молекулярно-генетические детерминанты бесплодия при генитальном эндометриозе. Научные результаты биомедицинских исследований. 2018;4(3):28-37. DOI: https://doi.org/10.18413/2313-8955-2018-4-3-0-3

Пономаренко ИВ, Полоников ЛВ, Чурносов МИ. Молекулярные механизмы и факторы риска развития эндометриоза. Акушерство и гинекология. 2019;3:26-31. DOI: https://dx.doi.org/10.18565/aig.2019.3.26-31

Ruth KS, Beaumont RN, Tyrrell J, et al. Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health. Human Reproduction. 2016;31(2):473-481. DOI: https://doi.org/10.1093/humrep/dev318

Bianco B, Loureiro FA, Trevisan CM, et al. Effects of FSHR and FSHB Variants on hormonal profile and reproductive outcomes of infertile women with endometriosis. Frontiers in Endocrinology. 2021;12:760616. DOI: https://doi.org/10.3389/fendo.2021.760616

Prescott J, Thompson DJ, Kraft P, et al. Genome-wide association study of circulating estradiol, testosterone, and sex hormone-binding globulin in postmenopausal women. PLoS ONE. 2012;7:e37815. DOI: https://doi.org/10.1371/journal.pone.0037815

Wood AR, Perry JR, Tanaka T, et al. Imputation of variants from the 1000 Genomes Project modestly improves known associations and can identify low-frequency variant-phenotype associations undetected by HapMap based imputation. PLoS ONE. 2013;8:e64343. DOI: https://doi.org/10.1371/journal.pone.0064343

Ruth KS, Campbell PJ, Chew S, et al. Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes. European Journal of Human Genetics. 2016;24:284-290. DOI: https://doi.org/10.1038/ejhg.2015.102

Ruth KS, Day FR, Tyrrell J, et al. Using human genetics to understand the disease impacts of testosterone in men and women. Nature Medicine. 2020;26(2):252-258. DOI: https://doi.org/10.1038/s41591-020-0751-5

Ponomarenko I, Reshetnikov E, Polonikov A, et al. Candidate genes for age at menarche are associated with endometriosis. Reproductive BioMedicine Online. 2020;41(5):943-956. DOI: https://doi.org/10.1016/j.rbmo.2020.04.016

Garitazelaia A, Rueda-Martínez A, Arauzo R, et al. A Systematic two-sample Mendelian randomization analysis identifies shared genetic origin of endometriosis and associated phenotypes. Life. 2021;11(1):24. DOI: https://doi.org/10.3390/life11010024

Сергеева КН, Сокорев СН, Ефремова ОА, и др. Анализ уровня эндогамии популяции как основа популяционно-генетических и медикo-гeнeтических исследований. Научные результаты биомедицинских исследований. 2021;7(4):375-387. DOI: https://doi.org/10.18413/2658-6533-2021-7-4-0-4

Churnosov MI, Altuchova OB, Demakova NA, et al. Associations of cytokines genetic variants with myomatous knots sizes. Research Journal of Pharmaceutical, Biological and Chemical Sciences. 2014;5(6):1344-1347.

Krivoshei IV, Altuchova OB, Golovchenko OV, et al. Genetic factors of hysteromyoma. Research Journal of Medical Sciences. 2015;9(4):182-185. DOI: https://doi.org/10.3923/rjmsci.2015.182.185

Bushueva O, Solodilova M, Churnosov M, et al. The Flavin-Containing Monooxygenase 3 Gene and Essential Hypertension: The Joint Effect of Polymorphism E158K and Cigarette Smoking on Disease Susceptibility. International Journal of Hypertension. 2014;2014:712169. DOI: https://doi.org/10.1155/2014/712169

Пономаренко ИВ, Полоников АВ, Чурносов МИ. Ассоциация полиморфизма rs4986938 гена ESR2 с развитием гиперплазии эндометрия. Акушерство и гинекология. 2019;4:66-72. DOI: https://dx.doi.org/10.18565/aig.2019.4.66-72

Gudjonsson A, Gudmundsdottir V, Axelsson GT, et al. A genome-wide association study of serum proteins reveals shared loci with common diseases. Nature Communications. 2022;13:480. DOI: https://doi.org/10.1038/s41467-021-27850-z

Tyrmi JS, Arffman RK, Pujol-Gualdo N, et al. Leveraging Northern European population history: Novel low-frequency variants for polycystic ovary syndrome. Human Reproduction. 2022;37(2):352-365. DOI: https://doi.org/10.1093/humrep/deab250

