Polymorphism of folate cycle genes as a risk factor of hyperhomocysteinemia
A.M. Ivanov1, A.Zh. Gil'manov2, N.N. Malyutina3, Ya.B. Khovaeva3, O.Yu. Nenasheva3,4, G.I. El'kin1, D.Yu. Sosnin3
1Military Medical Academy named after S.M. Kirov, 6 Akademika Lebedeva Str., Saint Petersburg, 194044, Russian Federation
2Bashkirian State Medical University, 3 Lenina Str., Ufa, 450000, Russian Federation
3Perm State Medical University named after Academician E.A. Wagner, 26 Petropavlovskaya Str., Perm, 614000, Russian Federation
4«MedLabEkspress» LLC, 14 A Gaidara Str., Perm, 614000, Russian Federation
Hyperhomocysteinemia (HHc) is a new factor being considered at the moment that can cause damage to vessel walls. Its occurrence depends on genetic peculiarities of a body.
Our research goal was to estimate frequency of genetic polymorphisms (SNP) in folate cycle genes among people living in Perm region and its influence on homocysteine (Hc) concentration in blood serum.
We examined 189 women (32.2±5.25). Hc concentration in blood serum was determined with immune chemiluminescent procedure. We examined frequency of SNP in folate cycle genes with pyrosequencing.
Homozygote state as per minor alleles in methylene tetrahydrofolate reductase (MTHFR) gene (rs 1801133 и rs 1801131) and MTR gene (rs 1805087) was registered 7.5, 5.4, and 13.75 times less frequently than homozygote state as per neutral alleles. Heterozygote state prevailed for genes of methionine synthase reductase and folate transport protein among examined SNP. Homozygotes as per minor allele SNP in MTHFR gene (Ala222Val; rs 1801133) had higher Hc concentration in blood serum that amounted to 8.476 ± 3.193 mmol/L and was 1.276 times higher than the same parameter in homozygotes as per neutral allele (р=0.0036). We didn’t establish any influence on Hc contents in blood serum for the remaining 4 SNP in folate cycle genes (р> 0.1).
Examined SNP in MTHFR and MTR genes tended to have neutral alleles more frequently than minor ones. SNP in genes of other examined proteins belonging to folate cycle didn’t have any differences in frequency of examined alleles. We didn’t detect a combination of homozygote state as per two SNP in MTHFR gene or homozygote state as per one SNP and heterozygote state as per another one in a genome. Only SNP in MTHFR gene (Ala222Val, rs 1801133) authentically causes increase in homocysteine concentration out of all the examined SNP in genes of folate cycle enzymes and proteins.
- Reddy V.S., Trinath J., Reddy G.B. Implication of homocysteine in protein quality control processes. Biochimie, 2019, no. 165, pp. 19–31. DOI: 10.1016/j.biochi.2019.06.017
- Jakubowski H. Homocysteine Modification in Protein Structure/Function and Human Disease. Physiol Rev, 2019, vol. 99, no. 1, pp. 555–604. DOI: 10.1152/physrev.00003.2018
- Alam S.F., Kumar S., Ganguly P. Measurement of homocysteine: a historical perspective. J Clin Biochem Nutr, 2019, vol. 65, no. 3, pp. 171–177. DOI: 10.3164/jcbn.19-49
- Tsybikov N.N., Tsybikova N.M. Rol' gomotsisteina v patologii cheloveka [A role homocysteine plays in human pathology]. Uspekhi sovremennoi biologii, 2007, vol. 127, no. 5, pp. 471–481 (in Russian).
- Ubbink J.B. Assay methods for the measurement of total homocyst(e)ine in plasma. Semin Thromb Hemost, 2000, vol. 26, no. 3, pp. 233–241. DOI: 10.1055/s-2000-8468
- Ganguly P., Alam S.F. Role ofhomocysteine in the development of cardiovascular disease. Nutr J, 2015, vol. 14, no. 6, p. 10. DOI: 10.1186/1475-2891-14-6
- Stepanova T.V., Ivanov A.N., Tereshkina N.E., Popykhova E.B., Lagutina D.D. Markers of endothelial dysfunction: pathogenetic role and diagnostic significance. Klinicheskaya laboratornaya diagnostika, 2019, vol. 64, no. 1, pp. 34–41 (in Russian).
- Yang Q., He G.W. Imbalance of Homocysteine and H2S: Significance, Mechanisms, and Therapeutic Promise in Vascular Injury. Oxid Med Cell Longev, 2019, vol. 2019, pp. 7629673. DOI: 10.1155/2019/7629673
- Boldyrev A.A. Molecular mechanisms of homocysteine toxicity. Biokhimiya, 2009, vol. 74, no. 6, pp. 725–736 (in Russian).
