{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T07:23:43Z","timestamp":1772781823451,"version":"3.50.1"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,4,4]],"date-time":"2018-04-04T00:00:00Z","timestamp":1522800000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,4,4]],"date-time":"2018-04-04T00:00:00Z","timestamp":1522800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In humans the expression of lactase changes during post-natal development, leading to phenotypes known as lactase persistence and non-persistence. Polymorphisms within the lactase gene (<jats:italic>LCT<\/jats:italic>) enhancer, in particular the \u221213910C\u2009&gt;\u2009T, but also others, are linked to these phenotypes. We were interested in identifying dynamic mediators of <jats:italic>LCT<\/jats:italic> regulation, beyond the genotype at \u221213910C\u2009&gt;\u2009T. To this end, we investigated two levels of lactase regulation in human intestinal samples obtained from New England children and adolescents of mixed European ancestry: differential expression of transcriptional regulators of <jats:italic>LCT<\/jats:italic>, and variations in DNA methylation, and their relation to phenotype. Variations in expression of CDX2, POU2F1, GATA4, GATA6, and HNF1\u03b1 did not correlate with phenotype. However, an epigenome-wide approach using the Illumina Infinium HM450 bead chip identified a differentially methylated position in the <jats:italic>LCT<\/jats:italic> promoter where methylation levels are associated with the genotype at \u221213910C\u2009&gt;\u2009T, the persistence\/non-persistence phenotype and lactase enzymatic activity. DNA methylation levels at this promoter site and CpGs in the <jats:italic>LCT<\/jats:italic> enhancer are associated with genotype. Indeed, taken together they have a higher power to predict lactase phenotypes than the genotype alone.<\/jats:p>","DOI":"10.1038\/s41598-018-23957-4","type":"journal-article","created":{"date-parts":[[2018,3,29]],"date-time":"2018-03-29T22:15:04Z","timestamp":1522361704000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Differences in DNA Methylation and Functional Expression in Lactase Persistent and Non-persistent Individuals"],"prefix":"10.1038","volume":"8","author":[{"given":"Milena N.","family":"Leseva","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard J.","family":"Grand","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hagen","family":"Klett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie","family":"Boerries","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4763-4521","authenticated-orcid":false,"given":"Hauke","family":"Busch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra M.","family":"Binder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin B.","family":"Michels","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2018,4,4]]},"reference":[{"key":"23957_CR1","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1172\/JCI115609","volume":"89","author":"JC Escher","year":"1992","unstructured":"Escher, J. C. et al. Molecular basis of lactase levels in adult humans. J Clin Invest 89, 480\u2013483 (1992).","journal-title":"J Clin Invest"},{"key":"23957_CR2","doi-asserted-by":"publisher","first-page":"2824","DOI":"10.1096\/fasebj.5.13.1916106","volume":"5","author":"RK Montgomery","year":"1991","unstructured":"Montgomery, R. K., B\u00fcller, H. A., Rings, E. H. & Grand, R. J. Lactose intolerance and the genetic regulation of intestinal lactase-phlorizin hydrolase. FASEB J 5, 2824\u20132832 (1991).","journal-title":"FASEB J"},{"issue":"Suppl 2","key":"23957_CR3","doi-asserted-by":"publisher","first-page":"S131","DOI":"10.1097\/MPG.0b013e31812e68f6","volume":"45","author":"RK Montgomery","year":"2007","unstructured":"Montgomery, R. K., Krasinski, S. D., Hirschhorn, J. N. & Grand, R. J. Lactose and lactase\u2013who is lactose intolerant and why? J Pediatr Gastroenterol Nutr 45(Suppl 2), S131\u2013137 (2007).","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"23957_CR4","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/ng1946","volume":"39","author":"SA Tishkoff","year":"2007","unstructured":"Tishkoff, S. A. et al. Convergent adaptation of human lactase