Kim SK. Identification of 613 new loci associated with heel bone mineral density and a polygenic risk score for bone mineral density, osteoporosis and fracture. PLoS ONE. 2018;13:e0200785. DOI: https://doi.org/10.1371/journal.pone.0200785

Pickrell JK, Berisa T, Liu JZ, et al. Detection and interpretation of shared genetic influences on 42 human traits. Nature Genetics. 2016;48(7):709-717. DOI: https://doi.org/10.1038/ng.3570

Kichaev G, Bhatia G, Loh PR, et al. Leveraging polygenic functional enrichment to improve GWAS power. American Journal of Human Genetics. 2019;104(1):65-75. DOI: https://doi.org/10.1016/j.ajhg.2018.11.008

Day F, Karaderi T, Jones MR, et al. Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLoS Genetics. 2019;15(12):e1008517. DOI: https://doi.org/10.1371/journal.pgen.1008517

Sakaue S, Kanai M, Tanigawa Y, et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nature Genetics. 2021;53:1415-1424. DOI: https://doi.org/10.1038/s41588-021-00931-x

Crespi B. Variation among human populations in endometriosis and PCOS A test of the inverse comorbidity model. Evolution, Medicine and Public Health. 2021;9(1):295-310. DOI: https://doi.org/10.1093/emph/eoab029

Sinnott-Armstrong N, Naqvi S, Rivas M, et al. GWAS of three molecular traits highlights core genes and pathways alongside a highly polygenic background. eLife. 2021;10:e58615. DOI: https://doi.org/10.7554/eLife.58615

Day FR, Thompson DJ, Helgason H, et al. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nature Genetics. 2017;49:834-841. DOI: https://doi.org/10.1038/ng.3841

Day FR, Ruth KS, Thompson DJ, et al. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nature Genetics. 2015;47(11):1294-1303. DOI: https://doi.org/10.1038/ng.3412

Laisk T, Kuku&scaron;kina V, Palmer D, et al. Large-scale meta-analysis highlights the hypothalamic-pituitary-gonadal axis in the genetic regulation of menstrual cycle length. Human Molecular Genetics. 2018;27(24):4323-4332. DOI: https://doi.org/10.1093/hmg/ddy317

Mbarek H, Steinberg S, Nyholt DR, et al. Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility. American Journal of Human Genetics. 2016;98(5):898-908. DOI: https://doi.org/10.1016/j.ajhg.2016.03.008

Gallagher CS, Mäkinen N, Harris HR, et al. Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis. Nature Communications. 2019;10:4857. DOI: https://doi.org/10.1038/s41467-019-12536-4

Day FR, Hinds DA, Tung JY, et al. Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nature Communications. 2015;6:8464. DOI: https://doi.org/10.1038/ncomms9464

Hayes MG, Urbanek M, Ehrmann DA, et al. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nature Communications. 2015;6:7502. DOI: https://doi.org/10.1038/ncomms8502

Rull K, Grigorova M, Ehrenberg A, et al. FSHB -211 G>T is a major genetic modulator of reproductive physiology and health in childbearing age women. Human Reproduction. 2018;33(5):954-966. DOI: https://doi.org/10.1093/humrep/dey057

Trevisan CM, de Oliveira R, Christofolini DM, et al. Effects of a Polymorphism in the Promoter Region of the Follicle-Stimulating Hormone Subunit Beta (FSHB) Gene on Female Reproductive Outcomes. Genetic Testing and Molecular Biomarkers. 2019;23(1):39-44. DOI: https://doi.org/10.1089/gtmb.2018.0182

Dapas M, Lin FTJ, Nadkarni GN, et al. Distinct subtypes of polycystic ovary syndrome with novel genetic associations: An unsupervised, phenotypic clustering analysis. PLoS Medicine. 2020;17(6):e1003132. DOI: https://doi.org/10.1371/journal.pmed.1003132

He C, Kraft P, Buring JE, et al. A large-scale candidate-gene association study of age at menarche and age at natural menopause. Human Genetics. 2010;128:515-527. DOI: https://doi.org/10.1007/s00439-010-0878-4

Tian Y, Zhao H, Chen H, et al. Variants in FSHB are associated with polycystic ovary syndrome and luteinizing hormone level in han chinese women. Journal of Clinical Endocrinology and Metabolism. 2016;101(5):2178-2184. DOI: https://doi.org/10.1210/jc.2015-3776

Stolk L, Perry JR, Chasman DI, et al. Meta-analyses identify 13 novel loci associated with age at menopause and highlights DNA repair and immune pathways. Nature Genetics. 2012;44(3):260-8. DOI: https://doi.org/10.1038/ng.1051