MTHFR promoter methylation might mitigate the effect of smoking at the level of LINE-1 in cleft lip tissues: A preliminary study.
DNA methylation
LINE-1
MTHFR c.677C > T
MTHFR promoter methylation
nonsyndromic cleft lip with or without cleft palate
Journal
Birth defects research
ISSN: 2472-1727
Titre abrégé: Birth Defects Res
Pays: United States
ID NLM: 101701004
Informations de publication
Date de publication:
01 12 2021
01 12 2021
Historique:
revised:
18
07
2021
received:
05
05
2021
accepted:
10
09
2021
pubmed:
21
10
2021
medline:
25
12
2021
entrez:
20
10
2021
Statut:
ppublish
Résumé
The medial and maxillary aspects of the upper lip originate at separate embryonic stages and therefore may experience different maternal exposure patterns which may affect methylation. Based on this hypothesis, we investigated the level of methylation of the methylene tetrahydrofolate reductase promoter gene (mMTHFR) in tissues from cleft lip, and mMTHFR levels by MTHFR c.677C > T genotype. We further investigated whether mMTHFR mitigates the effect of smoking on long interspersed nuclear element (LINE-1) methylation in these tissues. DNA extracted from medial and lateral tissues of 26 infants with nonsyndromic cleft lip with or without cleft palate (nsCL/P) was bisulfite converted and mMTHFR was measured on a pyrosequenser. LINE-1 methylation and MTHFR c.677C > T genotype data were obtained in our previous study. There was no substantial difference in mMTHFR (p = .733) and LINE-1 (p = .148) between the two tissues. mMTHFR was not influenced by MTHFR c.677C > T genotype, but there was suggestive evidence that the difference was larger among infants exposed to maternal smoking compared to nonexposed. LINE-1 methylation differences were significant (p = .025) in infants born to nonsmoking mothers, but this was not apparent (p = .872) in infants born to mothers who smoked. Our Pearson's correlation analysis suggested a weak inverse association between mMTHFR and LINE-1 (r = -.179, p = .381). Our preliminary observation of differences in patterns of mMTHFR levels in lip tissue suggests the interplay of gene and environment in the establishment of methylation in tissues at both sides of cleft lip. This requires investigation in a larger cohort, integrated with metabolic assessment.
Sections du résumé
BACKGROUND
The medial and maxillary aspects of the upper lip originate at separate embryonic stages and therefore may experience different maternal exposure patterns which may affect methylation. Based on this hypothesis, we investigated the level of methylation of the methylene tetrahydrofolate reductase promoter gene (mMTHFR) in tissues from cleft lip, and mMTHFR levels by MTHFR c.677C > T genotype. We further investigated whether mMTHFR mitigates the effect of smoking on long interspersed nuclear element (LINE-1) methylation in these tissues.
METHODS
DNA extracted from medial and lateral tissues of 26 infants with nonsyndromic cleft lip with or without cleft palate (nsCL/P) was bisulfite converted and mMTHFR was measured on a pyrosequenser. LINE-1 methylation and MTHFR c.677C > T genotype data were obtained in our previous study.
RESULTS
There was no substantial difference in mMTHFR (p = .733) and LINE-1 (p = .148) between the two tissues. mMTHFR was not influenced by MTHFR c.677C > T genotype, but there was suggestive evidence that the difference was larger among infants exposed to maternal smoking compared to nonexposed. LINE-1 methylation differences were significant (p = .025) in infants born to nonsmoking mothers, but this was not apparent (p = .872) in infants born to mothers who smoked. Our Pearson's correlation analysis suggested a weak inverse association between mMTHFR and LINE-1 (r = -.179, p = .381).
CONCLUSION
Our preliminary observation of differences in patterns of mMTHFR levels in lip tissue suggests the interplay of gene and environment in the establishment of methylation in tissues at both sides of cleft lip. This requires investigation in a larger cohort, integrated with metabolic assessment.
Substances chimiques
MTHFR protein, human
EC 1.5.1.20
Methylenetetrahydrofolate Reductase (NADPH2)
EC 1.5.1.20
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1463-1469Informations de copyright
© 2021 Wiley Periodicals LLC.
