Полиморфизм генов фолатного цикла при осложнениях беременности у женщин казахской этнической группы
Ключевые слова:
полиморфизм генов, MTR, MTRR, MTHFR, осложнения беременности.Аннотация
Целью данного исследования явилось определение частот аллелей и генотипов полиморфных вариантов генов фолатного цикла A2756G rs1805087 гена метионин-синтазы (MTR), А66G rs1801394 гена метионин-синтазы-редуктазы (MTRR) и С677Т rs1801133 гена 5,10-метилентетрагидрофолатредуктазы (MTHFR) у женщин казахской этнической группы с осложнениями беременности. Исследования велось с применением методики «случай-контроль». Основную группу составила 121 беременная женщина, имевшие самопроизвольные выкидыши, акушерские осложнения при первых двух беременностях. В контрольную группу вошли 120 беременных женщин, завершившие первые две беременности нормальными родами и без случаев осложнения беременности в анамнезе. Материалом исследования послужила геномная ДНК, выделенная из венозной крови обследованных женщин. Определение генетических полиморфизмов осуществлялось на RealTime амплификаторе CFX96 (BioRad, USA). Статистический анализ в онлайн-программе SNPstats с использованием кодоминантной, доминантной, рецессивной, сверхдоминантной и лог-аддитивной моделей наследования не выявил статистически значимых различий в частотах встречаемости рассмотренных полиморфизмов у женщин основной и контрольной группы. Полученные результаты исследований позволяют дополнить сведения о распространенности полиморфных аллелей генов фолатного цикла MTR, MTRR, MTHFR среди женщин казахской этнической группы. В тоже время необходимы дальнейшие молекулярно-генетические исследования для однозначной трактовки вклада генетических и средовых факторов на течение беременности.
Библиографические ссылки
1. Ford, H. B., Schust, D. J. Recurrent pregnancy loss: etiology, diagnosis, and therapy // Rev. Obstet Gynecol. – 2009. – № 2. – P. 76 – 83.
2. Tamura T., Picciano M.F. Folate and human reproduction // Am. J Clin. Nutr. – 2006. – Vol. 83. – P. 993–1016.
3. Molloy A.M. Folate and homocysteine interrelationships including genetics of the relevant enzymes// Curr. Opin. Lipidol. – 2004. – Vol. 15. – № 1. – P. 49–57.
4. Molloy A.M. Genetic aspects of folate metabolism // Subcell Biochem.– 2012. – Vol. 56. – № 105. – P. 30.
5. Barbosa, P. R., Stabler, S. P., Machado, A. L. et al. Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphismsas determinats for elevated total homocysteine concentrations in pregnant women // Eur. J. Clin. Nutr. – 2008. – Vol. 62. – № 8. – Р. 1010–1121.
6. Forges T., Monnier–Barbarino P., Alberto J. M. et al. Impact of folate and homocysteine metabolism on human reproductive health // Hum. Reprod. – 2007. – Vol. 13. – № 3. – P. 225–238.
7. Rosenblatt D. S. Folate and homocysteine metabolism and gene polymorphisms in the etiology of Down syn-drome. Am. J. Clin. Nutrition. – 1999. – Vol. 70. – № 4. – P. 429–430.
8. Binia A., Contreras A., Canizales–Quinteros S. et al. Geographical and ethnic distribution of single nucleotide polymorphisms within genes of the folate/homocysteine pathway metabolism // Genes Nutr. – 2014. – Vol. 9. – № 5. – P. 421.
9. Рапильбекова Г. К., Мамедалиева Н.М. Роль тромбофилии в генезе синдрома потери плода у женщин казахской популяции // Журнал акушерства и женских болезней. – 2006. – № 3. – С. 31–34.
10. Slager S.L., Schaid D.J. Evaluation of candidate genes in case–control studies: a statistical method to account for related subjects // Am. J. Hum. Genet. – 2001. – Vol. 68. – P 1457–1462.
11. Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies // Bi-oinformatics – 2006. – Vol. 22. – № 15. – P. 1928–1929.
12. Kim J.H., et al. Association of methionine synthase and thymidylate synthase genetic polymorphisms with idi-opathic recurrent pregnancy loss // Fertil. Steril. – 2013. – P. 1674–1680.
13. Guo Q.N., et al. Association of methionine synthase reductase gene polymorphism with unexplained recurrent spontaneous abortion // Zhonghua Fu Chan Ke Za Zhi. – 2012. – № 10. – Р. 742–746.
14. Schwahn B, Rozen R. Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences // Am J Pharmacogenomics. – 2001. – Vol 1. – №3. – P. 189–201.
15. Bae, J., Shin, S.J., Cha, S.H. et al. Prevalent genotypes ofmethylenetetrahydrofolatereductase (MTHFR C677T and A1298C) inspontaneously aborted embryos // Fertility and Sterility. – 2007. – Vol. 87. – № 2. – P. 351–355.
16. Engel, S.M., Olshan, A.F., Siega–RIZ, et al. Polymorphisms in folate metabolizing genes and risk for sponta-neous preterm and small–forgestationalage birth // Am. J. Obstet. Gynecol. – 2001. – Vol. 95. – P. 1231–1251.
17. Holmes, Z. R., Regan L., Chilcott, I., Cohen, H. The C677T MTHFR gene mutation is not predictive of risk for recurrent fetal loss // Br. J. Haematol. – 1999. – Vol. 105. – P. 98–101.
18. Wu, X., Zhao, L., Zhu, H. et al. Association between the MTHFR C677 Tpolymorphism and recurrent preg-nancy loss: a meta–analysis // Genet Test Mol. Biomarkers. – 2012. – Vol. 16. – № 7. – Р. 806–811.
19. Botto L., Yang Q. 5,10–Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a huge review // Am J Epidemiol. – 2000. – Vol. 151. – № 9. – Р. 862–877.
20. Fodinger M., Horl W., Sunder–Plassmann G. Molecular biology of 5,10–methylenetetrahydrofolate reductase // J. Nephrol. – 1999. – № 13. – Р. 1–17.
21. Wilcken B., Bamforth F., Li Z. et al. Geographical and ethnic variation of the 677C>T allele of 5,10 methyl-enetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas worldwide // J. Med. Genet. – 2003. – Vol. 40. – P. 619–625.
References
1. Ford HB, Schust DJ (2009) Recurrent pregnancy loss: etiology, diagnosis, and therapy, Rev. Obstet Gynecol, No 2, pp. 76–83.
2. Tamura T, Picciano MF (2006) Folate and human reproduction, Am. J Clin. Nutr, Vol. 83, pp. 993–1016.
3. Molloy AM (2004) Folate and homocysteine interrelationships including genetics of the relevant enzymes, Curr. Opin. Lipidol, Vol. 15, No 1, pp 49–57.
4. Molloy AM (2012) Genetic aspects of folate metabolism, Subcell Biochem, Vol. 56, No 105, pp 30.
5. Barbosa PR, Stabler SP, Machado AL. et al (2008) Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphismsas determinats for elevated total homocysteine concentrations in pregnant women, Eur. J. Clin. Nutr, Vol. 62, No 8, pp. 1010–1121.
6. Forges T, Monnier–Barbarino PP, Alberto JM. et al (2008) Impact of folate and homocysteine metabolism on human repproductive health, Hum. Repprod, Vol. 13, No 3, рр. 225–238.
7. Rosenblatt DS (1999) Folate and homocysteine metabolism and gene ppolymorpphisms in the etiology of Down syndrome, Am. J. Clin. Nutrition, Vol. 70, No 4, рр. 429–430.
8. Binia A, Contreras A, Canizales–Quinteros S. et al (2014) Geograpphical and ethnic distribution of single nu-cleotide ppolymorphisms within genes of the folate/homocysteine pathway metabolism, Genes Nutr, Vol.9, No 5, рр. 421.
