ASSOCIATION OF MTHFR 677CT, 1298AC POLYMORPHISMS AND FOLIC ACID WITH SPINA BIFIDA IN PAKISTANI POPULATION
Main Article Content
Keywords
MTHFR, spina bifida, neural tube defect, folic acid, HbA1c
Abstract
Spina Bifida (SB) is a neural tube defect that is commonly increasing substantial with genetic component. Complex pattern and various genetic polymorphisms may affect genetic predisposition of the disease that is mostly characterized by folic acid deficiency. Between diverse ethnic populations, the genetic architecture of SB may vary, so it is crucial that such variants are examined in Pakistani population. The present study was specifically targeted to find out the association of blood folate level and methylenetetrahydrofolate (MTHFR) gene polymorphisms with SB in Pakistan. In present study significant p value 0.001 showed the association of blood folate level and SB. Differences of genotypes among MTHFR 1298A→C highly significant between normal groups and SB X2=13.273(0.001). While 677C→T found to be non-associated X2= 0.327 (0.827) with SB in population. To conclude, low blood folate level of parents and MTHFR gene polymorphisms 1298A→C can be a cause of inception and progression of SB in local population of Pakistan but relationship between MTHFR genetic polymorphisms to diverse SB complications is yet not obvious and warrants further studies of functional genomics to validate the SB onset and progression with genetic susceptibility of MTHFR gene.
References
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14. Chen, Z., Lin, T., & Wang, K. (2017). A powerful variant-set association test based on chisquare distribution. Genetics, 207(3), 903-910.
15. Liptak, G. S., and El Samra, A. (2010). Optimizing health care for children with spina bifida. Developmental disabilities research reviews, 16(1), 66-75.
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17. Liu, H. Y., Liu, S. M., and Zhang, Y. Z. (2020). Maternal folic acid supplementation mediates offspring health via DNA methylation. Reproductive Sciences, 27(4), 963-976.
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22. Stiles-Shields, C., and Holmbeck, G. N. (2020). Health behaviors and disordered eating in adolescents and young adults with spina bifida: results from a national survey. Disability and rehabilitation, 42(20), 2910-2916.
23. Rendeli, C., Kuczynska, E., Giuliano, A. C., Chiaretti, A., and Ausili, E. (2020). Dietary approach to prevent obesity risk in Spina Bifida patients. Child's Nervous System, 36(7), 1515-1520.
24. Ayaz, R., and Asoglu, M. R. (2020). Neural tube defects in eastern Turkey; Is low folate status or vitamin B12 deficiency or both associated with a high rate of NTDs?. The Journal of Maternal-Fetal and Neonatal Medicine, 33(22), 3835-3840.
25. Yu, Y., Jia, C., Shi, Q., Zhu, Y., and Liu, Y. (2019). Hyperhomocysteinemia in men with a reproductive history of fetal neural tube defects: Three case reports and literature review. Medicine, 98(2).
26. Van Der Put, N. M., Van Straaten, H. W., Trijbels, F. J., and Blom, H. J. (2001). Folate, homocysteine and neural tube defects: an overview. Experimental Biology and Medicine, 226(4), 243-270.
27. Liu, H. Y., Liu, S. M., and Zhang, Y. Z. (2020). Maternal folic acid supplementation mediates offspring health via DNA methylation. Reproductive Sciences, 27(4), 963-976.
28. Tabatabaei, R. S., Fatahi-Meibodi, N., Meibodi, B., Javaheri, A., Abbasi, H., Hadadan, A., and Neamatzadeh, H. (2020). Association of Fetal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects: A Systematic Review and Update MetaAnalysis. Fetal and Pediatric Pathology, 1-17.
29. Zhou-Cun, A., Yang, Y., Zhang, S. Z., Li, N., and Zhang, W. (2007). Single nucleotide polymorphism C677T in the methylenetetrahydrofolate reductase gene might be a genetic risk factor for infertility for Chinese men with azoospermia or severe oligozoospermia. Asian J Androl, 9(1), 57-62.
30. Eggink, A. J., and Steegers-Theunissen, R. P. (2020). Neural tube anomalies: An update on the pathophysiology and prevention. Fetal therapy: Scientific basis and critical appraisal of clinical benefits, 449-455.
31. Tabatabaei, R. S., Fatahi-Meibodi, N., Meibodi, B., Javaheri, A., Abbasi, H., Hadadan, A., & Neamatzadeh, H. (2022). Association of fetal MTHFR C677T polymorphism with susceptibility to neural tube defects: a systematic review and update meta-analysis. Fetal and pediatric pathology, 41(2), 225-241.