persistence in Africa and Europe. Nat Genet 39, 31\u201340 (2007).","journal-title":"Nat Genet"},{"key":"23957_CR5","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1016\/j.ajhg.2013.07.008","volume":"93","author":"BL Jones","year":"2013","unstructured":"Jones, B. L. et al. Diversity of lactase persistence alleles in Ethiopia: signature of a soft selective sweep. Am J Hum Genet 93, 538\u2013544 (2013).","journal-title":"Am J Hum Genet"},{"key":"23957_CR6","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/ng826","volume":"30","author":"NS Enattah","year":"2002","unstructured":"Enattah, N. S. et al. Identification of a variant associated with adult-type hypolactasia. Nat Genet 30, 233\u2013237 (2002).","journal-title":"Nat Genet"},{"key":"23957_CR7","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1007\/s00439-012-1140-z","volume":"131","author":"L Fang","year":"2012","unstructured":"Fang, L., Ahn, J. K., Wodziak, D. & Sibley, E. The human lactase persistence-associated SNP \u221213910*T enables in vivo functional persistence of lactase promoter-reporter transgene expression. Hum Genet 131, 1153\u20131159 (2012).","journal-title":"Hum Genet"},{"key":"23957_CR8","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1097\/MPG.0000000000000595","volume":"60","author":"NY Baffour-Awuah","year":"2015","unstructured":"Baffour-Awuah, N. Y. et al. Functional significance of single nucleotide polymorphisms in the lactase gene in diverse US patients and evidence for a novel lactase persistence allele at \u221213909 in those of European ancestry. J Pediatr Gastroenterol Nutr 60, 182\u2013191 (2015).","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"23957_CR9","doi-asserted-by":"publisher","first-page":"197","DOI":"10.3109\/10409239509085143","volume":"30","author":"EH Van Beers","year":"1995","unstructured":"Van Beers, E. H., B\u00fcller, H. A., Grand, R. J., Einerhand, A. W. & Dekker, J. Intestinal brush border glycohydrolases: structure, function, and development. Crit Rev Biochem Mol Biol 30, 197\u2013262 (1995).","journal-title":"Crit Rev Biochem Mol Biol"},{"key":"23957_CR10","doi-asserted-by":"crossref","unstructured":"J. Kraiczy et al., Assessing DNA methylation in the developing human intestinal epithelium: potential link to inflammatory bowel disease. Mucosal Immunol, (2015).","DOI":"10.1038\/mi.2015.88"},{"key":"23957_CR11","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1101\/gad.230318.113","volume":"28","author":"KL Sheaffer","year":"2014","unstructured":"Sheaffer, K. L. et al. DNA methylation is required for the control of stem cell differentiation in the small intestine. Genes Dev 28, 652\u2013664 (2014).","journal-title":"Genes Dev"},{"key":"23957_CR12","doi-asserted-by":"publisher","first-page":"2163","DOI":"10.1242\/dev.117341","volume":"142","author":"EN Elliott","year":"2015","unstructured":"Elliott, E. N., Sheaffer, K. L., Schug, J., Stappenbeck, T. S. & Kaestner, K. H. Dnmt1 is essential to maintain progenitors in the perinatal intestinal epithelium. Development 142, 2163\u20132172 (2015).","journal-title":"Development"},{"key":"23957_CR13","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2013-14-5-r50","volume":"14","author":"LT Kaaij","year":"2013","unstructured":"Kaaij, L. T. et al. DNA methylation dynamics during intestinal stem cell differentiation reveals enhancers driving gene expression in the villus. Genome Biol 14, R50 (2013).","journal-title":"Genome Biol"},{"key":"23957_CR14","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-015-0763-5","volume":"16","author":"DH Yu","year":"2015","unstructured":"Yu, D. H. et al. Postnatal epigenetic regulation of intestinal stem cells requires DNA methylation and is guided by the microbiome. Genome Biol 16, 211 (2015).","journal-title":"Genome Biol"},{"key":"23957_CR15","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1038\/nsmb.3227","volume":"23","author":"V Labrie","year":"2016","unstructured":"Labrie, V. et al. Lactase nonpersistence is directed by DNA-variation-dependent epigenetic aging. Nat Struct Mol Biol 23, 566\u2013573 (2016).","journal-title":"Nat Struct Mol Biol"},{"key":"23957_CR16","doi-asserted-by":"publisher","first-page":"692","DOI":"10.4161\/epi.6.6.16196","volume":"6","author":"J Sandoval","year":"2011","unstructured":"Sandoval, J. et al. Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics 6, 692\u2013702 (2011).","journal-title":"Epigenetics"},{"key":"23957_CR17","doi-asserted-by":"publisher","first-page":"771","DOI":"10.2217\/epi.11.105","volume":"3","author":"S Dedeurwaerder","year":"2011","unstructured":"Dedeurwaerder, S. et al. Evaluation of the Infinium Methylation 450K technology. Epigenomics 3, 771\u2013784 (2011).","journal-title":"Epigenomics"},{"key":"23957_CR18","doi-asserted-by":"publisher","first-page":"3945","DOI":"10.1093\/hmg\/ddi418","volume":"14","author":"RH Lewinsky","year":"2005","unstructured":"Lewinsky, R. H. et al. T-13910 DNA variant associated with lactase persistence interacts with Oct-1 and stimulates lactase promoter activity in vitro. Hum Mol Genet 14, 3945\u20133953 (2005).","journal-title":"Hum Mol Genet"},{"key":"23957_CR19","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1016\/j.devcel.2009.02.010","volume":"16","author":"N Gao","year":"2009","unstructured":"Gao, N., White, P. & Kaestner, K. H. Establishment of intestinal identity and epithelial-mesenchymal signaling by Cdx2. Dev Cell 16, 588\u2013599 (2009).","journal-title":"Dev Cell"},{"key":"23957_CR20","doi-asserted-by":"publisher","first-page":"9060","DOI":"10.1128\/MCB.00124-06","volume":"26","author":"T Bosse","year":"2006","unstructured":"Bosse, T. et al. Gata4 is essential for the maintenance of jejunal-ileal identities in the adult mouse small intestine. Mol Cell Biol 26, 9060\u20139070 (2006).","journal-title":"Mol Cell Biol"},{"key":"23957_CR21","doi-asserted-by":"publisher","first-page":"G1302","DOI":"10.1152\/ajpgi.00418.2006","volume":"292","author":"T Bosse","year":"2007","unstructured":"Bosse, T. et al. Gata4 and Hnf1alpha are partially required for the expression of specific intestinal genes during development. Am J Physiol Gastrointest Liver Physiol 292, G1302\u20131314 (2007).","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"1219\u20131229","key":"23957_CR22","first-page":"e1211","volume":"140","author":"E Beuling","year":"2011","unstructured":"Beuling, E. et al. GATA factors regulate proliferation, differentiation, and gene expression in small intestine of mature mice. Gastroenterology 140(1219\u20131229), e1211\u20131212 (2011).","journal-title":"Gastroenterology"},{"key":"23957_CR23","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1136\/gut.2009.204990","volume":"59","author":"E Beuling","year":"2010","unstructured":"Beuling, E. et al. Conditional Gata4 deletion in mice induces bile acid absorption in the proximal small intestine. Gut 59, 888\u2013895 (2010).","journal-title":"Gut"},{"key":"23957_CR24","doi-asserted-by":"publisher","first-page":"31909","DOI":"10.1074\/jbc.M204622200","volume":"277","author":"F Boudreau","year":"2002","unstructured":"Boudreau, F. et al. Hepatocyte nuclear factor-1 alpha, GATA-4, and caudal related homeodomain protein Cdx2 interact functionally to modulate intestinal gene transcription. Implication for the developmental regulation of the sucrase-isomaltase gene. J Biol Chem 277, 31909\u201331917 (2002).","journal-title":"J Biol Chem"},{"key":"23957_CR25","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1097\/00005176-199102000-00011","volume":"12","author":"LA Heitlinger","year":"1991","unstructured":"Heitlinger, L. A., Rossi, T. M., Lee, P. C. & Lebenthal, E. Human intestinal disaccharidase activities: correlations with age, biopsy technique, and degree of villus atrophy. J Pediatr Gastroenterol Nutr 12, 204\u2013208 (1991).","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"23957_CR26","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/j.chom.2016.04.017","volume":"19","author":"JK Goodrich","year":"2016","unstructured":"Goodrich, J. K. et al. Genetic Determinants of the Gut Microbiome in UK Twins. Cell Host Microbe 19, 731\u2013743 (2016).","journal-title":"Cell Host Microbe"},{"key":"23957_CR27","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1093\/biostatistics\/kxj037","volume":"8","author":"WE Johnson","year":"2007","unstructured":"Johnson, W. E., Li, C. & Rabinovic, A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8, 