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2. Dose–Response Associations Between Diet and Risk of Rheumatoid Arthritis: A Meta-Analysis of Prospective Cohort Studies.

Author

Dong, Yuanyuan, Greenwood, Darren C., Webster, James, Uzokwe, Chinwe, Tao, Jinhui, Hardie, Laura J., and Cade, Janet E.

Abstract

To provide a systematic and quantitative summary of dietary factors and rheumatoid arthritis (RA) risk. A systematic review and meta-analysis included prospective cohort studies from 2000 to 2024 reporting relative risks (RRs) with 95% confidence intervals (CIs) for RA incidence relating to 32 different dietary exposures. Linear and non-linear dose–response analyses were conducted. Thirty studies were included, involving 2,986,747 participants with 9,677 RA cases. Linear dose–response analysis suggested that each 2-unit per week increase in total alcohol intake was linked to 4% risk reduction (RR (95%-CI), heterogeneity (I2), NutriGrade score: 0.96 (0.94, 0.98), 58%, moderate certainty), and beer consumption was associated with a 10% reduction per 2 units/week increase (0.90 (0.84, 0.97), 0%, very low certainty). Each 2-unit/week increase in total alcohol intake was associated with a 3% decrease in seropositive RA risk (0.97 (0.96, 0.99), 28%, moderate certainty). Increased intakes of fruit (per 80 g/day) and cereals (per 30 g/day) were associated with 5% (0.95 (0.92, 0.99), 57%, moderate certainty) and 3% (0.97 (0.96, 0.99), 20%, moderate certainty) reduced risk, respectively. Conversely, tea consumption showed a 4% increased risk per additional cup/day (1.04 (1.02, 1.05), 0%, moderate certainty). Non-linear associations were observed for total coffee, vegetables, oily fish, and vitamin D supplementation. Data on dietary patterns and specific micronutrients were limited. The findings suggest that moderate alcohol consumption and a higher intake of fruits, oily fish, and cereals are associated with a reduced risk of RA, while tea and coffee may be linked to an increased risk. Optimising dietary intake of certain food components may reduce RA risk, despite moderate-quality evidence. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Association Between Levels of Sex Hormones and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus

Author

Xie, Shao-Hua, Fang, Rui, Huang, Mingtao, Dai, Juncheng, Thrift, Aaron P., Anderson, Lesley A., Chow, Wong-Ho, Bernstein, Leslie, Gammon, Marilie D., Risch, Harvey A., Shaheen, Nicholas J., Reid, Brian J., Wu, Anna H., Iyer, Prasad G., Liu, Geoffrey, Corley, Douglas A., Whiteman, David C., Caldas, Carlos, Pharoah, Paul D., Hardie, Laura J., Fitzgerald, Rebecca C., Shen, Hongbing, Vaughan, Thomas L., and Lagergren, Jesper

Published
2020
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7. Interactions Between Genetic Variants and Environmental Factors Affect Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus

Author

Dong, Jing, Levine, David M., Buas, Matthew F., Zhang, Rui, Onstad, Lynn, Fitzgerald, Rebecca C., Corley, Douglas A., Shaheen, Nicholas J., Lagergren, Jesper, Hardie, Laura J., Reid, Brian J., Iyer, Prasad G., Risch, Harvey A., Caldas, Carlos, Caldas, Isabel, Pharoah, Paul D., Liu, Geoffrey, Gammon, Marilie D., Chow, Wong-Ho, Bernstein, Leslie, Bird, Nigel C., Ye, Weimin, Wu, Anna H., Anderson, Lesley A., MacGregor, Stuart, Whiteman, David C., Vaughan, Thomas L., and Thrift, Aaron P.

Published
2018
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8. Determining Risk of Barrett’s Esophagus and Esophageal Adenocarcinoma Based on Epidemiologic Factors and Genetic Variants

Author

Dong, Jing, Buas, Matthew F., Gharahkhani, Puya, Kendall, Bradley J., Onstad, Lynn, Zhao, Shanshan, Anderson, Lesley A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Bernstein, Leslie, Chow, Wong-Ho, Gammon, Marilie D., Liu, Geoffrey, Caldas, Carlos, Pharoah, Paul D., Risch, Harvey A., Iyer, Prasad G., Reid, Brian J., Hardie, Laura J., Lagergren, Jesper, Shaheen, Nicholas J., Corley, Douglas A., Fitzgerald, Rebecca C., Whiteman, David C., Vaughan, Thomas L., and Thrift, Aaron P.

