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BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

Plasma S-adenosylmethionine, DNMTpolymorphisms, and peripheral blood LINE-1 methylation among healthy Chinese adults in Singapore

Authors: Maki Inoue-Choi, Heather H Nelson, Kim Robien, Erland Arning, Teodoro Bottiglieri, Woon-Puay Koh, Jian-Min Yuan

Published in: BMC Cancer | Issue 1/2013

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Abstract

Background

Global hypomethylation of repetitive DNA sequences is believed to occur early in tumorigenesis. There is a great interest in identifying factors that contribute to global DNA hypomethylation and associated cancer risk. We tested the hypothesis that plasma S-adenosylmethionine (SAM) level alone or in combination with genetic variation in DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) was associated with global DNA methylation extent at long interspersed nucleotide element-1 (LINE-1) sequences.

Methods

Plasma SAM level and LINE-1 DNA methylation index were measured using stored blood samples collected from 440 healthy Singaporean Chinese adults during 1994-1999. Genetic polymorphisms of 13 loci in DNMT1, DNMT3A and DNMT3B were determined.

Results

LINE-1 methylation index was significantly higher in men than in women (p = 0.001). LINE-1 methylation index was positively associated with plasma SAM levels (p ≤ 0.01), with a plateau at approximately 78% of LINE-1 methylation index (55 nmol/L plasma SAM) in men and 77% methylation index (50 nmol/L plasma SAM) in women. In men only, the T allele of DNMT1 rs21124724 was associated with a statistically significantly higher LINE-1 methylation index (p trend = 0.001). The DNMT1 rs2114724 genotype modified the association between plasma SAM and LINE-1 methylation index at low levels of plasma SAM in men.