118\u2013127 (2007).","journal-title":"Biostatistics"},{"key":"23957_CR28","doi-asserted-by":"publisher","first-page":"e89","DOI":"10.1136\/jmg.2007.051631","volume":"44","author":"F Imtiaz","year":"2007","unstructured":"Imtiaz, F. et al. The T\/G 13915 variant upstream of the lactase gene (LCT) is the founder allele of lactase persistence in an urban Saudi population. J Med Genet 44, e89 (2007).","journal-title":"J Med Genet"},{"key":"23957_CR29","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.ajhg.2014.02.009","volume":"94","author":"A Ranciaro","year":"2014","unstructured":"Ranciaro, A. et al. Genetic origins of lactase persistence and the spread of pastoralism in Africa. Am J Hum Genet 94, 496\u2013510 (2014).","journal-title":"Am J Hum Genet"},{"key":"23957_CR30","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/S0016-5085(76)80277-6","volume":"70","author":"RJ Grand","year":"1976","unstructured":"Grand, R. J., Watkins, J. B. & Torti, F. M. Development of the human gastrointestinal tract. A review. Gastroenterology 70, 790\u2013810 (1976).","journal-title":"Gastroenterology"},{"key":"23957_CR31","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/S0022-3476(67)80234-8","volume":"71","author":"MD Kogut","year":"1967","unstructured":"Kogut, M. D., Donnell, G. N. & Shaw, K. N. Studies of lactose absorption in patients with galactosemia. J Pediatr 71, 75\u201381 (1967).","journal-title":"J Pediatr"},{"key":"23957_CR32","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1016\/S0016-5085(72)80080-5","volume":"62","author":"T Gilat","year":"1972","unstructured":"Gilat, T., Russo, S., Gelman-Malachi, E. & Aldor, T. A. Lactase in man: a nonadaptable enzyme. Gastroenterology 62, 1125\u20131127 (1972).","journal-title":"Gastroenterology"},{"issue":"Pt 3","key":"23957_CR33","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1042\/bj3020929","volume":"302","author":"SW Lacey","year":"1994","unstructured":"Lacey, S. W., Naim, H. Y., Magness, R. R., Gething, M. J. & Sambrook, J. F. Expression of lactase-phlorizin hydrolase in sheep is regulated at the RNA level. Biochem J 302(Pt 3), 929\u2013935 (1994).","journal-title":"Biochem J"},{"key":"23957_CR34","first-page":"G584","volume":"267","author":"SD Krasinski","year":"1994","unstructured":"Krasinski, S. D. et al. Transcriptional regulation of intestinal hydrolase biosynthesis during postnatal development in rats. Am J Physiol 267, G584\u2013594 (1994).","journal-title":"Am J Physiol"},{"key":"23957_CR35","doi-asserted-by":"crossref","first-page":"6978","DOI":"10.1016\/S0021-9258(19)39247-6","volume":"265","author":"HA B\u00fcller","year":"1990","unstructured":"B\u00fcller, H. A. et al. Coordinate expression of lactase-phlorizin hydrolase mRNA and enzyme levels in rat intestine during development. J Biol Chem 265, 6978\u20136983 (1990).","journal-title":"J Biol Chem"},{"key":"23957_CR36","doi-asserted-by":"publisher","first-page":"10630","DOI":"10.1074\/jbc.275.14.10630","volume":"275","author":"R Jacob","year":"2000","unstructured":"Jacob, R., Weiner, J. R., Stadge, S. & Naim, H. Y. Additional N-glycosylation and its impact on the folding of intestinal lactase-phlorizin hydrolase. J Biol Chem 275, 10630\u201310637 (2000).","journal-title":"J Biol Chem"},{"key":"23957_CR37","first-page":"25494","volume":"267","author":"HY Naim","year":"1992","unstructured":"Naim, H. Y. & Lentze, M. J. Impact of O-glycosylation on the function of human intestinal lactase-phlorizin hydrolase. Characterization of glycoforms varying in enzyme activity and localization of O-glycoside addition. J Biol Chem 267, 25494\u201325504 (1992).","journal-title":"Characterization of glycoforms varying in enzyme activity and localization of O-glycoside addition. J Biol Chem"},{"key":"23957_CR38","doi-asserted-by":"publisher","first-page":"6650","DOI":"10.1074\/jbc.273.12.6650","volume":"273","author":"J Ouwendijk","year":"1998","unstructured":"Ouwendijk, J. et al. Routing and processing of lactase-phlorizin hydrolase in transfected Caco-2 cells. J Biol Chem 273, 6650\u20136655 (1998).","journal-title":"J Biol Chem"},{"key":"23957_CR39","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s10620-010-1480-2","volume":"56","author":"NY