Genome-wide measures of DNA methylation in peripheral blood and the risk of urothelial cell carcinoma: a prospective nested case–control study
Identifieur interne : 000710 ( Pmc/Curation ); précédent : 000709; suivant : 000711Genome-wide measures of DNA methylation in peripheral blood and the risk of urothelial cell carcinoma: a prospective nested case–control study
Auteurs : Pierre-Antoine Dugué [Australie] ; Maree T. Brinkman [Australie] ; Roger L. Milne [Australie] ; Ee Ming Wong [Australie] ; Liesel M. Fitzgerald [Australie] ; Julie K. Bassett [Australie] ; Jihoon E. Joo [Australie] ; Chol-Hee Jung [Australie] ; Enes Makalic [Australie] ; Daniel F. Schmidt [Australie] ; Daniel J. Park [Australie] ; Jessica Chung [Australie] ; Anthony D. Ta [Australie] ; Damien M. Bolton [Australie] ; Andrew Lonie [Australie] ; Anthony Longano [Australie] ; John L. Hopper [Australie] ; Gianluca Severi [Australie, France, Italie] ; Richard Saffery [Australie] ; Dallas R. English [Australie] ; Melissa C. Southey [Australie] ; Graham G. Giles [Australie]Source :
- British Journal of Cancer [ 0007-0920 ] ; 2016.
Abstract
Global DNA methylation has been reported to be associated with urothelial cell carcinoma (UCC) by studies using blood samples collected at diagnosis. Using the Illumina HumanMethylation450 assay, we derived genome-wide measures of blood DNA methylation and assessed them for their prospective association with UCC risk.
We used 439 case–control pairs from the Melbourne Collaborative Cohort Study matched on age, sex, country of birth, DNA sample type, and collection period. Conditional logistic regression was used to compute odds ratios (OR) of UCC risk per s.d. of each genome-wide measure of DNA methylation and 95% confidence intervals (CIs), adjusted for potential confounders. We also investigated associations by disease subtype, sex, smoking, and time since blood collection.
The risk of superficial UCC was decreased for individuals with higher levels of our genome-wide DNA methylation measure (OR=0.71, 95% CI: 0.54–0.94;
Higher levels of our genome-wide DNA methylation measure were associated with decreased risk of superficial UCC and intermediate levels were associated with reduced risk of invasive disease. These findings require replication by other prospective studies.
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DOI: 10.1038/bjc.2016.237
PubMed: 27490804
PubMed Central: 5023776
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Bolton</name><affiliation wicri:level="1"><nlm:aff id="aff6"><institution>Department of Surgery, University of Melbourne</institution>, Melbourne, VIC 3004,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lonie, Andrew" sort="Lonie, Andrew" uniqKey="Lonie A" first="Andrew" last="Lonie">Andrew Lonie</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>VLSCI Life Sciences Computation Centre, University of Melbourne</institution>, Carlton, VIC 3053,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Longano, Anthony" sort="Longano, Anthony" uniqKey="Longano A" first="Anthony" last="Longano">Anthony Longano</name><affiliation wicri:level="1"><nlm:aff id="aff7"><institution>Department of Anatomical Pathology, Monash Medical Centre</institution>, Clayton, VIC 3800,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L" last="Hopper">John L. Hopper</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Severi, Gianluca" sort="Severi, Gianluca" uniqKey="Severi G" first="Gianluca" last="Severi">Gianluca Severi</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer Epidemiology Centre, Cancer Council Victoria</institution>, Melbourne, VIC 3004,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff8"><institution>Université Paris-Saclay, Univ. Paris-Sud, UVSQ, CESP, INSERM</institution>, Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff9"><institution>Gustave Roussy</institution>, Villejuif F-94805,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff10"><institution>HuGeF, Human Genetics Foundation</institution>, Torino 10126,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Saffery, Richard" sort="Saffery, Richard" uniqKey="Saffery R" first="Richard" last="Saffery">Richard Saffery</name><affiliation wicri:level="1"><nlm:aff id="aff11"><institution>Department of Paediatrics, University of Melbourne</institution>, Melbourne, VIC,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff12"><institution>Cancer, Disease and Developmental Epigenetics Group, Cell Biology, Development and Disease Theme, Murdoch Childrens Research Institute, Royal Children's Hospital</institution>, Melbourne, VIC,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="English, Dallas R" sort="English, Dallas R" uniqKey="English D" first="Dallas R" last="English">Dallas R. English</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer Epidemiology Centre, Cancer Council Victoria</institution>, Melbourne, VIC 3004,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C" last="Southey">Melissa C. Southey</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G" last="Giles">Graham G. Giles</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer Epidemiology Centre, Cancer Council Victoria</institution>, Melbourne, VIC 3004,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27490804</idno><idno type="pmc">5023776</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023776</idno><idno type="RBID">PMC:5023776</idno><idno type="doi">10.1038/bjc.2016.237</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000711</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000711</idno><idno type="wicri:Area/Pmc/Curation">000710</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000710</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Genome-wide measures of DNA methylation in peripheral blood and the risk of urothelial cell carcinoma: a prospective nested case–control study</title><author><name sortKey="Dugue, Pierre Antoine" sort="Dugue, Pierre Antoine" uniqKey="Dugue P" first="Pierre-Antoine" last="Dugué">Pierre-Antoine Dugué</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer Epidemiology Centre, Cancer Council Victoria</institution>, Melbourne, VIC 3004,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Brinkman, Maree T" sort="Brinkman, Maree T" uniqKey="Brinkman M" first="Maree T" last="Brinkman">Maree T. Brinkman</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer Epidemiology Centre, Cancer Council Victoria</institution>, Melbourne, VIC 3004,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Milne, Roger L" sort="Milne, Roger L" uniqKey="Milne R" first="Roger L" last="Milne">Roger L. Milne</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer Epidemiology Centre, Cancer Council Victoria</institution>, Melbourne, VIC 3004,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wong, Ee Ming" sort="Wong, Ee Ming" uniqKey="Wong E" first="Ee Ming" last="Wong">Ee Ming Wong</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fitzgerald, Liesel M" sort="Fitzgerald, Liesel M" uniqKey="Fitzgerald L" first="Liesel M" last="Fitzgerald">Liesel M. Fitzgerald</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer Epidemiology Centre, Cancer Council Victoria</institution>, Melbourne, VIC 3004,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Menzies