Published
2018
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9. Maternal iodine status in a multi-ethnic UK birth cohort: associations with autism spectrum disorder

Author

Cromie, Kirsten Jade, Threapleton, Diane Erin, Snart, Charles Jonathan Peter, Taylor, Elizabeth, Mason, Dan, Wright, Barry, Kelly, Brian, Reid, Stephen, Azad, Rafaq, Keeble, Claire, Waterman, Amanda H., Meadows, Sarah, McKillion, Amanda, Alwan, Nisreen A., Cade, Janet Elizabeth, Simpson, Nigel A. B., Stewart, Paul M., Zimmermann, Michael, Wright, John, Waiblinger, Dagmar, Mon-Williams, Mark, Hardie, Laura J., and Greenwood, Darren Charles

Published
2020
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10. Maternal iodine status, intrauterine growth, birth outcomes and congenital anomalies in a UK birth cohort

Author

Snart, Charles Jonathan Peter, Threapleton, Diane Erin, Keeble, Claire, Taylor, Elizabeth, Waiblinger, Dagmar, Reid, Stephen, Alwan, Nisreen A., Mason, Dan, Azad, Rafaq, Cade, Janet Elizabeth, Simpson, Nigel A. B., Meadows, Sarah, McKillion, Amanda, Santorelli, Gillian, Waterman, Amanda H., Zimmermann, Michael, Stewart, Paul M., Wright, John, Mon-Williams, Mark, Greenwood, Darren Charles, and Hardie, Laura J.

Published
2020
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13. Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus

Author

Palles, Claire, Chegwidden, Laura, Li, Xinzhong, Findlay, John M., Farnham, Garry, Castro Giner, Francesc, Peppelenbosch, Maikel P., Kovac, Michal, Adams, Claire L., Prenen, Hans, Briggs, Sarah, Harrison, Rebecca, Sanders, Scott, MacDonald, David, Haigh, Chris, Tucker, Art, Love, Sharon, Nanji, Manoj, deCaestecker, John, Ferry, David, Rathbone, Barrie, Hapeshi, Julie, Barr, Hugh, Moayyedi, Paul, Watson, Peter, Zietek, Barbara, Maroo, Neera, Gay, Laura, Underwood, Tim, Boulter, Lisa, McMurtry, Hugh, Monk, David, Patel, Praful, Ragunath, Krish, Al Dulaimi, David, Murray, Iain, Koss, Konrad, Veitch, Andrew, Trudgill, Nigel, Nwokolo, Chuka, Rembacken, Bjorn, Atherfold, Paul, Green, Elaine, Ang, Yeng, Kuipers, Ernst J., Chow, Wu, Paterson, Stuart, Kadri, Sudarshan, Beales, Ian, Grimley, Charles, Mullins, Paul, Beckett, Conrad, Farrant, Mark, Dixon, Andrew, Kelly, Sean, Johnson, Matthew, Wajed, Shahjehan, Dhar, Anjan, Sawyer, Elinor, Roylance, Rebecca, Onstad, Lynn, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Reid, Brian J., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Casson, Alan G., Fitzgerald, Rebecca, Whiteman, David C., Risch, Harvey A., Levine, David M., Vaughan, Tom L., Verhaar, Auke P., van den Brande, Jan, Toxopeus, Eelke L., Spaander, Manon C., Wijnhoven, Bas P.L., van der Laan, Luc J.W., Krishnadath, Kausilia, Wijmenga, Cisca, Trynka, Gosia, McManus, Ross, Reynolds, John V., O’Sullivan, Jacintha, MacMathuna, Padraic, McGarrigle, Sarah A., Kelleher, Dermot, Vermeire, Severine, Cleynen, Isabelle, Bisschops, Raf, Tomlinson, Ian, and Jankowski, Janusz

Published
2015
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14. The effects of dietary vitamins, lipids and temperature on teleost immunity

Author

Hardie, Laura J.