Références
Andersen, A. M., Dogan, M. V., Beach, S. R., & Philibert, R. A. (2015). Current and future prospects for epigenetic biomarkers of substance use disorders. Genes (Basel), 6(4), 991-1022. https://doi.org/10.3390/genes6040991
Armstrong, R. A. (2014). When to use the Bonferroni correction. Ophthalmic & Physiological Optics, 34(5), 502-508. https://doi.org/10.1111/opo.12131
Asim, A., Agarwal, S., Panigrahi, I., Saiyed, N., & Bakshi, S. (2017). MTHFR promoter hypermethylation may lead to congenital heart defects in Down syndrome. Intractable & Rare Diseases Research, 6(4), 295-298. https://doi.org/10.5582/irdr.2017.01068
Beach, S. R. H., Lei, M. K., Ong, M. L., Brody, G. H., Dogan, M. V., & Philibert, R. A. (2017). MTHFR methylation moderates the impact of smoking on DNA methylation at AHRR for African American young adults. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 174(6), 608-618. https://doi.org/10.1002/ajmg.b.32544
Breton, C. V., Marsit, C. J., Faustman, E., Nadeau, K., Goodrich, J. M., Dolinoy, D. C., … Murphy, S. K. (2017). Small-magnitude effect sizes in epigenetic end points are important in children's environmental health studies: The Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. Environmental Health Perspectives, 125(4), 511-526. https://doi.org/10.1289/EHP595
Coppede, F., Denaro, M., Tannorella, P., & Migliore, L. (2016). Increased MTHFR promoter methylation in mothers of Down syndrome individuals. Mutation Research, 787, 1-6. https://doi.org/10.1016/j.mrfmmm.2016.02.008
Coppede, F., Stoccoro, A., Tannorella, P., Gallo, R., Nicoli, V., & Migliore, L. (2019). Association of polymorphisms in genes involved in one-carbon metabolism with MTHFR methylation levels. International Journal of Molecular Sciences, 20(15), 3754. https://doi.org/10.3390/ijms20153754
Del Gobbo, G. F., Price, E. M., Hanna, C. W., & Robinson, W. P. (2018). No evidence for association of MTHFR 677C>T and 1298A>C variants with placental DNA methylation. Clinical Epigenetics, 10, 34. https://doi.org/10.1186/s13148-018-0468-1
Dixon, M. J., Marazita, M. L., Beaty, T. H., & Murray, J. C. (2011). Cleft lip and palate: Understanding genetic and environmental influences. Nature Reviews. Genetics, 12(3), 167-178. https://doi.org/10.1038/nrg2933
Faul, F., Erdfelder, E., Lang, A. G., & Buchner, A. (2007). G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods, 39(2), 175-191. https://doi.org/10.3758/bf03193146
Ge, J., Wang, J., Zhang, F., Diao, B., Song, Z. F., Shan, L. L., … Li, X. Q. (2015). Correlation between MTHFR gene methylation and pre-eclampsia, and its clinical significance. Genetics and Molecular Research, 14(3), 8021-8028. https://doi.org/10.4238/2015.July.17.10
Grassia, V., Lombardi, A., Kawasaki, H., Ferri, C., Perillo, L., Mosca, L., … Caraglia, M. (2018). Salivary microRNAs as new molecular markers in cleft lip and palate. Oncotarget, 9(27), 18929-18938. https://doi.org/10.18632/oncotarget.24838
Jiang, R., Bush, J. O., & Lidral, A. C. (2006). Development of the upper lip: Morphogenetic and molecular mechanisms. Developmental Dynamics, 235(5), 1152-1166. https://doi.org/10.1002/dvdy.20646
Johnson, C. Y., & Little, J. (2008). Folate intake, markers of folate status and oral clefts: Is the evidence converging? International Journal of Epidemiology, 37(5), 1041-1058. https://doi.org/10.1093/ije/dyn098
Joubert, B. R., Felix, J. F., Yousefi, P., Bakulski, K. M., Just, A. C., Breton, C., … London, S. J. (2016). DNA methylation in newborns and maternal smoking in pregnancy: Genome-wide Consortium meta-analysis. American Journal of Human Genetics, 98(4), 680-696. https://doi.org/10.1016/j.ajhg.2016.02.019
Khan, M. F. J., Little, J., Abelli, L., Mossey, P. A., Autelitano, L., Nag, T. C., & Rubini, M. (2018). Muscle fiber diameter assessment in cleft lip using image processing. Oral Diseases, 24(3), 476-481. https://doi.org/10.1111/odi.12790