Institute for Medical Research, University of Tasmania</institution>, Hobart, TAS 7000,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Bassett, Julie K" sort="Bassett, Julie K" uniqKey="Bassett J" first="Julie K" last="Bassett">Julie K. Bassett</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer Epidemiology Centre, Cancer Council Victoria</institution>, Melbourne, VIC 3004,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Joo, Jihoon E" sort="Joo, Jihoon E" uniqKey="Joo J" first="Jihoon E" last="Joo">Jihoon E. Joo</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Jung, Chol Hee" sort="Jung, Chol Hee" uniqKey="Jung C" first="Chol-Hee" last="Jung">Chol-Hee Jung</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>VLSCI Life Sciences Computation Centre, University of Melbourne</institution>, Carlton, VIC 3053,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Makalic, Enes" sort="Makalic, Enes" uniqKey="Makalic E" first="Enes" last="Makalic">Enes Makalic</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Schmidt, Daniel F" sort="Schmidt, Daniel F" uniqKey="Schmidt D" first="Daniel F" last="Schmidt">Daniel F. Schmidt</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Park, Daniel J" sort="Park, Daniel J" uniqKey="Park D" first="Daniel J" last="Park">Daniel J. Park</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Chung, Jessica" sort="Chung, Jessica" uniqKey="Chung J" first="Jessica" last="Chung">Jessica Chung</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Menzies Institute for Medical Research, University of Tasmania</institution>, Hobart, TAS 7000,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ta, Anthony D" sort="Ta, Anthony D" uniqKey="Ta A" first="Anthony D" last="Ta">Anthony D. Ta</name><affiliation wicri:level="1"><nlm:aff id="aff6"><institution>Department of Surgery, University of Melbourne</institution>, Melbourne, VIC 3004,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Bolton, Damien M" sort="Bolton, Damien M" uniqKey="Bolton D" first="Damien M" last="Bolton">Damien M. Bolton</name><affiliation wicri:level="1"><nlm:aff id="aff6"><institution>Department of Surgery, University of Melbourne</institution>, Melbourne, VIC 3004,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lonie, Andrew" sort="Lonie, Andrew" uniqKey="Lonie A" first="Andrew" last="Lonie">Andrew Lonie</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>VLSCI Life Sciences Computation Centre, University of Melbourne</institution>, Carlton, VIC 3053,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Longano, Anthony" sort="Longano, Anthony" uniqKey="Longano A" first="Anthony" last="Longano">Anthony Longano</name><affiliation wicri:level="1"><nlm:aff id="aff7"><institution>Department of Anatomical Pathology, Monash Medical Centre</institution>, Clayton, VIC 3800,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L" last="Hopper">John L. Hopper</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Severi, Gianluca" sort="Severi, Gianluca" uniqKey="Severi G" first="Gianluca" last="Severi">Gianluca Severi</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer Epidemiology Centre, Cancer Council Victoria</institution>, Melbourne, VIC 3004,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff8"><institution>Université Paris-Saclay, Univ. Paris-Sud, UVSQ, CESP, INSERM</institution>, Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff9"><institution>Gustave Roussy</institution>, Villejuif F-94805,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff10"><institution>HuGeF, Human Genetics Foundation</institution>, Torino 10126,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Saffery, Richard" sort="Saffery, Richard" uniqKey="Saffery R" first="Richard" last="Saffery">Richard Saffery</name><affiliation wicri:level="1"><nlm:aff id="aff11"><institution>Department of Paediatrics, University of Melbourne</institution>, Melbourne, VIC,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff12"><institution>Cancer, Disease and Developmental Epigenetics Group, Cell Biology, Development and Disease Theme, Murdoch Childrens Research Institute, Royal Children's Hospital</institution>, Melbourne, VIC,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="English, Dallas R" sort="English, Dallas R" uniqKey="English D" first="Dallas R" last="English">Dallas R. English</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer Epidemiology Centre, Cancer Council Victoria</institution>, Melbourne, VIC 3004,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C" last="Southey">Melissa C. Southey</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G" last="Giles">Graham G. Giles</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Cancer Epidemiology Centre, Cancer Council Victoria</institution>, Melbourne, VIC 3004,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">British Journal of Cancer</title><idno type="ISSN">0007-0920</idno><idno type="eISSN">1532-1827</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background:</title><p>Global DNA methylation has been reported to be associated with urothelial cell carcinoma (UCC) by studies using blood samples collected at diagnosis. Using the Illumina HumanMethylation450 assay, we derived genome-wide measures of blood DNA methylation and assessed them for their prospective association with UCC risk.</p></sec><sec><title>Methods:</title><p>We used 439 case–control pairs from the Melbourne Collaborative Cohort Study matched on age, sex, country of birth, DNA sample type, and collection period. Conditional logistic regression was used to compute odds ratios (OR) of UCC risk per s.d. of each genome-wide measure of DNA methylation and 95% confidence intervals (CIs), adjusted for potential confounders. We also investigated associations by disease subtype, sex, smoking, and time since blood collection.</p></sec><sec><title>Results:</title><p>The risk of superficial UCC was decreased for individuals with higher levels of our genome-wide DNA methylation measure (OR=0.71, 95% CI: 0.54–0.94; <italic>P</italic>=0.02). This association was particularly strong for current smokers at sample collection (OR=0.47, 95% CI: 0.27–0.83). Intermediate levels of our genome-wide measure were associated with decreased risk of invasive UCC. Some variation was observed between UCC subtypes and the location and regulatory function of the CpGs included in the genome-wide measures of methylation.</p></sec><sec><title>Conclusions:</title><p>Higher levels of our genome-wide DNA methylation measure were associated with decreased risk of superficial UCC and intermediate levels were associated with reduced risk of invasive disease. These findings require replication by other prospective studies.