9. Rappilbekоva GK, Mamedalieva NM (2006) The rоle оf thrоmbоpphilia in the genesis оf fetal lоss syndrоme in wоmen оf the Kazakh ppоppulatiоn, Jоurnal оf Оbstetrics and Wоmen's Diseases, Nо. 3, pp. 31-34.
10. Slager SL, Schaid DJ (2001) Evaluation of candidate genes in case–control studies: a statistical method to ac-count for related subjects, Am. J. Hum. Genet, Vol. 68, рр. 1457–1462.
11. Solé X, Guinó E, Valls J, Iniesta R, Moreno V (2006) SNPStats: a web tool for the analysis of association studies, Bioinformatics, Vol. 22, No 15, рр. 1928–1929.
12. Kim JH, et al (20130 Association of methionine synthase and thymidylate synthase genetic ppolymorpphisms with idiopathic recurrent pregnancy loss, Fertil. Steril, рр. 1674–1680.
13. Guo QN, et al (2012) Association of methionine synthase reductase gene polymorphism with unexplained re-current spontaneous abortion, Zhonghua Fu Chan Ke Za Zhi, No 10, рр. 742–746.
14. Schwahn B, Rozen R (2001) Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical conse-quences // Am J Pharmacogenomics. – 2001. – Vol 1. – No3. – PP. 189–201.
15. Bae J, Shin SJ, Cha SH. et al (2007) Prevalent genotypes of methylenetetrahydrofolatereductase (MTHFR C677T and A1298C) inspontaneously aborted embryos, Fertility and Sterility, Vol. 87, No 2, рр. 351–355.
16. Engel SM, Olshan AF et al (2001) Polymorphisms in folate metabolizing genes and risk for spontaneous pre-term and small–for gestational age birth, Am. J. Obstet. Gynecol, Vol. 95, рр. 1231–1251.
17. Holmes ZR, Regan L, Chilcott I, Cohen H (1999) The C677T MTHFR gene mutation is not ppredictive of risk for recurrent fetal loss, Br. J. Haematol, Vol. 105, рр. 98–101.
18. Wu X, Zhao L, Zhu H et al (2012) Association between the MTHFR C677 Tppolymorpphism and recurrent ppregnancy loss: a meta–analysis, Genet Test Mol. Biomarkers, Vol. 16, No 7, рр. 806–811.
19. Botto L, Yang Q (2000) 5,10–Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a huge review, Am J Eppidemiol, Vol. 151, No 9, рр. 862–877.
20. Fodinger M, Horl W, Sunder–Plassmann G (1999) Molecular biology of 5,10–methylenetetrahydrofolate re-ductase, J. Nepphrol, No 13, рр. 1–17.
21. Wilcken B, Bamforth F, Li Z et al (2003) Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas worldwide, J. Med. Genet, Vol. 40, рр. 619–625.
2. Tamura T., Picciano M.F. Folate and human reproduction // Am. J Clin. Nutr. – 2006. – Vol. 83. – P. 993–1016.
3. Molloy A.M. Folate and homocysteine interrelationships including genetics of the relevant enzymes// Curr. Opin. Lipidol. – 2004. – Vol. 15. – № 1. – P. 49–57.
4. Molloy A.M. Genetic aspects of folate metabolism // Subcell Biochem.– 2012. – Vol. 56. – № 105. – P. 30.
5. Barbosa, P. R., Stabler, S. P., Machado, A. L. et al. Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphismsas determinats for elevated total homocysteine concentrations in pregnant women // Eur. J. Clin. Nutr. – 2008. – Vol. 62. – № 8. – Р. 1010–1121.
6. Forges T., Monnier–Barbarino P., Alberto J. M. et al. Impact of folate and homocysteine metabolism on human reproductive health // Hum. Reprod. – 2007. – Vol. 13. – № 3. – P. 225–238.