32. Hassan, M. H., Raslan, M. A., Tharwat, M., Sakhr, H. M., El-Khateeb, E. E. S., Sakr, S. F., & Hamdan, A. R. (2022). Metabolic Analysis of Methylenetetrahydrofolate Reductase Single Nucleotide Polymorphisms (MTHFR 677C< T and MTHFR 1298A< C), Serum Folate and Vitamin B12 in Neural Tube Defects. Indian Journal of Clinical Biochemistry, 1-11.
33. Weisberg, I., Tran, P., Christensen, B., Sibani, S., and Rozen, R. (1998). A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Molecular genetics and metabolism, 64(3), 169-172.
34. Joibari, R. M., Movafagh, A., and Molaei, A. (2021). Association between Maternal and Fetal MTHFR C677T and MTRR A66G Polymorphisms with the Risk of NTDs: A Systematic Review and Meta-Analysis Study. Iranian Red Crescent Medical Journal, 23(11).
35. Aranda‐Sánchez, C. I., Bobadilla‐Morales, L., Corona‐Rivera, A., Cuero‐Quezada, I., SantanaHernández, J., Baldomero‐López, A., & Corona‐Rivera, J. R. (2021). MTHFR C677T and A1298C variants in Mexican Mestizo infants with neural tube defects from Western Mexico. Congenital Anomalies, 61(5), 188-192
36. Soleimani-Jadidi, S., Meibodi, B., Javaheri, A., Tabatabaei, R. S., Hadadan, A., Zanbagh, L., and Neamatzadeh, H. (2020). Association between Fetal MTHFR A1298C (rs1801131) Polymorphism and Neural Tube Defects Risk: A Systematic Review and MetaAnalysis. Fetal and Pediatric Pathology, 1-18.
37. Volcik, K. A., Blanton, S. H., Tyerman, G. H., Jong, S. T., Rott, E. J., Page, T. Z., & Northrup, H. (2000). Methylenetetrahydrofolate reductase and spina bifida: evaluation of level of defect and maternal genotypic risk in Hispanics. American Journal of Medical Genetics, 95(1), 21-27.
38. Goyal, A., Kumawat, M., Vashisth, M., Gill, P. S., Sing, I., and Dhaulakhandi, D. B. (2021). Study of C677T methylene tetrahydrofolate reductase gene polymorphism as a risk factor for neural tube defects. Asian Journal of Neurosurgery, 16(3), 554.
2. Bhide, P., Sagoo, G. S., Moorthie, S., Burton, H., and Kar, A. (2013). Systematic review of birth prevalence of neural tube defects in India. Birth Defects Research Part A: Clinical and Molecular Teratology, 97(7), 437-443.
3. Behrooz, A. (2007). Prevalence of neural tube defect and its relative factors in south-west of Iran. Pakistan Journal Of Medical Sciences, 23(4), 654.
4. Khan, M. Y., Khan, K., and Ahmed, M. (2006). Short term outcome of surgical management of patients with neural tube defect (spina bifida). Journal of Postgraduate Medical Institute (Peshawar-Pakistan), 20(3).
5. Kocylowski, R., Grzesiak, M., Gaj, Z., Lorenc, W., Bakinowska, E., Barałkiewicz, D., and Suliburska, J. (2019). Associations between the level of trace elements and minerals and folate in maternal serum and amniotic fluid and congenital abnormalities. Nutrients, 11(2), 328.
6. Marriott, B. P., Birt, D. F., Stalling, V. A., and Yates, A. A. (Eds.). (2020). Present Knowledge in Nutrition: Basic Nutrition and Metabolism. Academic Press.
7. Pei, L., Kang, Y., Cheng, Y., and Yan, H. (2015). The association of maternal lifestyle with birth defects in Shaanxi Province, Northwest China. PloS one, 10(9), e0139452.
8. Bailey, S. W., and Ayling, J. E. (2009). The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proceedings of the National Academy of Sciences, 106(36), 15424-15429.
9. Martinez, C. A., Northrup, H., Lin, J. I., Morrison, A. C., Fletcher, J. M., Tyerman, G. H., and Au, K. S. (2009). Genetic association study of putative functional single nucleotide polymorphisms of genes in folate metabolism and spina bifida. American journal of obstetrics and gynecology, 201(4), 394-e1.
10. Penttilä, I., Penttilä, K., Holm, P., Laitinen, H., Ranta, P., Törrönen, J., & Rauramaa, R. (2016). Methods, units and quality requirements for the analysis of haemoglobin A1c in diabetes mellitus. World journal of methodology, 6(2), 133.