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Br J Cancer</journal-id><journal-id journal-id-type="iso-abbrev">Br. J. Cancer</journal-id><journal-title-group><journal-title>British Journal of Cancer</journal-title></journal-title-group><issn pub-type="ppub">0007-0920</issn><issn pub-type="epub">1532-1827</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27490804</article-id><article-id pub-id-type="pmc">5023776</article-id><article-id pub-id-type="pii">bjc2016237</article-id><article-id pub-id-type="doi">10.1038/bjc.2016.237</article-id><article-categories><subj-group subj-group-type="heading"><subject>Clinical Study</subject></subj-group></article-categories><title-group><article-title>Genome-wide measures of DNA methylation in peripheral blood and the risk of urothelial cell carcinoma: a prospective nested case–control study</article-title><alt-title alt-title-type="running">Genome-wide measures of DNA methylation and risk of UCC</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Dugué</surname><given-names>Pierre-Antoine</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="author-notes" rid="note1"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brinkman</surname><given-names>Maree T</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="author-notes" rid="note1"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Milne</surname><given-names>Roger L</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Wong</surname><given-names>Ee Ming</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>FitzGerald</surname><given-names>Liesel M</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Bassett</surname><given-names>Julie K</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Joo</surname><given-names>Jihoon E</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Jung</surname><given-names>Chol-Hee</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Makalic</surname><given-names>Enes</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Schmidt</surname><given-names>Daniel F</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Daniel J</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Chung</surname><given-names>Jessica</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Ta</surname><given-names>Anthony D</given-names></name><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Bolton</surname><given-names>Damien M</given-names></name><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Lonie</surname><given-names>Andrew</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Longano</surname><given-names>Anthony</given-names></name><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Hopper</surname><given-names>John L</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Severi</surname><given-names>Gianluca</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff8">8</xref><xref ref-type="aff" rid="aff9">9</xref><xref ref-type="aff" rid="aff10">10</xref></contrib><contrib contrib-type="author"><name><surname>Saffery</surname><given-names>Richard</given-names></name><xref ref-type="aff" rid="aff11">11</xref><xref ref-type="aff" rid="aff12">12</xref></contrib><contrib contrib-type="author"><name><surname>English</surname><given-names>Dallas R</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Southey</surname><given-names>Melissa C</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Giles</surname><given-names>Graham G</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="corresp" rid="caf1">*</xref></contrib><aff id="aff1"><label>1</label><institution>Cancer Epidemiology Centre, Cancer Council Victoria</institution>, Melbourne, VIC 3004,<country>Australia</country></aff><aff id="aff2"><label>2</label><institution>Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></aff><aff id="aff3"><label>3</label><institution>Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne</institution>, Parkville, VIC 3052,<country>Australia</country></aff><aff id="aff4"><label>4</label><institution>Menzies Institute for Medical Research, University of Tasmania</institution>, Hobart, TAS 7000,<country>Australia</country></aff><aff id="aff5"><label>5</label><institution>VLSCI Life Sciences Computation Centre, University of Melbourne</institution>, Carlton, VIC 3053,<country>Australia</country></aff><aff id="aff6"><label>6</label><institution>Department of Surgery, University of Melbourne</institution>, Melbourne, VIC 3004,<country>Australia</country></aff><aff id="aff7"><label>7</label><institution>Department of Anatomical Pathology, Monash Medical Centre</institution>, Clayton, VIC 3800,<country>Australia</country></aff><aff id="aff8"><label>8</label><institution>Université Paris-Saclay, Univ. Paris-Sud, UVSQ, CESP, INSERM</institution>, Villejuif,<country>France</country></aff><aff id="aff9"><label>9</label><institution>Gustave Roussy</institution>, Villejuif F-94805,<country>France</country></aff><aff id="aff10"><label>10</label><institution>HuGeF, Human Genetics Foundation</institution>, Torino 10126,<country>Italy</country></aff><aff id="aff11"><label>11</label><institution>Department of Paediatrics, University of Melbourne</institution>, Melbourne, VIC,<country>Australia</country></aff><aff id="aff12"><label>12</label><institution>Cancer, Disease and Developmental Epigenetics Group, Cell Biology, Development and Disease Theme, Murdoch Childrens Research Institute, Royal Children's Hospital</institution>, Melbourne, VIC,<country>Australia</country></aff></contrib-group><author-notes><corresp id="caf1"><label>*</label>E-mail: <email>Graham.Giles@cancervic.org.au</email></corresp><fn fn-type="present-address" id="note1"><label>13</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><day>06</day><month>09</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>04</day><month>08</month><year>2016</year></pub-date><volume>115</volume><issue>6</issue><fpage>664</fpage><lpage>673</lpage><history><date date-type="received"><day>26</day><month>01</month><year>2016</year></date><date date-type="rev-recd"><day>13</day><month>05</month><year>2016</year></date><date date-type="accepted"><day>08</day><month>07</month><year>2016</year></date></history><permissions><copyright-statement>Copyright © 2016 Cancer Research UK</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>Cancer Research UK</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-sa/4.0/"><license-p>From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc-sa/4.0/">http://creativecommons.org/licenses/by-nc-sa/4.0/</ext-link></license-p></license></permissions><abstract><sec><title>Background:</title><p>Global DNA methylation has been reported to be associated with urothelial cell carcinoma (UCC) by studies using blood samples collected at diagnosis. Using the Illumina HumanMethylation450 assay, we derived genome-wide measures of blood DNA methylation and assessed them for their prospective association with UCC risk.</p></sec><sec><title>Methods:</title><p>We used 439 case–control pairs from the Melbourne Collaborative Cohort Study matched on age, sex, country of birth, DNA sample type, and collection period. Conditional logistic regression was used to compute odds ratios (OR) of UCC risk per s.d. of each genome-wide measure of DNA methylation and 95% confidence intervals (CIs), adjusted for potential confounders. We also investigated associations by disease subtype, sex, smoking, and time since blood collection.</p></sec><sec><title>Results:</title><p>The risk of superficial UCC was decreased for individuals with higher levels of our genome-wide DNA methylation measure (OR=0.71, 95% CI: 0.54–0.94; <italic>P</italic>=0.02). This association was particularly strong for current smokers at sample collection (OR=0.47, 95% CI: 0.27–0.83). Intermediate levels of our genome-wide measure were associated with decreased risk of invasive UCC. Some variation was observed between UCC subtypes and the location and regulatory function of the CpGs included in the genome-wide measures of methylation.