- Stanger O., Herrmann W., Pietrzik K., Fowler B., Geisel J., Dierkes J., Weger M. Clinical use and rational management of homocysteine, folic acid, and B vitamins in cardiovascular and thrombotic diseases. Z Kardiol, 2004, vol. 93, no. 6, pp. 439–453. DOI: 10.1007/s00392-004-0075-3
- Yang Y., Jiang H., Tang A., Xiang Z. Changes of serum homocysteine levels during pregnancy and the establishment of reference intervals in pregnant Chinese women. Clin Chim Acta, 2019, no. 489, pp. 1–4. DOI: 10.1016/j.cca.2018.11.026
- Masoura S., Kalogiannidis I.A., Gitas G., Goutsioulis A., Koiou E., Athanasiadis A., Vavatsi N. Biomarkers in pre-eclampsia: a novel approach to early detection of the disease. J Obstet Gynaecol, 2012, vol. 32, no. 7, pp. 609–616. DOI: 10.3109/01443615.2012.709290
- Piazzolla G., Candigliota M., Fanelli M., Castrovilli A., Berardi E., Antonica G., Battaglia S., Solfrizzi V., Sabbà C., Tortorella C. Hyperhomocysteinemia is an independent risk factor of atherosclerosis in patients with metabolic syndrome. Diabetol Metab Syndr, 2019, vol. 26, no. 11, pp. 87. DOI: 10.1186/s13098-019-0484-0
- Marković Boras M., Čaušević A., Brizić I., Mikulić I., Vasilj M., Jelić Knezović N. A relation of serum homocysteine, uric acid and C-reactive protein level in patients with acute myocardial infarction. Med Glas (Zenica), 2018, vol. 15, no. 2, pp. 101–108. DOI: 10.17392/956-18
- Tang Y., Geng D. Associations of plasma LP(a), Hcy and D-D levels with the subtype of ischemic cerebrovascular disease. Medicine (Baltimore), 2019, vol. 98, no. 11, pp. e14910. DOI: 10.1097/MD.0000000000014910
- L'vova O.A., Gusev V.V., Kovtun O.P., Gavrilov I.V., Reshetova A.N., Stepanova A.E., Voroshilina E.S. Ischemic stroke in children: the role of folate pathway genetic polymorphisms and hyperhomocysteinemia. Sibirskii meditsinskii zhurnal, 2013, vol. 28, no. 3, pp. 34–40 (in Russian).
- Lobzin V.Yu., Litvinenko I.V., Emelin A.Yu. Hyperhomocysteinemia – vascular damage, neurodegeneration and cognitive impairment progression risk factor. Vestnik Rossiiskoi voenno-meditsinskoi akademii, 2015, no. 4 (52), pp. 100–105 (in Russian).
- Kundal M., Saha A., Dubey N.K., Kapoor K., Basak T., Bhardwaj G., Tanwar V.S., Sengupta S. [et al.]. Homocysteine metabolism in children with idiopathic nephrotic syndrome. Clin Transl Sci, 2014, vol. 7, no. 2, pp. 132–136. DOI: 10.1111/cts.12145
- Tadtaeva Z.G., Katsadze Yu.L. Gene polymorphism of methylene-tetrahydrofolatreductase, hyperhomocysteinaemia and possibilities of its correction in children with migraine. Kazanskii meditsinskii zhurnal, 2007, vol. 88, no. 1, pp. 16–20 (in Russian).
- Shevchuk V.V., Malyutina N.N. Gomotsisteinemya association with a functional condition of a thyroid gland at teenagers in the goiter region. Sovremennye problem nauki i obrazovaniya, 2012, no. 2, pp. 105 (in Russian).
