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We conducted a case\u2013control study nested in a three-arm randomized clinical pragmatic trial (ASCUS-COL trial) to evaluate the risk of CIN3+\u2009associated with methylation levels according to serum folate concentrations.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Cases (<jats:italic>n<\/jats:italic>\u2009=\u2009155) were women with histologically confirmed CIN2+\u2009(113 CIN2, 38 CIN3, and 4 SCC) and controls were age and follow-up time at diagnosis-matched women with histologically confirmed\u2009\u2264\u2009CIN1 (<jats:italic>n<\/jats:italic>\u2009=\u2009155), selected from the 1122 hrHPV\u2009+\u2009women of this trial. The concentrations of serum folate were determined by the radioimmunoassay SimulTRAC-SNB-VitaminB12\/Folate-RIAKit and the methylation levels by the S5 classifier. Stepwise logistic regression models were used to estimate the association between folate or methylation levels and CIN2+\u2009or CIN3+. The joint effect of folate levels and methylation on the risk of CIN3+\u2009was estimated using combinations of categorical stratifications.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Folate levels were significantly lower in women with CIN3+\u2009than in other diagnostic groups (<jats:italic>p<\/jats:italic>\u2009=\u20090.019). The risk of CIN3+\u2009was eight times higher (OR 8.9, 95% CI 3.4\u201324.9) in women with folate deficiency and high methylation levels than in women with normal folate and high methylation levels (OR 1.4, 95% CI 0.4\u20134.6).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>High methylation and deficient folate independently increased the risk of CIN3+\u2009while deficient folate combined with high methylation was associated with a substantially elevated risk of CIN3+.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00394-023-03289-4","type":"journal-article","created":{"date-parts":[[2023,12,21]],"date-time":"2023-12-21T20:02:13Z","timestamp":1703188933000},"page":"563-572","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Folate deficiency modifies the risk of CIN3+\u2009associated with DNA methylation levels: a nested case\u2013control study from the ASCUS-COL trial"],"prefix":"10.1007","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9248-8204","authenticated-orcid":false,"given":"Mar\u00eda C.","family":"Agudelo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0031-8513","authenticated-orcid":false,"given":"Samuel","family":"Agudelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7097-6223","authenticated-orcid":false,"given":"Attila","family":"Lorincz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8317-0130","authenticated-orcid":false,"given":"Arianis Tatiana","family":"Ram\u00edrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4520-1706","authenticated-orcid":false,"given":"Kelly Melisa","family":"Casta\u00f1eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0531-276X","authenticated-orcid":false,"given":"Isabel","family":"Garc\u00e9s-Palacio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1272-0027","authenticated-orcid":false,"given":"Arnold H.","family":"Zea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3857-7035","authenticated-orcid":false,"given":"Chandrika","family":"Piyathilake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5992-0475","authenticated-orcid":false,"given":"Gloria Ines","family":"Sanchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,12,21]]},"reference":[{"issue":"Suppl 3","key":"3289_CR1","doi-asserted-by":"publisher","first-page":"S3\/1\u201310","DOI":"10.1016\/j.vaccine.2006.05.115","volume":"24","author":"N Mu\u00f1oz","year":"2006","unstructured":"Mu\u00f1oz N, Castellsagu\u00e9 X, de Gonz\u00e1lez AB, Gissmann L (2006) Chapter 1: HPV in the etiology of human cancer. 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