Khan, M. F. J., Little, J., Aleotti, V., Mossey, P. A., Steegers-Theunissen, R. P. M., Autelitano, L., … Rubini, M. (2019). LINE-1 methylation in cleft lip tissues: Influence of infant MTHFR c.677C>T genotype. Oral Diseases, 25, 1668-1671. https://doi.org/10.1111/odi.13136
Khan, M. F. J., Little, J., Mossey, P. A., Steegers-Theunissen, R. P., Autelitano, L., Lombardo, I., … Rubini, M. (2018). Evaluating LINE-1 methylation in cleft lip tissues and its association with early pregnancy exposures. Epigenomics, 10(1), 105-113. https://doi.org/10.2217/epi-2017-0081
Khan, M. F. J., Little, J., Mossey, P. A., Steegers-Theunissen, R. P. M., Bonsi, M., Bassi Andreasi, R., & Rubini, M. (2018). Association between a common missense variant in LOXL3 gene and the risk of non-syndromic cleft palate. Congenital Anomalies (Kyoto), 58(4), 136-140. https://doi.org/10.1111/cga.12288
Khan, M. F. J., Little, J., Nag, T. C., Mossey, P. A., Autelitano, L., Meazzini, M. C., … Rubini, M. (2019). Ultrastructural analysis of collagen fibril diameter distribution in cleft lip. Oral Diseases, 25(1), 206-214. https://doi.org/10.1111/odi.12962
Leslie, E. J., & Marazita, M. L. (2013). Genetics of cleft lip and cleft palate. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 163C(4), 246-258. https://doi.org/10.1002/ajmg.c.31381
Liew, S. C., & Gupta, E. D. (2015). Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: Epidemiology, metabolism and the associated diseases. European Journal of Medical Genetics, 58(1), 1-10. https://doi.org/10.1016/j.ejmg.2014.10.004
Lisanti, S., Omar, W. A., Tomaszewski, B., De Prins, S., Jacobs, G., Koppen, G., … Langie, S. A. (2013). Comparison of methods for quantification of global DNA methylation in human cells and tissues. PLoS One, 8(11), e79044. https://doi.org/10.1371/journal.pone.0079044
Little, J., Cardy, A., & Munger, R. G. (2004). Tobacco smoking and oral clefts: A meta-analysis. Bulletin of the World Health Organization, 82(3), 213-218.
Mandaviya, P. R., Joehanes, R., Aissi, D., Kuhnel, B., Marioni, R. E., Truong, V., … Consortium, B. (2017). Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes. PLoS One, 12(10), e0182472. https://doi.org/10.1371/journal.pone.0182472
McLeod, S. A. (2019, July 10). What does effect size tell you? Simply Psychology. Retrieved from https://www.simplypsychology.org/effect-size.html
Mishra, J., Talwar, S., Kaur, L., Chandiok, K., Yadav, S., Puri, M., … Saraswathy, K. N. (2019). Differential global and MTHFR gene specific methylation patterns in preeclampsia and recurrent miscarriages: A case-control study from North India. Gene, 704, 68-73. https://doi.org/10.1016/j.gene.2019.04.036
Mossey, P. A., & Little, J. (2002). Epidemiology of oral clefts: An international perspective. In D. F. Wyszynski (Ed.), Cleft lip and palate: From origin to treatment. New York, NY: Oxford University Press.
Mossey, P. A., Little, J., Steegers-Theunissen, R., Molloy, A., Peterlin, B., Shaw, W. C., … Rubini, M. (2017). Genetic interactions in nonsyndromic orofacial clefts in Europe-EUROCRAN Study. The Cleft Palate-Craniofacial Journal, 54(6), 623-630. https://doi.org/10.1597/16-037
Mossey, P. A., Shaw, W. C., Munger, R. G., Murray, J. C., Murthy, J., & Little, J. (2011). Global oral health inequalities: Challenges in the prevention and management of orofacial clefts and potential solutions. Advances in Dental Research, 23(2), 247-258. https://doi.org/10.1177/0022034511402083
Nafee, T. M., Farrell, W. E., Carroll, W. D., Fryer, A. A., & Ismail, K. M. (2008). Epigenetic control of fetal gene expression. BJOG, 115(2), 158-168. https://doi.org/10.1111/j.1471-0528.2007.01528.x
Nash, A. J., Mandaviya, P. R., Dib, M. J., Uitterlinden, A. G., van Meurs, J., Heil, S. G., … Ahmadi, K. R. (2019). Interaction between plasma homocysteine and the MTHFR c.677C>T polymorphism is associated with site-specific changes in DNA methylation in humans. The FASEB Journal, 33(1), 833-843. https://doi.org/10.1096/fj.201800400R