</p></sec><sec><title>Conclusions:</title><p>Higher levels of our genome-wide DNA methylation measure were associated with decreased risk of superficial UCC and intermediate levels were associated with reduced risk of invasive disease. These findings require replication by other prospective studies.</p></sec></abstract><kwd-group><kwd>urothelial cell carcinoma</kwd><kwd>bladder cancer</kwd><kwd>DNA methylation</kwd><kwd>peripheral blood</kwd><kwd>biomarker</kwd><kwd>EWAS</kwd></kwd-group></article-meta></front><floats-group><fig id="fig1"><label>Figure 1</label><caption><p><bold>Urothelial cell carcinoma (UCC) risk according to the genome-wide measure of DNA methylation quintiles</bold>. Ref=lowest quintile of the genome-wide measure of DNA methylation.</p></caption><graphic xlink:href="bjc2016237f1"></graphic></fig><table-wrap id="tbl1"><label>Table 1</label><caption><title>Characteristics of study participants and estimated ORs and 95% CIs for UCC associated with risk factors</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="center"></col><col align="center"></col><col align="char" char=""></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"><bold>Matching variables</bold></th><th align="center" valign="top" charoff="50"><bold>Controls</bold><italic><bold>N</bold></italic><bold>=439</bold></th><th align="center" valign="top" charoff="50"><bold>Cases</bold><italic><bold>N</bold></italic><bold>=439</bold></th><th align="char" valign="top" charoff="50"> </th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" charoff="50">Age at blood draw</td><td align="center" valign="top" charoff="50">Median=65.6</td><td align="center" valign="top" charoff="50">Median=65.3</td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50">IQR=60.3–69.2</td><td align="center" valign="top" charoff="50">IQR=60.2–69.6</td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50">DNA source</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Dried blood spot</td><td align="center" valign="top" charoff="50">178 (41%)</td><td align="center" valign="top" charoff="50">178 (41%)</td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> PBMC</td><td align="center" valign="top" charoff="50">98 (22%)</td><td align="center" valign="top" charoff="50">98 (22%)</td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Buffy coat</td><td align="center" valign="top" charoff="50">163 (37%)</td><td align="center" valign="top" charoff="50">163 (37%)</td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50">Sex</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Male</td><td align="center" valign="top" charoff="50">335 (76%)</td><td align="center" valign="top" charoff="50">335 (76%)</td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50">Country of birth</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Aus/NZ/UK</td><td align="center" valign="top" charoff="50">302 (69%)</td><td align="center" valign="top" charoff="50">302 (69%)</td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Italy</td><td align="center" valign="top" charoff="50">79 (18%)</td><td align="center" valign="top" charoff="50">79 (18%)</td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Greece</td><td align="center" valign="top" charoff="50">58 (13%)</td><td align="center" valign="top" charoff="50">58 (13%)</td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"><bold>Other risk factors (at blood draw)</bold></td><td align="center" valign="top" charoff="50"><bold>Controls</bold><italic><bold>N</bold></italic><bold>=439</bold></td><td align="center" valign="top" charoff="50"><bold>Cases</bold><italic><bold>N</bold></italic><bold>=439</bold></td><td align="char" valign="top" charoff="50"><bold>Adjusted OR</bold><xref ref-type="fn" rid="t1-fn2">a</xref><bold>(95% CI)</bold></td></tr><tr><td align="left" valign="top" charoff="50">Smoking</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Never</td><td align="center" valign="top" charoff="50">185 (42%)</td><td align="center" valign="top" charoff="50">128 (29%)</td><td align="char" valign="top" charoff="50">Ref.</td></tr><tr><td align="left" valign="top" charoff="50"> Current</td><td align="center" valign="top" charoff="50">56 (13%)</td><td align="center" valign="top" charoff="50">78 (18%)</td><td align="char" valign="top" charoff="50">2.1 (1.3–3.3)</td></tr><tr><td align="left" valign="top" charoff="50"> Former</td><td align="center" valign="top" charoff="50">198 (45%)</td><td align="center" valign="top" charoff="50">233 (53%)</td><td align="char" valign="top" charoff="50">1.9 (1.4–2.7)</td></tr><tr><td align="left" valign="top" charoff="50">Alcohol consumption<xref ref-type="fn" rid="t1-fn3">b</xref></td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> None</td><td align="center" valign="top" charoff="50">102 (23%)</td><td align="center" valign="top" charoff="50">112 (26%)</td><td align="char" valign="top" charoff="50">Ref.</td></tr><tr><td align="left" valign="top" charoff="50"> Low</td><td align="center" valign="top" charoff="50">273 (62%)</td><td align="center" valign="top" charoff="50">253 (58%)</td><td align="char" valign="top" charoff="50">0.8 (0.5–1.1)</td></tr><tr><td align="left" valign="top" charoff="50"> Moderate</td><td align="center" valign="top" charoff="50">39 (9%)</td><td align="center" valign="top" charoff="50">41 (9%)</td><td align="char" valign="top" charoff="50">0.9 (0.5–1.5)</td></tr><tr><td align="left" valign="top" charoff="50"> High</td><td align="center" valign="top" charoff="50">25 (6%)</td><td align="center" valign="top" charoff="50">33 (7%)</td><td align="char" valign="top" charoff="50">1.0 (0.5–2.8)</td></tr><tr><td align="left" valign="top" charoff="50">BMI</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> <25 kg m<sup>−2</sup></td><td align="center" valign="top" charoff="50">135 (30%)</td><td align="center" valign="top" charoff="50">113 (26%)</td><td align="char" valign="top" charoff="50">Ref.</td></tr><tr><td align="left" valign="top" charoff="50"> 25–30 kg m<sup>−2</sup></td><td align="center" valign="top" charoff="50">216 (51%)</td><td align="center" valign="top" charoff="50">224 (51%)</td><td align="char" valign="top" charoff="50">1.1 (0.8–1.5)</td></tr><tr><td align="left" valign="top" charoff="50"> ⩾30 kg m<sup>−2</sup></td><td align="center" valign="top" charoff="50">88 (19%)</td><td align="center" valign="top" charoff="50">102 (23%)</td><td align="char" valign="top" charoff="50">1.2 (0.8–1.8)</td></tr><tr><td align="left" valign="top" charoff="50">SES indicator<xref ref-type="fn" rid="t1-fn4">c</xref></td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Quintile 1</td><td align="center" valign="top" charoff="50">61 (14%)</td><td align="center" valign="top" charoff="50">78 (18%)</td><td align="char" valign="top" charoff="50">Ref.