7. Rosenblatt D. S. Folate and homocysteine metabolism and gene polymorphisms in the etiology of Down syn-drome. Am. J. Clin. Nutrition. – 1999. – Vol. 70. – № 4. – P. 429–430.
8. Binia A., Contreras A., Canizales–Quinteros S. et al. Geographical and ethnic distribution of single nucleotide polymorphisms within genes of the folate/homocysteine pathway metabolism // Genes Nutr. – 2014. – Vol. 9. – № 5. – P. 421.
9. Рапильбекова Г. К., Мамедалиева Н.М. Роль тромбофилии в генезе синдрома потери плода у женщин казахской популяции // Журнал акушерства и женских болезней. – 2006. – № 3. – С. 31–34.
10. Slager S.L., Schaid D.J. Evaluation of candidate genes in case–control studies: a statistical method to account for related subjects // Am. J. Hum. Genet. – 2001. – Vol. 68. – P 1457–1462.
11. Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies // Bi-oinformatics – 2006. – Vol. 22. – № 15. – P. 1928–1929.
12. Kim J.H., et al. Association of methionine synthase and thymidylate synthase genetic polymorphisms with idi-opathic recurrent pregnancy loss // Fertil. Steril. – 2013. – P. 1674–1680.
13. Guo Q.N., et al. Association of methionine synthase reductase gene polymorphism with unexplained recurrent spontaneous abortion // Zhonghua Fu Chan Ke Za Zhi. – 2012. – № 10. – Р. 742–746.
14. Schwahn B, Rozen R. Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences // Am J Pharmacogenomics. – 2001. – Vol 1. – №3. – P. 189–201.
15. Bae, J., Shin, S.J., Cha, S.H. et al. Prevalent genotypes ofmethylenetetrahydrofolatereductase (MTHFR C677T and A1298C) inspontaneously aborted embryos // Fertility and Sterility. – 2007. – Vol. 87. – № 2. – P. 351–355.
16. Engel, S.M., Olshan, A.F., Siega–RIZ, et al. Polymorphisms in folate metabolizing genes and risk for sponta-neous preterm and small–forgestationalage birth // Am. J. Obstet. Gynecol. – 2001. – Vol. 95. – P. 1231–1251.
17. Holmes, Z. R., Regan L., Chilcott, I., Cohen, H. The C677T MTHFR gene mutation is not predictive of risk for recurrent fetal loss // Br. J. Haematol. – 1999. – Vol. 105. – P. 98–101.
18. Wu, X., Zhao, L., Zhu, H. et al. Association between the MTHFR C677 Tpolymorphism and recurrent preg-nancy loss: a meta–analysis // Genet Test Mol. Biomarkers. – 2012. – Vol. 16. – № 7. – Р. 806–811.
19. Botto L., Yang Q. 5,10–Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a huge review // Am J Epidemiol. – 2000. – Vol. 151. – № 9. – Р. 862–877.
20. Fodinger M., Horl W., Sunder–Plassmann G. Molecular biology of 5,10–methylenetetrahydrofolate reductase // J. Nephrol. – 1999. – № 13. – Р. 1–17.
21. Wilcken B., Bamforth F., Li Z. et al. Geographical and ethnic variation of the 677C>T allele of 5,10 methyl-enetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas worldwide // J. Med. Genet. – 2003. – Vol. 40. – P. 619–625.
References
1. Ford HB, Schust DJ (2009) Recurrent pregnancy loss: etiology, diagnosis, and therapy, Rev. Obstet Gynecol, No 2, pp. 76–83.
2. Tamura T, Picciano MF (2006) Folate and human reproduction, Am. J Clin. Nutr, Vol. 83, pp. 993–1016.
3. Molloy AM (2004) Folate and homocysteine interrelationships including genetics of the relevant enzymes, Curr. Opin. Lipidol, Vol. 15, No 1, pp 49–57.