Ni, G., Qin, J., Chen, Z., Li, H., Zhou, J., Huang, M., & Zhou, L. (2018). Associations between genetic variation in one-carbon metabolism and leukocyte DNA methylation in valproate-treated patients with epilepsy. Clinical Nutrition, 37(1), 308-312. https://doi.org/10.1016/j.clnu.2017.01.004
Pautz, N., Olivier, B., & Steyn, F. (2018). The use of parametric effect sizes in single study musculoskeletal physiotherapy research: A practical primer. Physical Therapy in Sport, 32, 87-97. https://doi.org/10.1016/j.ptsp.2018.05.002
Perneger, T. V. (1998). What's wrong with Bonferroni adjustments. BMJ, 316(7139), 1236-1238. https://doi.org/10.1136/bmj.316.7139.1236
Piras, I. S., Costa, A., Tirindelli, M. C., Stoccoro, A., Huentelman, M. J., Sacco, R., … Lintas, C. (2020). Genetic and epigenetic MTHFR gene variants in the mothers of attention-deficit/hyperactivity disorder affected children as possible risk factors for neurodevelopmental disorders. Epigenomics, 12, 813-823. https://doi.org/10.2217/epi-2019-0356
Rai, V. (2018). Strong association of C677T polymorphism of methylenetetrahydrofolate reductase gene with nosyndromic cleft lip/palate (nsCL/P). Indian Journal of Clinical Biochemistry, 33(1), 5-15. https://doi.org/10.1007/s12291-017-0673-2
Raut, J. R., Simeone, R. M., Tinker, S. C., Canfield, M. A., Day, R. S., & Agopian, A. J. (2019). Proportion of orofacial clefts attributable to recognized risk factors. The Cleft Palate-Craniofacial Journal, 56(2), 151-158. https://doi.org/10.1177/1055665618774019
Reutter, H., Birnbaum, S., Lacava, A. D., Mende, M., Henschke, H., Berge, S., … Mangold, E. (2008). Family-based association study of the MTHFR polymorphism C677T in patients with nonsyndromic cleft lip and palate from central Europe. The Cleft Palate-Craniofacial Journal, 45(3), 267-271. https://doi.org/10.1597/06-174
Richmond, R. C., & Joubert, B. R. (2017). Contrasting the effects of intra-uterine smoking and one-carbon micronutrient exposures on offspring DNA methylation. Epigenomics, 9(3), 351-367. https://doi.org/10.2217/epi-2016-0135
Shaw, G. M., Todoroff, K., Finnell, R. H., Rozen, R., & Lammer, E. J. (1999). Maternal vitamin use, infant C677T mutation in MTHFR, and isolated cleft palate risk. American Journal of Medical Genetics, 85(1), 84-85.
Sinclair, K. D., Allegrucci, C., Singh, R., Gardner, D. S., Sebastian, S., Bispham, J., … Young, L. E. (2007). DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proceedings of the National Academy of Sciences of the United States of America, 104(49), 19351-19356. https://doi.org/10.1073/pnas.0707258104
Stock, N. M., Humphries, K., Pourcain, B. S., Bailey, M., Persson, M., Ho, K. M., … Sandy, J. (2016). Opportunities and challenges in establishing a cohort study: An example from cleft lip/palate research in the United Kingdom. The Cleft Palate-Craniofacial Journal, 53(3), 317-325. https://doi.org/10.1597/14-306
Stover, P. J. (2009). One-carbon metabolism-genome interactions in folate-associated pathologies. Journal of Nutrition, 139(12), 2402-2405. https://doi.org/10.3945/jn.109.113670
van der Put, N. M., Gabreels, F., Stevens, E. M., Smeitink, J. A., Trijbels, F. J., Eskes, T. K., … Blom, H. J. (1998). A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural-tube defects? American Journal of Human Genetics, 62(5), 1044-1051. https://doi.org/10.1086/301825
Xuan, Z., Zhongpeng, Y., Yanjun, G., Jiaqi, D., Yuchi, Z., Bing, S., & Chenghao, L. (2016). Maternal active smoking and risk of oral clefts: A meta-analysis. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, 122(6), 680-690. https://doi.org/10.1016/j.oooo.2016.08.007
Zhou, Y., Sinnathamby, V., Yu, Y., Sikora, L., Johnson, C. Y., Mossey, P., & Little, J. (2020). Folate intake, markers of folate status and oral clefts: An updated set of systematic reviews and meta-analyses. Birth Defects Research, 112(19), 1699-1719. https://doi.org/10.1002/bdr2.1827