</td></tr><tr><td align="left" valign="top" charoff="50"> Quintile 2</td><td align="center" valign="top" charoff="50">96 (22%)</td><td align="center" valign="top" charoff="50">96 (22%)</td><td align="char" valign="top" charoff="50">0.9 (0.6–1.3)</td></tr><tr><td align="left" valign="top" charoff="50"> Quintile 3</td><td align="center" valign="top" charoff="50">83 (19%)</td><td align="center" valign="top" charoff="50">84 (19%)</td><td align="char" valign="top" charoff="50">0.9 (0.5–1.3)</td></tr><tr><td align="left" valign="top" charoff="50"> Quintile 4</td><td align="center" valign="top" charoff="50">92 (21%)</td><td align="center" valign="top" charoff="50">82 (19%)</td><td align="char" valign="top" charoff="50">0.8 (0.5–1.2)</td></tr><tr><td align="left" valign="top" charoff="50"> Quintile 5</td><td align="center" valign="top" charoff="50">107 (24%)</td><td align="center" valign="top" charoff="50">99 (23%)</td><td align="char" valign="top" charoff="50">0.8 (0.5–1.3)</td></tr><tr><td align="left" valign="top" charoff="50">Folate intake<xref ref-type="fn" rid="t1-fn5">d</xref></td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Quintile 1</td><td align="center" valign="top" charoff="50">85 (19%)</td><td align="center" valign="top" charoff="50">89 (20%)</td><td align="char" valign="top" charoff="50">Ref.</td></tr><tr><td align="left" valign="top" charoff="50"> Quintile 2</td><td align="center" valign="top" charoff="50">85 (19%)</td><td align="center" valign="top" charoff="50">91 (21%)</td><td align="char" valign="top" charoff="50">1.2 (0.7–1.9)</td></tr><tr><td align="left" valign="top" charoff="50"> Quintile 3</td><td align="center" valign="top" charoff="50">88 (20%)</td><td align="center" valign="top" charoff="50">89 (20%)</td><td align="char" valign="top" charoff="50">1.0 (0.6–1.6)</td></tr><tr><td align="left" valign="top" charoff="50"> Quintile 4</td><td align="center" valign="top" charoff="50">84 (19%)</td><td align="center" valign="top" charoff="50">91 (21%)</td><td align="char" valign="top" charoff="50">1.2 (0.7–2.0)</td></tr><tr><td align="left" valign="top" charoff="50"> Quintile 5</td><td align="center" valign="top" charoff="50">97 (22%)</td><td align="center" valign="top" charoff="50">79 (18%)</td><td align="char" valign="top" charoff="50">0.9 (0.5–1.6)</td></tr><tr><td align="left" valign="top" charoff="50">Vitamin B12<xref ref-type="fn" rid="t1-fn5">d</xref></td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Quintile 1</td><td align="center" valign="top" charoff="50">89 (20%)</td><td align="center" valign="top" charoff="50">85 (19%)</td><td align="char" valign="top" charoff="50">Ref.</td></tr><tr><td align="left" valign="top" charoff="50"> Quintile 2</td><td align="center" valign="top" charoff="50">84 (19%)</td><td align="center" valign="top" charoff="50">92 (21%)</td><td align="char" valign="top" charoff="50">1.1 (0.7–1.7)</td></tr><tr><td align="left" valign="top" charoff="50"> Quintile 3</td><td align="center" valign="top" charoff="50">93 (21%)</td><td align="center" valign="top" charoff="50">84 (19%)</td><td align="char" valign="top" charoff="50">1.0 (0.6–1.6)</td></tr><tr><td align="left" valign="top" charoff="50"> Quintile 4</td><td align="center" valign="top" charoff="50">78 (18%)</td><td align="center" valign="top" charoff="50">97 (22%)</td><td align="char" valign="top" charoff="50">1.4 (0.9–2.2)</td></tr><tr><td align="left" valign="top" charoff="50"> Quintile 5</td><td align="center" valign="top" charoff="50">95 (22%)</td><td align="center" valign="top" charoff="50">81 (18%)</td><td align="char" valign="top" charoff="50">0.9 (0.6–1.5)</td></tr><tr><td align="left" valign="top" charoff="50"><bold>Clinical variables</bold></td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"><bold>Cases</bold><italic><bold>N</bold></italic><bold>=439</bold></td><td align="char" valign="top" charoff="50"><bold>Adjusted OR</bold><xref ref-type="fn" rid="t1-fn2">a</xref><bold>(95% CI)</bold></td></tr><tr><td align="left" valign="top" charoff="50">Time between blood draw and diagnosis</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50">Median=6.3</td><td align="char" valign="top" charoff="50">Per year increase</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50">IQR=3.5–10.4</td><td align="char" valign="top" charoff="50">1.1 (0.9–1.3)</td></tr><tr><td align="left" valign="top" charoff="50">Age at diagnosis</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50">Median=73.3</td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50">IQR=67.1–77.9</td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50">Tumour invasiveness</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Invasive</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50">193 (44%)</td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Superficial</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50">246 (56%)</td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50">Tumour grade</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Grade 1</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50">108 (25%)</td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Grade 2</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50">104 (24%)</td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Grade 3</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50">147 (33%)</td><td align="char" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Unknown</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50">80 (18%)</td><td align="char" valign="top" charoff="50"> </td></tr></tbody></table><table-wrap-foot><fn id="t1-fn1"><p>Abbreviations: Aus=Australia; BMI=body mass index; CI=confidence interval; IQR=interquartile range; NZ=New Zealand; OR=odds ratio; PBMC=peripheral blood mononuclear cell; Ref=reference; SES=socioeconomic status; UCC=urothelial cell carcinoma.</p></fn><fn id="t1-fn2"><label>a</label><p>Mutually adjusted ORs using a conditional logistic regression model with matching on age, DNA source, sex, and country of birth, and included covariates: smoking, alcohol consumption, body mass index, socioeconomic status, folate and vitamin B12 intakes, and time between blood draw and diagnosis.</p></fn><fn id="t1-fn3"><label>b</label><p>Alcohol consumption was defined according to the Australian National Health and Medical Research Council categories as follows: None=0 g per day (males and females); Low=1–39 g per day (males) and 1–19 g per day (females); Moderate=40–59 g per day (males) and 20–39 g per day (females); High=60+ g per day (males) and 40+ g per day (females).</p></fn><fn id="t1-fn4"><label>c</label><p>Index of Relative Socioeconomic Disadvantage score from the Socio Economic Indexes for Area defined by the Australian Bureau of Statistics, divided into quintiles (quintile 1 is the most disadvantaged).</p></fn><fn id="t1-fn5"><label>d</label><p>Folate and vitamin intakes were computed using the Melbourne Collaborative Cohort Study (MCCS) 121-item Food Frequency Questionnaire.