- Al-Sadeq D.W., Nasrallah G.K. The Spectrum of Mutations of Homocystinuria in the MENA Region. Genes (Basel), 2020, vol. 11, no. 3, pp. 330. DOI: 10.3390/genes11030330
- Lupi-Herrera E., Soto-López M.E., Lugo-Dimas A.J., Núñez-Martínez M.E., Gamboa R., Huesca-Gómez C., Sierra-Galán L.M., Guarner-Lans V. Polymorphisms C677T and A1298C of MTHFR Gene: Homocysteine Levels and Prothrombotic Biomarkers in Coronary and Pulmonary Thromboembolic Disease. Clin Appl Thromb Hemost, 2019, vol. 25, pp. 1076029618780344. DOI: 10.1177/1076029618780344
- Zaric B.L., Obradovic M., Bajic V., Haidara M.A., Jovanovic M., Isenovic E.R. Homocysteine and Hyperhomocysteinaemia. Curr Med Chem, 2019, vol. 26, no. 16, pp. 2948–2961. DOI: 10.2174/0929867325666180313105949
- Sadiq W., Subhan M. Isolated Homocysteinemia Leading to Thromboembolism in Young Male with Normal Vitamin B12 and Folate Levels. Cureus, 2017, vol. 9, no. 12, pp. e1978. DOI: 10.7759/cureus.1978
- Tanaka M., Taniguchi T., Saito N., T. Kimura Inferior vena cava thrombus due to hyperhomocysteinemia. J Cardiol Cases, 2018, vol. 18, no. 5, pp. 168–170. DOI: 10.1016/j.jccase.2018.07.003
- Weiner A.S., Beresina O.V., Voronina E.N., Voropaeva E.N., Boyarskih U.A., Pospelova T.I., Filipenko M.L. Polymorphism in folate-metabolizing genes and risk of non-Hodgkin’s lymphoma. Leuk Res, 2011, vol. 35, no. 4, pp. 509–515. DOI: 10.1016/j.leukres.2010.10.004
- Zhang X., Tang J., Shen N., Ren K. A single-nucleotide polymorphism (rs1805087) in the methionine synthase (METH) gene increases the risk of prostate cancer. Aging (Albany NY), 2018, vol. 10, no. 10, pp. 2741–2754. DOI: 10.18632/aging.101584
- Wang B.J., Liu M.J., Wang Y., Dai J.R., Tao J.Y., Wang S.N., Zhong N., Chen Y. Association between SNPs in genes involved in folate metabolism and preterm birth risk. Genet Mol Res, 2015, vol. 14, no. 1, pp. 850–859. DOI: 10.4238/2015.February.2.9
- Hobbs C.A., Sherman S.L., Yi P., Hopkins S.E., Torfs C.P., Hine R.J., Pogribna M., Rozen R., James S.J. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am J Hum Genet, 2000, vol. 67, no. 3, pp. 623–630. DOI: 10.1086/303055
- Lee H.C., Jeong Y.M., Lee S.H., Cha K.Y., Song S.H., Kim N.K., Lee K.W., Lee S. Association study of four polymorphisms in three folate-related enzyme genes with non-obstructive male in fertility. Hum Reprod, 2006, vol. 21, no. 12, pp. 3162–3170. DOI: 10.1093/humrep/del280
- Gava M.M., Kayaki E.A., Bianco B., Teles J.S., Christofolini D.M., Pompeo A.C., Glina S., Barbosa C.P. Polymorphisms infolate-related enzyme genes in idiopathic infertile Brazilian men. Reprod Sci, 2011, vol. 18, no. 12, pp. 1267–1272. DOI: 10.1177/1933719111411729
- Kulyutsina E.R., Levashova O.A., Denisova A.G., Druzhinina E.A. Hyperhomocysteinemia and polymorphysm of folate metabolism genes in healthy population of Penza region. Zhurnal nauchnykh statei Zdorov'e i obrazovanie v XXI veke, 2016, vol. 18, no. 2, pp. 640–645 (in Russian).
- Strozenko L.A., Gordeev V.V., Lobanov Yu.F., Momot A.P., Voronina E.N. Distribution of genes in the folate cycle adolescent population of Barnaul, Altai region. Mat' i ditya v Kuzbasse, 2015, no. 1 (60), pp. 29–34 (in Russian).
- Aiala F. Vvedenie v populyatsionnuyu i evolyutsionnuyu genetiku [Introduction to population and evolution genetics]. Moscow, Mir Publ., 1984, 232 p. (in Russian).
- Refsum H., Nurk E., Smith A.D., Ueland P.M., Gjesdal C.G., Bjelland I., Tverdal A., Tell G.S., Nygård O., Vollset S.E. The Hordal and Homocysteine Study: a community. J Nutr, 2006, vol. 136, no. 6, pp. 1731–1740. DOI: 10.1093/jn/136.6.1731S
- Poodineh M., Saravani R., Mirhosseini M., Sargazi S. Association of Two Methylenetetrahydrofolate Reductase Polymorphisms (rs1801133, rs1801131) with the Risk of Type 2 Diabetes in South-East of Iran. Rep Biochem Mol Biol, 2019, vol. 8, no. 2, pp. 178–183.