Baffour-Awuah","year":"2011","unstructured":"Baffour-Awuah, N. Y. et al. Characterization of expression in mice of a transgene containing 3.3 kb of the human lactase-phlorizin hydrolase (LPH) 5\u2032 flanking sequence. Dig Dis Sci 56, 59\u201369 (2011).","journal-title":"Dig Dis Sci"},{"key":"23957_CR40","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1101\/gr.154187.112","volume":"23","author":"H Heyn","year":"2013","unstructured":"Heyn, H. et al. DNA methylation contributes to natural human variation. Genome Res 23, 1363\u20131372 (2013).","journal-title":"Genome Res"},{"key":"23957_CR41","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-15-145","volume":"15","author":"AK Smith","year":"2014","unstructured":"Smith, A. K. et al. Methylation quantitative trait loci (meQTLs) are consistently detected across ancestry, developmental stage, and tissue type. BMC Genomics 15, 145 (2014).","journal-title":"BMC Genomics"},{"key":"23957_CR42","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-015-0842-7","volume":"16","author":"JL McClay","year":"2015","unstructured":"McClay, J. L. et al. High density methylation QTL analysis in human blood via next-generation sequencing of the methylated genomic DNA fraction. Genome Biol 16, 291 (2015).","journal-title":"Genome Biol"},{"key":"23957_CR43","doi-asserted-by":"publisher","first-page":"e1000952","DOI":"10.1371\/journal.pgen.1000952","volume":"6","author":"JR Gibbs","year":"2010","unstructured":"Gibbs, J. R. et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet 6, e1000952 (2010).","journal-title":"PLoS Genet"},{"key":"23957_CR44","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1038\/nn.4182","volume":"19","author":"E Hannon","year":"2016","unstructured":"Hannon, E. et al. Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci. Nat Neurosci 19, 48\u201354 (2016).","journal-title":"Nat Neurosci"},{"key":"23957_CR45","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1016\/j.ajhg.2013.10.004","volume":"93","author":"E Grundberg","year":"2013","unstructured":"Grundberg, E. et al. Global analysis of DNA methylation variation in adipose tissue from twins reveals links to disease-associated variants in distal regulatory elements. Am J Hum Genet 93, 876\u2013890 (2013).","journal-title":"Am J Hum Genet"},{"key":"23957_CR46","doi-asserted-by":"publisher","first-page":"e1004663","DOI":"10.1371\/journal.pgen.1004663","volume":"10","author":"NE Banovich","year":"2014","unstructured":"Banovich, N. E. et al. Methylation QTLs are associated with coordinated changes in transcription factor binding, histone modifications, and gene expression levels. PLoS Genet 10, e1004663 (2014).","journal-title":"PLoS Genet"},{"key":"23957_CR47","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/nmeth.1871","volume":"9","author":"D Diep","year":"2012","unstructured":"Diep, D. et al. Library-free methylation sequencing with bisulfite padlock probes. Nat Methods 9, 270\u2013272 (2012).","journal-title":"Nat Methods"},{"key":"23957_CR48","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/nbt.1530","volume":"27","author":"J Deng","year":"2009","unstructured":"Deng, J. et al. Targeted bisulfite sequencing reveals changes in DNA methylation associated with nuclear reprogramming. Nat Biotechnol 27, 353\u2013360 (2009).","journal-title":"Nat Biotechnol"},{"key":"23957_CR49","unstructured":"Antonioli, D. A. & Madara, J. L. Functional anatomy of the gastrointestinal tract, In: Pathology of the gastrointestinal tract; p14. Ming, S. C. & Goldman, H., Ed. (WB Saunders, Philadelphia, 1992)."