</p></fn></table-wrap-foot></table-wrap><table-wrap id="tbl2"><label>Table 2</label><caption><title>ORs for UCC and genome-wide measure of DNA methylation by disease subtypes and potential modifiers</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"> </th><th align="center" valign="top" charoff="50"><bold>OR</bold><xref ref-type="fn" rid="t2-fn2">a</xref></th><th align="center" valign="top" charoff="50"><bold>95% CI</bold></th><th align="center" valign="top" charoff="50"><italic><bold>P</bold></italic><bold>-value</bold></th><th align="center" valign="top" charoff="50"><italic><bold>P</bold></italic><bold>-value for heterogeneity</bold></th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" charoff="50">Overall</td><td align="center" valign="top" charoff="50">0.88</td><td align="center" valign="top" charoff="50">0.72–1.06</td><td align="center" valign="top" charoff="50">0.17</td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50">Invasiveness</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Invasive</td><td align="center" valign="top" charoff="50">1.06</td><td align="center" valign="top" charoff="50">0.79–1.43</td><td align="center" valign="top" charoff="50">0.70</td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Superficial</td><td align="center" valign="top" charoff="50">0.71</td><td align="center" valign="top" charoff="50">0.54–0.94</td><td align="center" valign="top" charoff="50">0.02</td><td align="center" valign="top" charoff="50">0.09</td></tr><tr><td align="left" valign="top" charoff="50">Time since blood draw</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> <5 Years</td><td align="center" valign="top" charoff="50">0.77</td><td align="center" valign="top" charoff="50">0.54–1.08</td><td align="center" valign="top" charoff="50">0.13</td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> 5–10 Years</td><td align="center" valign="top" charoff="50">1.10</td><td align="center" valign="top" charoff="50">0.78–1.57</td><td align="center" valign="top" charoff="50">0.58</td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> >10 Years</td><td align="center" valign="top" charoff="50">0.72</td><td align="center" valign="top" charoff="50">0.43–1.20</td><td align="center" valign="top" charoff="50">0.20</td><td align="center" valign="top" charoff="50">0.26</td></tr><tr><td align="left" valign="top" charoff="50">DNA source</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> PBMC</td><td align="center" valign="top" charoff="50">0.69</td><td align="center" valign="top" charoff="50">0.42–1.15</td><td align="center" valign="top" charoff="50">0.22</td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> DBS</td><td align="center" valign="top" charoff="50">0.93</td><td align="center" valign="top" charoff="50">0.61–1.42</td><td align="center" valign="top" charoff="50">0.74</td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Buffy coats</td><td align="center" valign="top" charoff="50">0.81</td><td align="center" valign="top" charoff="50">0.61–1.08</td><td align="center" valign="top" charoff="50">0.16</td><td align="center" valign="top" charoff="50">0.67</td></tr><tr><td align="left" valign="top" charoff="50">Blood collection period</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Baseline (1990–1994)</td><td align="center" valign="top" charoff="50">0.89</td><td align="center" valign="top" charoff="50">0.68–1.16</td><td align="center" valign="top" charoff="50">0.38</td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Follow-up (2003–2007)</td><td align="center" valign="top" charoff="50">0.78</td><td align="center" valign="top" charoff="50">0.57–1.07</td><td align="center" valign="top" charoff="50">0.13</td><td align="center" valign="top" charoff="50">0.29</td></tr><tr><td align="left" valign="top" charoff="50">Sex</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Male</td><td align="center" valign="top" charoff="50">0.89</td><td align="center" valign="top" charoff="50">0.72–1.11</td><td align="center" valign="top" charoff="50">0.31</td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Female</td><td align="center" valign="top" charoff="50">0.66</td><td align="center" valign="top" charoff="50">0.36–1.22</td><td align="center" valign="top" charoff="50">0.18</td><td align="center" valign="top" charoff="50">0.50</td></tr><tr><td align="left" valign="top" charoff="50">Smoking status at blood collection</td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Never</td><td align="center" valign="top" charoff="50">0.94</td><td align="center" valign="top" charoff="50">0.71–1.25</td><td align="center" valign="top" charoff="50">0.67</td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Current</td><td align="center" valign="top" charoff="50">0.67</td><td align="center" valign="top" charoff="50">0.46–0.99</td><td align="center" valign="top" charoff="50">0.04</td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Former</td><td align="center" valign="top" charoff="50">0.92</td><td align="center" valign="top" charoff="50">0.72–1.17</td><td align="center" valign="top" charoff="50">0.48</td><td align="center" valign="top" charoff="50">0.27</td></tr></tbody></table><table-wrap-foot><fn id="t2-fn1"><p>Abbreviations: CI=confidence interval; DBS=dried blood spot; OR=odds ratio; PBMC=peripheral blood mononuclear cell; UCC=urothelial cell carcinoma.</p></fn><fn id="t2-fn2"><label>a</label><p>ORs per s.d. in median M-value were calculated using conditional logistic regression models, with matching on age, sex, ethnicity, type of sample, plate, and chip, and adjusting for smoking status, alcohol intake, body mass index (BMI), time since blood draw, folate intake, vitamin B12 intake, and socioeconomic status.</p></fn></table-wrap-foot></table-wrap><table-wrap id="tbl3"><label>Table 3</label><caption><title>OR for UCC and genome-wide measures of DNA methylation by CpG subgroup and disease subtype</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"> </th><th align="center" valign="top" charoff="50"> </th><th colspan="3" align="center" valign="top" charoff="50"><bold>All cases</bold><hr></hr></th><th colspan="3" align="center" valign="top" charoff="50"><bold>Invasive cases</bold><hr></hr></th><th colspan="3" align="center" valign="top" charoff="50"><bold>Superficial cases</bold><hr></hr></th></tr><tr><th align="left" valign="top" charoff="50"> </th><th align="center" valign="top" charoff="50"><italic><bold>N</bold></italic><bold>CpGs</bold></th><th align="center" valign="top" charoff="50"><bold>OR</bold><xref ref-type="fn" rid="t3-fn2">a</xref></th><th align="center" valign="top" charoff="50"><bold>95% CI</bold></th><th align="center" valign="top" charoff="50"><italic><bold>P</bold></italic></th><th align="center" valign="top" charoff="50"><bold>OR</bold></th><th align="center" valign="top" charoff="50"><bold>95% CI</bold></th><th align="center" valign="top" charoff="50"><italic><bold>P</bold></italic></th><th align="center" valign="top" charoff="50"><bold>OR</bold></th><th align="center" valign="top" charoff="50"><bold>95% CI</bold></th><th align="center" valign="top" charoff="50"><italic><bold>P</bold></italic></th></tr></thead><tbody valign="top"><tr><td colspan="11" align="left" valign="top" charoff="50">CpG region<hr></hr></td></tr><tr><td align="left" valign="top" charoff="50">Islands</td><td align="center" valign="top" charoff="50">71 728</td><td align="center" valign="top" charoff="50">0.97</td><td align="center" valign="top" charoff="50">0.81–1.15</td><td align="center" valign="top" charoff="50">0.72</td><td align="center" valign="top" charoff="50">1.04</td><td align="center" valign="top" charoff="50">0.79–1.36</td><td align="center" valign="top" charoff="50">0.77</td><td align="center" valign="top" charoff="50">0.89</td><td align="center" valign="top" charoff="50">0.69–1.15</td><td