Conclusions

Circulating SAM level was associated with LINE-1 methylation status among healthy Chinese adults. The DNMT1 genetic polymorphism may exert a modifying effect on the association between SAM and LINE-1 methylation status in men, especially when plasma SAM level is low. Our findings support a link between plasma SAM and global DNA methylation status at LINE-1 sequences.
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Literature
1.
Ehrlich M: DNA methylation in cancer: too much, but also too little. Oncogene. 2002, 21 (35): 5400-5413. 10.1038/sj.onc.1205651.CrossRefPubMed
2.
Esteller M, Corn PG, Baylin SB, Herman JG: A gene hypermethylation profile of human cancer. Cancer Res. 2001, 61 (8): 3225-3229.PubMed
3.
Zhu ZZ, Sparrow D, Hou L, Tarantini L, Bollati V, Litonjua AA, Zanobetti A, Vokonas P, Wright RO, Baccarelli A, et al: Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence, and mortality in elderly individuals: the Normative Aging Study. Cancer Causes Control. 2011, 22 (3): 437-447. 10.1007/s10552-010-9715-2.CrossRefPubMed
4.
Liao LM, Brennan P, Van Bemmel DM, Zaridze D, Matveev V, Janout V, Kollarova H, Bencko V, Navratilova M, Szeszenia-Dabrowska N, et al: LINE-1 methylation levels in leukocyte DNA and risk of renal cell cancer. PLoS One. 2011, 6 (11): e27361-10.1371/journal.pone.0027361.CrossRefPubMedPubMedCentral
5.
Goelz SE, Vogelstein B, Hamilton SR, Feinberg AP: Hypomethylation of DNA from benign and malignant human colon neoplasms. Science. 1985, 228 (4696): 187-190. 10.1126/science.2579435.CrossRefPubMed
6.
Suter CM, Martin DI, Ward RL: Hypomethylation of L1 retrotransposons in colorectal cancer and adjacent normal tissue. Int J Colorectal Dis. 2004, 19 (2): 95-101. 10.1007/s00384-003-0539-3.CrossRefPubMed
7.
Gama-Sosa MA, Slagel VA, Trewyn RW, Oxenhandler R, Kuo KC, Gehrke CW, Ehrlich M: The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res. 1983, 11 (19): 6883-6894. 10.1093/nar/11.19.6883.CrossRefPubMedPubMedCentral
8.
Cash HL, Tao L, Yuan JM, Marsit CJ, Houseman EA, Xiang YB, Gao YT, Nelson HH, Kelsey KT: LINE-1 hypomethylation is associated with bladder cancer risk among nonsmoking Chinese. Int J Cancer. 2012, 130 (5): 1151-1159. 10.1002/ijc.26098.CrossRefPubMed
9.
Wilhelm CS, Kelsey KT, Butler R, Plaza S, Gagne L, Zens MS, Andrew AS, Morris S, Nelson HH, Schned AR, et al: Implications of LINE1 methylation for bladder cancer risk in women. Clin Cancer Res. 2010, 16 (5): 1682-1689. 10.1158/1078-0432.CCR-09-2983.CrossRefPubMedPubMedCentral
10.
Bollati V, Baccarelli A, Hou L, Bonzini M, Fustinoni S, Cavallo D, Byun HM, Jiang J, Marinelli B, Pesatori AC, et al: Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Res. 2007, 67 (3): 876-880. 10.1158/0008-5472.CAN-06-2995.CrossRefPubMed
11.
Zhu ZZ, Hou L, Bollati V, Tarantini L, Marinelli B, Cantone L, Yang AS, Vokonas P, Lissowska J, Fustinoni S, et al: Predictors of global methylation levels in blood DNA of healthy subjects: a combined analysis. Int J Epidemiol. 2010, 41 (1): 126-139.CrossRefPubMedPubMedCentral
12.
Zhang FF, Morabia A, Carroll J, Gonzalez K, Fulda K, Kaur M, Vishwanatha JK, Santella RM, Cardarelli R: Dietary patterns are associated with levels of global genomic DNA methylation in a cancer-free population. J Nutr. 2011, 141 (6): 1165-1171. 10.3945/jn.110.134536.CrossRefPubMedPubMedCentral
13.
Zhang FF, Santella RM, Wolff M, Kappil MA, Markowitz SB, Morabia A: White blood cell global methylation and IL-6 promoter methylation in association with diet and lifestyle risk factors in a cancer-free population. Epigenetics. 2012, 7 (6): 606-614. 10.4161/epi.20236.CrossRefPubMedPubMedCentral
14.
Rusiecki JA, Baccarelli A, Bollati V, Tarantini L, Moore LE, Bonefeld-Jorgensen EC: Global DNA hypomethylation is associated with high serum-persistent organic pollutants in Greenlandic Inuit. Environ Health Perspect. 2008, 116 (11): 1547-1552. 10.1289/ehp.11338.CrossRefPubMedPubMedCentral
15.
Larsson SC, Giovannucci E, Wolk A: Folate and risk of breast cancer: a meta-analysis. J Natl Cancer Inst. 2007, 99 (1): 64-76. 10.1093/jnci/djk006.CrossRefPubMed
16.
Kim DH, Smith-Warner SA, Spiegelman D, Yaun SS, Colditz GA, Freudenheim JL, Giovannucci E, Goldbohm RA, Graham S, Harnack L, et al: Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer. Cancer Causes Control. 2010, 21 (11): 1919-1930. 10.1007/s10552-010-9620-8.CrossRefPubMedPubMedCentral
17.
Ma J, Stampfer MJ, Giovannucci E, Artigas C, Hunter DJ, Fuchs C, Willett WC, Selhub J, Hennekens CH, Rozen R: Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res. 1997, 57 (6): 1098-1102.PubMed
