title: Association between CYP2E1 polymorphisms and risk of differentiated thyroid carcinoma.
abstract: Differentiated thyroid carcinoma (DTC) results from complex interactions between genetic and environmental factors. Known etiological factors include exposure to ionizing radiations, previous thyroid diseases, and hormone factors. It has been speculated that dietary acrylamide (AA) formed in diverse foods following the Maillard's reaction could be a contributing factor for DTC in humans. Upon absorption, AA is biotransformed mainly by cytochrome P450 2E1 (CYP2E1) to glycidamide (GA). Considering that polymorphisms within CYP2E1 were found associated with endogenous levels of AA-Valine and GA-Valine hemoglobin adducts in humans, we raised the hypothesis that specific CYP2E1 genotypes could be associated with the risk of DTC. Analysis of four haplotype tagging SNPs (ht-SNPs) within the locus in a discovery case-control study (N = 350/350) indicated an association between rs2480258 and DTC risk. This ht-SNP resides within a linkage disequilibrium block spanning intron VIII and the 3'-untranslated region. Extended analysis in a large replication set (2429 controls and 767 cases) confirmed the association, with odds ratios for GA and AA genotypes of 1.24 (95 % confidence interval (CI) 1.03-1.48) and 1.56 (95 % CI, 1.06-2.30), respectively. Functionally, the minor allele was associated with low levels of CYP2E1 mRNA and protein expression as well as lower enzymatic activity in a series of 149 human liver samples. Our data support the hypothesis that inter-individual differences in CYP2E1 activity could modulate the risk of developing DTC suggesting that the exposure to specific xenobiotics, such as AA, could play a role in this process.
authors.affiliation: Department of Biology, University of Pisa, via Derna 1, 56126, Pisa, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Pellé
authors.affiliation: Department of Biology, University of Pisa, via Derna 1, 56126, Pisa, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Cipollini
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany.|University of Tuebingen, Tuebingen, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Tremmel
authors.affiliation: Department of Endocrinology and Metabolism, Orthopedics and Traumatology, Occupational Medicine, University of Pisa, via Paradisa 2, 56124, Pisa, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Romei
authors.affiliation: Department of Biology, University of Pisa, via Derna 1, 56126, Pisa, Italy.
authors.forename: Gisella
authors.initials: G
authors.lastname: Figlioli
authors.affiliation: Department of Biology, University of Pisa, via Derna 1, 56126, Pisa, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Gemignani
authors.affiliation: Department of Biology, University of Pisa, via Derna 1, 56126, Pisa, Italy.
authors.forename: Ombretta
authors.initials: O
authors.lastname: Melaiu
authors.affiliation: Department of Biology, University of Pisa, via Derna 1, 56126, Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: De Santi
authors.affiliation: Department of Biology, University of Pisa, via Derna 1, 56126, Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Barone
authors.affiliation: Department of Endocrinology and Metabolism, Orthopedics and Traumatology, Occupational Medicine, University of Pisa, via Paradisa 2, 56124, Pisa, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Elisei
authors.affiliation: University of North Carolina-Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC, 27599, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Seiser
authors.affiliation: University of North Carolina-Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC, 27599, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Innocenti
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany.|University of Tuebingen, Tuebingen, Germany.
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
authors.affiliation: Department of Biology, University of Pisa, via Derna 1, 56126, Pisa, Italy. stefano.landi@unipi.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Landi
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002454:Cell Differentiation; D015331:Cohort Studies; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006785:Hospitals, University; D006801:Humans; D007438:Introns; D007558:Italy; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D016324:Sequence Tagged Sites; D013961:Thyroid Gland / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D020413:3' Untranslated Regions; D012333:RNA, Messenger; D019392:Cytochrome P-450 CYP2E1
keywords: Case–control association study; Cytochrome P450 2E1; Differentiated thyroid carcinoma; Genetic susceptibility; Polymorphisms