align="center" valign="top" charoff="50">0.39</td></tr><tr><td align="left" valign="top" charoff="50">Shores</td><td align="center" valign="top" charoff="50">51 833</td><td align="center" valign="top" charoff="50">0.87</td><td align="center" valign="top" charoff="50">0.73–1.05</td><td align="center" valign="top" charoff="50">0.15</td><td align="center" valign="top" charoff="50">1.02</td><td align="center" valign="top" charoff="50">0.77–1.36</td><td align="center" valign="top" charoff="50">0.86</td><td align="center" valign="top" charoff="50">0.73</td><td align="center" valign="top" charoff="50">0.56–0.95</td><td align="center" valign="top" charoff="50">0.02</td></tr><tr><td align="left" valign="top" charoff="50">Shelves</td><td align="center" valign="top" charoff="50">14 261</td><td align="center" valign="top" charoff="50">0.94</td><td align="center" valign="top" charoff="50">0.79–1.12</td><td align="center" valign="top" charoff="50">0.50</td><td align="center" valign="top" charoff="50">0.79</td><td align="center" valign="top" charoff="50">0.59–1.06</td><td align="center" valign="top" charoff="50">0.11</td><td align="center" valign="top" charoff="50">1.07</td><td align="center" valign="top" charoff="50">0.84–1.37</td><td align="center" valign="top" charoff="50">0.58</td></tr><tr><td align="left" valign="top" charoff="50">None</td><td align="center" valign="top" charoff="50">58 438</td><td align="center" valign="top" charoff="50">0.99</td><td align="center" valign="top" charoff="50">0.83–1.18</td><td align="center" valign="top" charoff="50">0.90</td><td align="center" valign="top" charoff="50">0.83</td><td align="center" valign="top" charoff="50">0.63–1.10</td><td align="center" valign="top" charoff="50">0.20</td><td align="center" valign="top" charoff="50">1.13</td><td align="center" valign="top" charoff="50">0.89–1.43</td><td align="center" valign="top" charoff="50">0.33</td></tr><tr><td colspan="11" align="left" valign="top" charoff="50">Regulatory regions<hr></hr></td></tr><tr><td align="left" valign="top" charoff="50">Promoters</td><td align="center" valign="top" charoff="50">94 695</td><td align="center" valign="top" charoff="50">0.93</td><td align="center" valign="top" charoff="50">0.77–1.11</td><td align="center" valign="top" charoff="50">0.41</td><td align="center" valign="top" charoff="50">1.04</td><td align="center" valign="top" charoff="50">0.78–1.38</td><td align="center" valign="top" charoff="50">0.79</td><td align="center" valign="top" charoff="50">0.82</td><td align="center" valign="top" charoff="50">0.63–1.07</td><td align="center" valign="top" charoff="50">0.13</td></tr><tr><td align="left" valign="top" charoff="50">Other regulatory</td><td align="center" valign="top" charoff="50">46 154</td><td align="center" valign="top" charoff="50">0.92</td><td align="center" valign="top" charoff="50">0.78–1.09</td><td align="center" valign="top" charoff="50">0.32</td><td align="center" valign="top" charoff="50">1.02</td><td align="center" valign="top" charoff="50">0.78–1.33</td><td align="center" valign="top" charoff="50">0.88</td><td align="center" valign="top" charoff="50">0.80</td><td align="center" valign="top" charoff="50">0.63–1.02</td><td align="center" valign="top" charoff="50">0.07</td></tr><tr><td align="left" valign="top" charoff="50">Not regulatory</td><td align="center" valign="top" charoff="50">55 411</td><td align="center" valign="top" charoff="50">0.92</td><td align="center" valign="top" charoff="50">0.77–1.11</td><td align="center" valign="top" charoff="50">0.39</td><td align="center" valign="top" charoff="50">0.76</td><td align="center" valign="top" charoff="50">0.56–1.04</td><td align="center" valign="top" charoff="50">0.08</td><td align="center" valign="top" charoff="50">1.05</td><td align="center" valign="top" charoff="50">0.81–1.35</td><td align="center" valign="top" charoff="50">0.71</td></tr><tr><td colspan="11" align="left" valign="top" charoff="50">Within promoters<hr></hr></td></tr><tr><td align="left" valign="top" charoff="50">HCP</td><td align="center" valign="top" charoff="50">51 208</td><td align="center" valign="top" charoff="50">1.01</td><td align="center" valign="top" charoff="50">0.84–1.22</td><td align="center" valign="top" charoff="50">0.90</td><td align="center" valign="top" charoff="50">1.03</td><td align="center" valign="top" charoff="50">0.76–1.39</td><td align="center" valign="top" charoff="50">0.85</td><td align="center" valign="top" charoff="50">0.99</td><td align="center" valign="top" charoff="50">0.76–1.28</td><td align="center" valign="top" charoff="50">0.93</td></tr><tr><td align="left" valign="top" charoff="50">ICP</td><td align="center" valign="top" charoff="50">21 983</td><td align="center" valign="top" charoff="50">0.89</td><td align="center" valign="top" charoff="50">0.74–1.08</td><td align="center" valign="top" charoff="50">0.24</td><td align="center" valign="top" charoff="50">1.06</td><td align="center" valign="top" charoff="50">0.79–1.41</td><td align="center" valign="top" charoff="50">0.71</td><td align="center" valign="top" charoff="50">0.75</td><td align="center" valign="top" charoff="50">0.57–0.98</td><td align="center" valign="top" charoff="50">0.03</td></tr><tr><td align="left" valign="top" charoff="50">LCP</td><td align="center" valign="top" charoff="50">21 504</td><td align="center" valign="top" charoff="50">0.97</td><td align="center" valign="top" charoff="50">0.82–1.15</td><td align="center" valign="top" charoff="50">0.73</td><td align="center" valign="top" charoff="50">0.84</td><td align="center" valign="top" charoff="50">0.64–1.11</td><td align="center" valign="top" charoff="50">0.22</td><td align="center" valign="top" charoff="50">1.06</td><td align="center" valign="top" charoff="50">0.84–1.35</td><td align="center" valign="top" charoff="50">0.60</td></tr></tbody></table><table-wrap-foot><fn id="t3-fn1"><p>Abbreviations: CI=confidence interval; HCP=high-density CpG promoter; ICP=intermediate-density CpG promoter; LCP=low-density CpG promoter; OR=odds ratio; UCC=urothelial cell carcinoma.</p></fn><fn id="t3-fn2"><label>a</label><p>ORs per s.d. in median M-value were calculated using conditional logistic regression models, with matching on age, sex, ethnicity, type of sample, plate, and chip, and adjusting for smoking status, alcohol intake, body mass index (BMI), folate intake, vitamin B12 intake, and socioeconomic status.