18.
Kim YI: Nutritional epigenetics: impact of folate deficiency on DNA methylation and colon cancer susceptibility. J Nutr. 2005, 135 (11): 2703-2709.PubMed
19.
Choi SW, Friso S, Keyes MK, Mason JB: Folate supplementation increases genomic DNA methylation in the liver of elder rats. Br J Nutr. 2005, 93 (1): 31-35. 10.1079/BJN20041283.CrossRefPubMed
20.
Pradhan S, Bacolla A, Wells RD, Roberts RJ: Recombinant human DNA (cytosine-5) methyltransferase. I. Expression, purification, and comparison of de novo and maintenance methylation. J Biol Chem. 1999, 274 (46): 33002-33010. 10.1074/jbc.274.46.33002.CrossRefPubMed
21.
Zucker KE, Riggs AD, Smith SS: Purification of human DNA (cytosine-5-)-methyltransferase. J Cell Biochem. 1985, 29 (4): 337-349. 10.1002/jcb.240290407.CrossRefPubMed
22.
Okano M, Bell DW, Haber DA, Li E: DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999, 99 (3): 247-257. 10.1016/S0092-8674(00)81656-6.CrossRefPubMed
23.
Lyko F, Ramsahoye BH, Kashevsky H, Tudor M, Mastrangelo MA, Orr-Weaver TL, Jaenisch R: Mammalian (cytosine-5) methyltransferases cause genomic DNA methylation and lethality in Drosophila. Nat Genet. 1999, 23 (3): 363-366. 10.1038/15551.CrossRefPubMed
24.
Liang G, Chan MF, Tomigahara Y, Tsai YC, Gonzales FA, Li E, Laird PW, Jones PA: Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Mol Cell Biol. 2002, 22 (2): 480-491. 10.1128/MCB.22.2.480-491.2002.CrossRefPubMedPubMedCentral
25.
Chen T, Ueda Y, Dodge JE, Wang Z, Li E: Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol Cell Biol. 2003, 23 (16): 5594-5605. 10.1128/MCB.23.16.5594-5605.2003.CrossRefPubMedPubMedCentral
26.
Saw SM, Yuan JM, Ong CN, Arakawa K, Lee HP, Coetzee GA, Yu MC: Genetic, dietary, and other lifestyle determinants of plasma homocysteine concentrations in middle-aged and older Chinese men and women in Singapore. Am J Clin Nutr. 2001, 73 (2): 232-239.PubMed
27.
Chun JY, Bae JS, Park TJ, Kim JY, Park BL, Cheong HS, Lee HS, Kim YJ, Shin HD: Putative association of DNA methyltransferase 1 (DNMT1) polymorphisms with clearance of HBV infection. BMB Rep. 2009, 42 (12): 834-839. 10.5483/BMBRep.2009.42.12.834.CrossRefPubMed
28.
Fan H, Liu D, Qiu X, Qiao F, Wu Q, Su X, Zhang F, Song Y, Zhao Z, Xie W: A functional polymorphism in the DNA methyltransferase-3A promoter modifies the susceptibility in gastric cancer but not in esophageal carcinoma. BMC Med. 2010, 8: 12-20. 10.1186/1741-7015-8-12.CrossRefPubMedPubMedCentral
29.
Yang AS, Estecio MR, Doshi K, Kondo Y, Tajara EH, Issa JP: A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res. 2004, 32 (3): e38-10.1093/nar/gnh032.CrossRefPubMedPubMedCentral
30.
Singer H, Walier M, Nusgen N, Meesters C, Schreiner F, Woelfle J, Fimmers R, Wienker T, Kalscheuer VM, Becker T, et al: Methylation of L1Hs promoters is lower on the inactive X, has a tendency of being higher on autosomes in smaller genomes and shows inter-individual variability at some loci. Hum Mol Genet. 2011, 21 (1): 219-235.CrossRefPubMedPubMedCentral
31.
Zhang FF, Cardarelli R, Carroll J, Fulda KG, Kaur M, Gonzalez K, Vishwanatha JK, Santella RM, Morabia A: Significant differences in global genomic DNA methylation by gender and race/ethnicity in peripheral blood. Epigenetics. 2011, 6 (5): 623-629. 10.4161/epi.6.5.15335.CrossRefPubMedPubMedCentral
32.
El-Maarri O, Walier M, Behne F, Van Uum J, Singer H, Diaz-Lacava A, Nusgen N, Niemann B, Watzka M, Reinsberg J, et al: Methylation at global LINE-1 repeats in human blood are affected by gender but not by age or natural hormone cycles. PLoS One. 2011, 6 (1): e16252-10.1371/journal.pone.0016252.CrossRefPubMedPubMedCentral
33.
Loehrer FM, Angst CP, Brunner FP, Haefeli WE, Fowler B: Evidence for disturbed S-adenosylmethionine : S-adenosylhomocysteine ratio in patients with end-stage renal failure: a cause for disturbed methylation reactions?. Nephrol Dial Transplant. 1998, 13 (3): 656-661. 10.1093/ndt/13.3.656.CrossRefPubMed
34.
Stabler SP, Allen RH, Dolce ET, Johnson MA: Elevated serum S-adenosylhomocysteine in cobalamin-deficient elderly and response to treatment. Am J Clin Nutr. 2006, 84 (6): 1422-1429.PubMed
35.
Inoue-Choi M, Nelson HH, Robien K, Arning A, Bottiglieri T, Koh W-P, Yuan J-M: One-carbon metabolism nutrient status and plasma S-adenosylmethionine concentrations in middle-aged and older Chinese in Singapore. Int J Mol Epidemiol Genet. 2012, 3 (2): 160-173.PubMedPubMedCentral
36.