},{"key":"23957_CR50","doi-asserted-by":"crossref","unstructured":"DAHLQVIST, A. Method for assay of intestinal disaccharidases. Anal Biochem 7, 18\u201325 (1964).","DOI":"10.1016\/0003-2697(64)90115-0"},{"key":"23957_CR51","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1097\/00005176-199903000-00007","volume":"28","author":"SK Gupta","year":"1999","unstructured":"Gupta, S. K., Chong, S. K. & Fitzgerald, J. F. Disaccharidase activities in children: normal values and comparison based on symptoms and histologic changes. J Pediatr Gastroenterol Nutr 28, 246\u2013251 (1999).","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"23957_CR52","doi-asserted-by":"publisher","first-page":"e348","DOI":"10.1111\/j.1440-1746.2007.05248.x","volume":"23","author":"KK Prasad","year":"2008","unstructured":"Prasad, K. K., Thapa, B. R., Nain, C. K., Sharma, A. K. & Singh, K. Brush border enzyme activities in relation to histological lesion in pediatric celiac disease. J Gastroenterol Hepatol 23, e348\u2013352 (2008).","journal-title":"J Gastroenterol Hepatol"},{"key":"23957_CR53","doi-asserted-by":"publisher","first-page":"283","DOI":"10.4292\/wjgpt.v7.i2.283","volume":"7","author":"T Daileda","year":"2016","unstructured":"Daileda, T., Baek, P., Sutter, M. E. & Thakkar, K. Disaccharidase activity in children undergoing esophagogastroduodenoscopy: A systematic review. World J Gastrointest Pharmacol Ther 7, 283\u2013293 (2016).","journal-title":"World J Gastrointest Pharmacol Ther"},{"key":"23957_CR54","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-11-587","volume":"11","author":"P Du","year":"2010","unstructured":"Du, P. et al. Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis. BMC Bioinformatics 11, 587 (2010).","journal-title":"BMC Bioinformatics"},{"key":"23957_CR55","doi-asserted-by":"crossref","unstructured":"G. K. Smyth, Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3, Article3 (2004).","DOI":"10.2202\/1544-6115.1027"},{"key":"23957_CR56","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.1371\/journal.pgen.0030161","volume":"3","author":"JT Leek","year":"2007","unstructured":"Leek, J. T. & Storey, J. D. Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet 3, 1724\u20131735 (2007).","journal-title":"PLoS Genet"},{"key":"23957_CR57","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0935-y","volume":"17","author":"K McGregor","year":"2016","unstructured":"McGregor, K. et al. An evaluation of methods correcting for cell-type heterogeneity in DNA methylation studies. Genome Biol 17, 84 (2016).","journal-title":"Genome Biol"},{"key":"23957_CR58","doi-asserted-by":"publisher","first-page":"3940","DOI":"10.1093\/bioinformatics\/bti623","volume":"21","author":"T Sing","year":"2005","unstructured":"Sing, T., Sander, O., Beerenwinkel, N. & Lengauer, T. ROCR: visualizing classifier performance in R. Bioinformatics 21, 3940\u20133941 (2005).","journal-title":"Bioinformatics"},{"key":"23957_CR59","unstructured":"R. C. Team. (Vienna, Austria. https:\/\/www.R-project.org\/ 2015)."},{"key":"23957_CR60","doi-asserted-by":"publisher","first-page":"e45","DOI":"10.1093\/nar\/gkp045","volume":"37","author":"JM Ruijter","year":"2009","unstructured":"Ruijter, J. M. et al. Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data. Nucleic Acids Res 37, e45 (2009).","journal-title":"Nucleic Acids Res"},{"key":"23957_CR61","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.ymeth.2012.08.011","volume":"59","author":"JM Ruijter","year":"2013","unstructured":"Ruijter, J. M. et al. Evaluation of qPCR curve analysis methods for reliable biomarker discovery: bias, resolution, precision, and implications. Methods 59, 32\u201346 (2013).","journal-title":"Methods"},{"key":"23957_CR62","doi-asserted-by":"publisher","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","volume":"29","author":"MW Pfaffl","year":"2001","unstructured":"Pfaffl, M. W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29, e45 (2001).","journal-title":"Nucleic Acids Res"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-23957-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-23957-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-23957-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T04:03:47Z","timestamp":1671595427000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-23957-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,4]]},"references-count":62,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["23957"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-23957-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,4]]},"assertion":[{"value":"12 June 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 March 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 April 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"5649"}}