4. Molloy AM (2012) Genetic aspects of folate metabolism, Subcell Biochem, Vol. 56, No 105, pp 30.
5. Barbosa PR, Stabler SP, Machado AL. et al (2008) Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphismsas determinats for elevated total homocysteine concentrations in pregnant women, Eur. J. Clin. Nutr, Vol. 62, No 8, pp. 1010–1121.
6. Forges T, Monnier–Barbarino PP, Alberto JM. et al (2008) Impact of folate and homocysteine metabolism on human repproductive health, Hum. Repprod, Vol. 13, No 3, рр. 225–238.
7. Rosenblatt DS (1999) Folate and homocysteine metabolism and gene ppolymorpphisms in the etiology of Down syndrome, Am. J. Clin. Nutrition, Vol. 70, No 4, рр. 429–430.
8. Binia A, Contreras A, Canizales–Quinteros S. et al (2014) Geograpphical and ethnic distribution of single nu-cleotide ppolymorphisms within genes of the folate/homocysteine pathway metabolism, Genes Nutr, Vol.9, No 5, рр. 421.
9. Rappilbekоva GK, Mamedalieva NM (2006) The rоle оf thrоmbоpphilia in the genesis оf fetal lоss syndrоme in wоmen оf the Kazakh ppоppulatiоn, Jоurnal оf Оbstetrics and Wоmen's Diseases, Nо. 3, pp. 31-34.
10. Slager SL, Schaid DJ (2001) Evaluation of candidate genes in case–control studies: a statistical method to ac-count for related subjects, Am. J. Hum. Genet, Vol. 68, рр. 1457–1462.
11. Solé X, Guinó E, Valls J, Iniesta R, Moreno V (2006) SNPStats: a web tool for the analysis of association studies, Bioinformatics, Vol. 22, No 15, рр. 1928–1929.
12. Kim JH, et al (20130 Association of methionine synthase and thymidylate synthase genetic ppolymorpphisms with idiopathic recurrent pregnancy loss, Fertil. Steril, рр. 1674–1680.
13. Guo QN, et al (2012) Association of methionine synthase reductase gene polymorphism with unexplained re-current spontaneous abortion, Zhonghua Fu Chan Ke Za Zhi, No 10, рр. 742–746.
14. Schwahn B, Rozen R (2001) Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical conse-quences // Am J Pharmacogenomics. – 2001. – Vol 1. – No3. – PP. 189–201.
15. Bae J, Shin SJ, Cha SH. et al (2007) Prevalent genotypes of methylenetetrahydrofolatereductase (MTHFR C677T and A1298C) inspontaneously aborted embryos, Fertility and Sterility, Vol. 87, No 2, рр. 351–355.
16. Engel SM, Olshan AF et al (2001) Polymorphisms in folate metabolizing genes and risk for spontaneous pre-term and small–for gestational age birth, Am. J. Obstet. Gynecol, Vol. 95, рр. 1231–1251.
17. Holmes ZR, Regan L, Chilcott I, Cohen H (1999) The C677T MTHFR gene mutation is not ppredictive of risk for recurrent fetal loss, Br. J. Haematol, Vol. 105, рр. 98–101.
18. Wu X, Zhao L, Zhu H et al (2012) Association between the MTHFR C677 Tppolymorpphism and recurrent ppregnancy loss: a meta–analysis, Genet Test Mol. Biomarkers, Vol. 16, No 7, рр. 806–811.
19. Botto L, Yang Q (2000) 5,10–Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a huge review, Am J Eppidemiol, Vol. 151, No 9, рр. 862–877.
20. Fodinger M, Horl W, Sunder–Plassmann G (1999) Molecular biology of 5,10–methylenetetrahydrofolate re-ductase, J. Nepphrol, No 13, рр. 1–17.
21. Wilcken B, Bamforth F, Li Z et al (2003) Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas worldwide, J. Med. Genet, Vol. 40, рр. 619–625.
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Опубликован
2018-01-01
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Раздел
МОЛЕКУЛЯРНАЯ БИОЛОГИЯ И ГЕНЕТИКА