</p></fn></table-wrap-foot></table-wrap><table-wrap id="tbl4"><label>Table 4</label><caption><title>Genome-wide measure of DNA methylation and UCC risk by disease subtype: effect modification by smoking, time since blood collection, and sex</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col><col align="center"></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"> </th><th colspan="3" align="center" valign="top" charoff="50"><bold>All cases</bold><hr></hr></th><th colspan="3" align="center" valign="top" charoff="50"><bold>Invasive cases</bold><hr></hr></th><th colspan="3" align="center" valign="top" charoff="50"><bold>Superficial cases</bold><hr></hr></th></tr><tr><th align="left" valign="top" charoff="50"> </th><th align="center" valign="top" charoff="50"><bold>OR</bold><xref ref-type="fn" rid="t4-fn2">a</xref></th><th align="center" valign="top" charoff="50"><bold>95% CI</bold></th><th align="center" valign="top" charoff="50"><italic><bold>P</bold></italic></th><th align="center" valign="top" charoff="50"><bold>OR</bold><xref ref-type="fn" rid="t4-fn3">b</xref></th><th align="center" valign="top" charoff="50"><bold>95% CI</bold></th><th align="center" valign="top" charoff="50"><italic><bold>P</bold></italic></th><th align="center" valign="top" charoff="50"><bold>OR</bold><xref ref-type="fn" rid="t4-fn3">b</xref></th><th align="center" valign="top" charoff="50"><bold>95% CI</bold></th><th align="center" valign="top" charoff="50"><italic><bold>P</bold></italic></th></tr></thead><tbody valign="top"><tr><td colspan="10" align="left" valign="top" charoff="50">Smoking status at blood collection<hr></hr></td></tr><tr><td align="left" valign="top" charoff="50">Never</td><td align="center" valign="top" charoff="50">0.94</td><td align="center" valign="top" charoff="50">0.71–1.25</td><td align="center" valign="top" charoff="50">0.65</td><td align="center" valign="top" charoff="50">0.90</td><td align="center" valign="top" charoff="50">0.59–1.37</td><td align="center" valign="top" charoff="50">0.63</td><td align="center" valign="top" charoff="50">0.99</td><td align="center" valign="top" charoff="50">0.66–1.47</td><td align="center" valign="top" charoff="50">0.95</td></tr><tr><td align="left" valign="top" charoff="50">Current</td><td align="center" valign="top" charoff="50">0.68</td><td align="center" valign="top" charoff="50">0.46–0.99</td><td align="center" valign="top" charoff="50">0.05</td><td align="center" valign="top" charoff="50">1.06</td><td align="center" valign="top" charoff="50">0.61–1.86</td><td align="center" valign="top" charoff="50">0.83</td><td align="center" valign="top" charoff="50">0.47</td><td align="center" valign="top" charoff="50">0.27–0.83</td><td align="center" valign="top" charoff="50">0.01</td></tr><tr><td align="left" valign="top" charoff="50">Former</td><td align="center" valign="top" charoff="50">0.91</td><td align="center" valign="top" charoff="50">0.72–1.17</td><td align="center" valign="top" charoff="50">0.47</td><td align="center" valign="top" charoff="50">1.21</td><td align="center" valign="top" charoff="50">0.85–1.73</td><td align="center" valign="top" charoff="50">0.30</td><td align="center" valign="top" charoff="50">0.65</td><td align="center" valign="top" charoff="50">0.44–0.94</td><td align="center" valign="top" charoff="50">0.02</td></tr><tr><td align="left" valign="top" charoff="50">Heterogeneity test</td><td colspan="3" align="center" valign="top" charoff="50"><italic>P</italic>=0.30<hr></hr></td><td colspan="3" align="center" valign="top" charoff="50"><italic>P</italic>=0.51<hr></hr></td><td colspan="3" align="center" valign="top" charoff="50"><italic>P</italic>=0.03<hr></hr></td></tr><tr><td colspan="10" align="left" valign="top" charoff="50">Time since blood collection<hr></hr></td></tr><tr><td align="left" valign="top" charoff="50"><5 Years</td><td align="center" valign="top" charoff="50">0.77</td><td align="center" valign="top" charoff="50">0.55–1.09</td><td align="center" valign="top" charoff="50">0.14</td><td align="center" valign="top" charoff="50">1.00</td><td align="center" valign="top" charoff="50">0.64–1.60</td><td align="center" valign="top" charoff="50">0.97</td><td align="center" valign="top" charoff="50">0.66</td><td align="center" valign="top" charoff="50">0.44–0.98</td><td align="center" valign="top" charoff="50">0.04</td></tr><tr><td align="left" valign="top" charoff="50">5–10 Years</td><td align="center" valign="top" charoff="50">1.10</td><td align="center" valign="top" charoff="50">0.78–1.57</td><td align="center" valign="top" charoff="50">0.58</td><td align="center" valign="top" charoff="50">0.93</td><td align="center" valign="top" charoff="50">0.59–1.47</td><td align="center" valign="top" charoff="50">0.62</td><td align="center" valign="top" charoff="50">1.04</td><td align="center" valign="top" charoff="50">0.65–1.65</td><td align="center" valign="top" charoff="50">0.89</td></tr><tr><td align="left" valign="top" charoff="50">>10 Years</td><td align="center" valign="top" charoff="50">0.72</td><td align="center" valign="top" charoff="50">0.43–1.20</td><td align="center" valign="top" charoff="50">0.21</td><td align="center" valign="top" charoff="50">1.72</td><td align="center" valign="top" charoff="50">0.87–3.40</td><td align="center" valign="top" charoff="50">0.12</td><td align="center" valign="top" charoff="50">0.51</td><td align="center" valign="top" charoff="50">0.28–0.94</td><td align="center" valign="top" charoff="50">0.03</td></tr><tr><td align="left" valign="top" charoff="50">Heterogeneity test</td><td colspan="3" align="center" valign="top" charoff="50"><italic>P</italic>=0.34<hr></hr></td><td colspan="3" align="center" valign="top" charoff="50"><italic>P</italic>=0.22<hr></hr></td><td colspan="3" align="center" valign="top" charoff="50"><italic>P</italic>=0.07<hr></hr></td></tr><tr><td colspan="10" align="left" valign="top" charoff="50">Sex<hr></hr></td></tr><tr><td align="left" valign="top" charoff="50">Male</td><td align="center" valign="top" charoff="50">0.89</td><td align="center" valign="top" charoff="50">0.72–1.11</td><td align="center" valign="top" charoff="50">0.31</td><td align="center" valign="top" charoff="50">1.09</td><td align="center" valign="top" charoff="50">0.80–1.50</td><td align="center" valign="top" charoff="50">0.56</td><td align="center" valign="top" charoff="50">0.82</td><td align="center" valign="top" charoff="50">0.62–1.08</td><td align="center" valign="top" charoff="50">0.16</td></tr><tr><td align="left" valign="top" charoff="50">Female</td><td align="center" valign="top" charoff="50">0.66</td><td align="center" valign="top" charoff="50">0.36–1.22</td><td align="center" valign="top" charoff="50">0.18</td><td align="center" valign="top" charoff="50">1.43</td><td align="center" valign="top" charoff="50">0.66–3.09</td><td align="center" valign="top" charoff="50">0.36</td><td align="center" valign="top" charoff="50">0.59</td><td align="center" valign="top" charoff="50">0.24–0.96</td><td align="center" valign="top" charoff="50">0.05</td></tr><tr><td align="left" valign="top" charoff="50">Heterogeneity test</td><td colspan="3" align="center" valign="top" charoff="50"><italic>P</italic>=0.50</td><td colspan="3" align="center" valign="top" charoff="50"><italic>P</italic>=0.20</td><td colspan="3" align="center" valign="top" charoff="50"><italic>P</italic>=0.19</td></tr></tbody></table><table-wrap-foot><fn id="t4-fn1"><p>Abbreviations: CI=confidence interval; OR=odds ratio; UCC=urothelial cell carcinoma.</p></fn><fn id="t4-fn2"><label>a</label><p>ORs per s.d. in median M-value were calculated using conditional logistic regression models, with matching on age, sex, ethnicity, type of sample, plate, and chip, and adjusting for smoking status, alcohol intake, time since blood draw, body mass index (BMI), folate intake, vitamin B12 intake, and socioeconomic status.</p></fn><fn id="t4-fn3"><label>b</label><p>Adjusting for the matching variables, and smoking status and time since blood draw only, because of relatively small numbers of observed cases.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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