Yi P, Melnyk S, Pogribna M, Pogribny IP, Hine RJ, James SJ: Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. J Biol Chem. 2000, 275 (38): 29318-29323. 10.1074/jbc.M002725200.CrossRefPubMed
37.
Castro R, Rivera I, Martins C, Struys EA, Jansen EE, Clode N, Graca LM, Blom HJ, Jakobs C, De Almeida IT: Intracellular S-adenosylhomocysteine increased levels are associated with DNA hypomethylation in HUVEC. J Mol Med (Berl). 2005, 83 (10): 831-836. 10.1007/s00109-005-0679-8.CrossRef
38.
James SJ, Melnyk S, Pogribna M, Pogribny IP, Caudill MA: Elevation in S-adenosylhomocysteine and DNA hypomethylation: potential epigenetic mechanism for homocysteine-related pathology. J Nutr. 2002, 132 (8 Suppl): 2361S-2366S.PubMed
39.
Gaudet F, Hodgson JG, Eden A, Jackson-Grusby L, Dausman J, Gray JW, Leonhardt H, Jaenisch R: Induction of tumors in mice by genomic hypomethylation. Science. 2003, 300 (5618): 489-492. 10.1126/science.1083558.CrossRefPubMed
40.
Eden A, Gaudet F, Waghmare A, Jaenisch R: Chromosomal instability and tumors promoted by DNA hypomethylation. Science. 2003, 300 (5618): 455-10.1126/science.1083557.CrossRefPubMed
41.
Okano M, Xie S, Li E: Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet. 1998, 19 (3): 219-220. 10.1038/890.CrossRefPubMed
42.
Lyon MF: LINE-1 elements and X chromosome inactivation: a function for "junk" DNA?. Proc Natl Acad Sci U S A. 2000, 97 (12): 6248-6249. 10.1073/pnas.97.12.6248.CrossRefPubMedPubMedCentral
43.
Bailey JA, Carrel L, Chakravarti A, Eichler EE: Molecular evidence for a relationship between LINE-1 elements and X chromosome inactivation: the Lyon repeat hypothesis. Proc Natl Acad Sci U S A. 2000, 97 (12): 6634-6639. 10.1073/pnas.97.12.6634.CrossRefPubMedPubMedCentral
44.
Van Driel LM, Eijkemans MJ, De Jonge R, De Vries JH, Van Meurs JB, Steegers EA, Steegers-Theunissen RP: Body mass index is an important determinant of methylation biomarkers in women of reproductive ages. J Nutr. 2009, 139 (12): 2315-2321. 10.3945/jn.109.109710.CrossRefPubMed
45.
Kerins DM, Koury MJ, Capdevila A, Rana S, Wagner C: Plasma S-adenosylhomocysteine is a more sensitive indicator of cardiovascular disease than plasma homocysteine. Am J Clin Nutr. 2001, 74 (6): 723-729.PubMed
46.
Loehrer FM, Tschopl M, Angst CP, Litynski P, Jager K, Fowler B, Haefeli WE: Disturbed ratio of erythrocyte and plasma S-adenosylmethionine/S-adenosylhomocysteine in peripheral arterial occlusive disease. Atherosclerosis. 2001, 154 (1): 147-154. 10.1016/S0021-9150(00)00449-4.CrossRefPubMed
47.
Barbosa PR, Stabler SP, Trentin R, Carvalho FR, Luchessi AD, Hirata RD, Hirata MH, Allen RH, Guerra-Shinohara EM: Evaluation of nutritional and genetic determinants of total homocysteine, methylmalonic acid and S-adenosylmethionine/S-adenosylhomocysteine values in Brazilian childbearing-age women. Clin Chim Acta. 2008, 388 (1–2): 139-147.CrossRefPubMed
48.
Struys EA, Jansen EE, De Meer K, Jakobs C: Determination of S-adenosylmethionine and S-adenosylhomocysteine in plasma and cerebrospinal fluid by stable-isotope dilution tandem mass spectrometry. Clin Chem. 2000, 46 (10): 1650-1656.PubMed
49.
Melnyk S, Pogribna M, Pogribny IP, Yi P, James SJ: Measurement of plasma and intracellular S-adenosylmethionine and S-adenosylhomocysteine utilizing coulometric electrochemical detection: alterations with plasma homocysteine and pyridoxal 5'-phosphate concentrations. Clin Chem. 2000, 46 (2): 265-272.PubMed
50.
Gellekink H, Van Oppenraaij-Emmerzaal D, Van Rooij A, Struys EA, Den Heijer M, Blom HJ: Stable-isotope dilution liquid chromatography-electrospray injection tandem mass spectrometry method for fast, selective measurement of S-adenosylmethionine and S-adenosylhomocysteine in plasma. Clin Chem. 2005, 51 (8): 1487-1492. 10.1373/clinchem.2004.046995.CrossRefPubMed
51.
Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, et al: Initial sequencing and analysis of the human genome. Nature. 2001, 409 (6822): 860-921. 10.1038/35057062.CrossRefPubMed
52.
Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA, et al: The sequence of the human genome. Science. 2001, 291 (5507): 1304-1351. 10.1126/science.1058040.CrossRefPubMed
Metadata
Title
Plasma S-adenosylmethionine, DNMTpolymorphisms, and peripheral blood LINE-1 methylation among healthy Chinese adults in Singapore
Authors
Maki Inoue-Choi
Heather H Nelson
Kim Robien
Erland Arning
Teodoro Bottiglieri
Woon-Puay Koh
Jian-Min Yuan
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-389

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