11. Ashraf, M. J., Cook, J. R., & Rothberg, M. B. (2008). Clinical utility of folic acid testing for patients with anemia or dementia. Journal of general internal medicine, 23(6), 824-826.
12. Ghatak, S., Muthukumaran, R. B., & Nachimuthu, S. K. (2013). A simple method of genomic DNA extraction from human samples for PCR-RFLP analysis. Journal of biomolecular techniques: JBT, 24(4), 224.
13. Relton, C. L., Wilding, C. S., Pearce, M. S., Laffling, A. J., Jonas, P. A., Lynch, S. A., and Burn, J. (2004). Gene–gene interaction in folate-related genes and risk of neural tube defects in a UK population. Journal of medical genetics, 41(4), 256-260.
14. Chen, Z., Lin, T., & Wang, K. (2017). A powerful variant-set association test based on chisquare distribution. Genetics, 207(3), 903-910.
15. Liptak, G. S., and El Samra, A. (2010). Optimizing health care for children with spina bifida. Developmental disabilities research reviews, 16(1), 66-75.
16. Stichelen, O. V., Rother, K. I., and Hanover, J. A. (2019). Maternal exposure to non-nutritive sweeteners impacts progeny’s metabolism and microbiome. Frontiers in microbiology, 10, 1360.
17. Liu, H. Y., Liu, S. M., and Zhang, Y. Z. (2020). Maternal folic acid supplementation mediates offspring health via DNA methylation. Reproductive Sciences, 27(4), 963-976.
18. Ferrari, A., Torrezan, G. T., Carraro, D. M., and Aguiar Junior, S. (2019). Association of folate and vitamins involved in the 1-carbon cycle with polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) and global DNA methylation in patients with colorectal cancer. Nutrients, 11(6), 1368.
19. Barua, S., Kuizon, S., and Junaid, M. A. (2014). Folic acid supplementation in pregnancy and implications in health and disease. Journal of biomedical science, 21(1), 1-9.
20. Mowla, S., Gissler, M., Räisänen, S., and Kancherla, V. (2020). Association between maternal pregestational diabetes mellitus and spina bifida: A population‐based case–control study, Finland, 2000–2014. Birth defects research, 112(2), 186-195.
21. Liu, S., Evans, J., MacFarlane, A. J., Ananth, C. V., Little, J., Kramer, M. S., and Joseph, K. S. (2019). Association of maternal risk factors with the recent rise of neural tube defects in Canada. Paediatric and perinatal epidemiology, 33(2), 145-153.
22. Stiles-Shields, C., and Holmbeck, G. N. (2020). Health behaviors and disordered eating in adolescents and young adults with spina bifida: results from a national survey. Disability and rehabilitation, 42(20), 2910-2916.
23. Rendeli, C., Kuczynska, E., Giuliano, A. C., Chiaretti, A., and Ausili, E. (2020). Dietary approach to prevent obesity risk in Spina Bifida patients. Child's Nervous System, 36(7), 1515-1520.
24. Ayaz, R., and Asoglu, M. R. (2020). Neural tube defects in eastern Turkey; Is low folate status or vitamin B12 deficiency or both associated with a high rate of NTDs?. The Journal of Maternal-Fetal and Neonatal Medicine, 33(22), 3835-3840.
25. Yu, Y., Jia, C., Shi, Q., Zhu, Y., and Liu, Y. (2019). Hyperhomocysteinemia in men with a reproductive history of fetal neural tube defects: Three case reports and literature review. Medicine, 98(2).
26. Van Der Put, N. M., Van Straaten, H. W., Trijbels, F. J., and Blom, H. J. (2001). Folate, homocysteine and neural tube defects: an overview. Experimental Biology and Medicine, 226(4), 243-270.
27. Liu, H. Y., Liu, S. M., and Zhang, Y. Z. (2020). Maternal folic acid supplementation mediates offspring health via DNA methylation. Reproductive Sciences, 27(4), 963-976.
28. Tabatabaei, R. S., Fatahi-Meibodi, N., Meibodi, B., Javaheri, A., Abbasi, H., Hadadan, A., and Neamatzadeh, H. (2020). Association of Fetal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects: A Systematic Review and Update MetaAnalysis. Fetal and Pediatric Pathology, 1-17.
29. Zhou-Cun, A., Yang, Y., Zhang, S. Z., Li, N., and Zhang, W. (2007). Single nucleotide polymorphism C677T in the methylenetetrahydrofolate reductase gene might be a genetic risk factor for infertility for Chinese men with azoospermia or severe oligozoospermia. Asian J Androl, 9(1), 57-62.
30. Eggink, A. J., and Steegers-Theunissen, R. P. (2020). Neural tube anomalies: An update on the pathophysiology and prevention. Fetal therapy: Scientific basis and critical appraisal of clinical benefits, 449-455.
31. Tabatabaei, R. S., Fatahi-Meibodi, N., Meibodi, B., Javaheri, A., Abbasi, H., Hadadan, A., & Neamatzadeh, H. (2022). Association of fetal MTHFR C677T polymorphism with susceptibility to neural tube defects: a systematic review and update meta-analysis. Fetal and pediatric pathology, 41(2), 225-241.
32. Hassan, M. H., Raslan, M. A., Tharwat, M., Sakhr, H. M., El-Khateeb, E. E. S., Sakr, S. F., & Hamdan, A. R. (2022). Metabolic Analysis of Methylenetetrahydrofolate Reductase Single Nucleotide Polymorphisms (MTHFR 677C< T and MTHFR 1298A< C), Serum Folate and Vitamin B12 in Neural Tube Defects. Indian Journal of Clinical Biochemistry, 1-11.
33. Weisberg, I., Tran, P., Christensen, B., Sibani, S., and Rozen, R. (1998). A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Molecular genetics and metabolism, 64(3), 169-172.
34. Joibari, R. M., Movafagh, A., and Molaei, A. (2021). Association between Maternal and Fetal MTHFR C677T and MTRR A66G Polymorphisms with the Risk of NTDs: A Systematic Review and Meta-Analysis Study. Iranian Red Crescent Medical Journal, 23(11).
35. Aranda‐Sánchez, C. I., Bobadilla‐Morales, L., Corona‐Rivera, A., Cuero‐Quezada, I., SantanaHernández, J., Baldomero‐López, A., & Corona‐Rivera, J. R. (2021). MTHFR C677T and A1298C variants in Mexican Mestizo infants with neural tube defects from Western Mexico. Congenital Anomalies, 61(5), 188-192
36. Soleimani-Jadidi, S., Meibodi, B., Javaheri, A., Tabatabaei, R. S., Hadadan, A., Zanbagh, L., and Neamatzadeh, H. (2020). Association between Fetal MTHFR A1298C (rs1801131) Polymorphism and Neural Tube Defects Risk: A Systematic Review and MetaAnalysis. Fetal and Pediatric Pathology, 1-18.
37. Volcik, K. A., Blanton, S. H., Tyerman, G. H., Jong, S. T., Rott, E. J., Page, T. Z., & Northrup, H. (2000). Methylenetetrahydrofolate reductase and spina bifida: evaluation of level of defect and maternal genotypic risk in Hispanics. American Journal of Medical Genetics, 95(1), 21-27.
38. Goyal, A., Kumawat, M., Vashisth, M., Gill, P. S., Sing, I., and Dhaulakhandi, D. B. (2021). Study of C677T methylene tetrahydrofolate reductase gene polymorphism as a risk factor for neural tube defects. Asian Journal of Neurosurgery, 16(3), 554.
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Feb 9, 2024
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Madiha Sikander, Javed Anver Qureshi, Muhammad Sajjad Khattak, Muhammad Sikander Ghayas Khan, Bismillah Mubeen, Seerat Mubeen, Sultan Badar, & Malik Muhammad Qasim. (2024). ASSOCIATION OF MTHFR 677CT, 1298AC POLYMORPHISMS AND FOLIC ACID WITH SPINA BIFIDA IN PAKISTANI POPULATION. Journal of Population Therapeutics and Clinical Pharmacology, 31(2), 424–434. https://doi.org/10.53555/jptcp.v31i2.4370
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Author Biographies
Madiha Sikander
PhD Scholar, Biochemistry, University of Lahore, Lahore, Pakistan,
Javed Anver Qureshi
Professor Biochemistry, IMBB, University of Lahore, Lahore, Pakistan,
Muhammad Sajjad Khattak
Associate Professor, School of Biological Sciences, Punjab University, Lahore, Pakistan,
Muhammad Sikander Ghayas Khan
Professor, Dept of rehabilitation sciences, Allied Health Sciences, University of Lahore, Lahore, Pakistan,
Bismillah Mubeen
Post doc fellow, School of food and biological engineering, Jiangsu University, Zhenjiang 202013, China
Seerat Mubeen
Special education instructor, Government Special education center, Thokar Niazb Baig, Lahore, Pakistan,
Sultan Badar
Senior medical officer, Pediatric ENT, The University of Children Health Sciences, The children hospital, Lahore, Pakistan,
Malik Muhammad Qasim
Senior medical officer, Alnasr hospital, Lahore, Pakistan,