Subjects
590, Fish immunology
Abstract

Singular or dual dietary depletions of vitamins C and E in Atlantic salmon parr increased susceptibility to Aeromonas salmonicida challenge. An array of immune parameters were evaluated to identify the involvement of these vitamin depletions on the immune response. Dietary vitamin E levels in salmon had no impact on haematological parameters, total serum protein or lysozyme levels. Similarly, dietary vitamin E levels did not affect leucocyte antibody production, macrophage activating factor (MAF) release and respiratory burst (RB) phenomena. However, haemolytic and opsonic properties of complement were compromised in vitamin E depleted salmon. Parenteral administration of vitamin E to vitamin E depleted carp did not elevate phytohaemagglutinin (PHA) lymphocyte proliferation responses or complement activity. In vitro additions of vitamin E to lymphocytes from carp fed a commercial diet did not elevate PHA proliferation responses either. The increased disease susceptibility provoked by dietary vitamin C restriction in Atlantic salmon was not correlated with serum protein levels, differential leucocyte numbers or phagocyte functions as tested by RB activity or phagocytosis by macrophages. Lymphocyte functions were operational in these fish as examined by MAF secretion and antibody production. Analogous to vitamin E depletion, dietary vitamin C restriction in salmon compromised complement haemolytic activity. Elevating the vitamin C content of diets above normal levels enhanced complement activity in salmon. Vitamin C was a potent modulator of rainbow trout leucocyte functions. In vitro supplementation of vitamin C in the sodium (NaAsc) or polyphosphate (PPAsc) form was required for PHA-proliferation responses. MAF secretion was also augmented by in vitro additions of NaAsc to leucocytes obtained from vitamin C depleted trout. Injecting NaAsc into depleted fish elevated PHA proliferation responses compared with saline-injected controls. Leucocytes from the latter group could recover proliferative responses to levels associated with NaAsc-injected fish with in vitro additions of 1x10-3 and 1x10-4M PPAsc. Increased disease susceptibility, reduced complement activity and haematocrit values were symptomatic of combined dietary vitamin C and E depletion in salmon parr. Total and differential leucocyte numbers, or serum parameters including antiprotease activity and total protein level were unaffected by this dietary regime. Although poorly adherent, macrophages obtained from dually depleted salmon had similar RB values and expressed greater responsiveness to a MAF-containing supernatant than vitamin sufficient counterparts. Lymphocyte functions were impervious to dual vitamin depletion as antibody and MAF production responses were intact. In vitro additions of NaAsc and PPAsc were shown to elevate RB responses in macrophages from vitamin-restricted and -adequate salmon. MAF secretion was demonstrated to be a temperature-dependent phenomenon in rainbow trout leucocytes. After 48h acclimation at low in vitro temperatures (6 C), leucocytes obtained from trout at 14C expressed impoverished MAF production. Acclimation of trout to 7 C did riot rescue MAF production. Also, normal RB activity was reduced in macrophages obtained from fish at 14 C after 48h at 6 C in vitro. However, if allowed to acclimate, these macrophages become more responsive to MAF and recovered RB activity to levels associated with macrophages held at 10 and 18C. RB responses of macrophages from fish at 7 C functioned equally well across a wide range of in vitro temperature regimes. Phagocytic activity of macrophages obtained from fish at 14 C and placed at 6 C in vitro for 48h expressed temperature sensitivity. This was especially apparent in fish fed a dietary ?-3/?-6 fatty acid ratio of 2.0. However, this dietary regime also elevated phagocytic activity of these macrophages to such an extent, that their response surpassed that of macrophages from fish fed commercial diets or ?-3/?-6 ratios of 0.5 and 1 even at low in vitro temperatures.

Published
1991

15. Risk of Esophageal Adenocarcinoma Decreases With Height, Based on Consortium Analysis and Confirmed by Mendelian Randomization

Author

Thrift, Aaron P., Risch, Harvey A., Onstad, Lynn, Shaheen, Nicholas J., Casson, Alan G., Bernstein, Leslie, Corley, Douglas A., Levine, David M., Chow, Wong–Ho, Reid, Brian J., Romero, Yvonne, Hardie, Laura J., Liu, Geoffrey, Wu, Anna H., Bird, Nigel C., Gammon, Marilie D., Ye, Weimin, Whiteman, David C., and Vaughan, Thomas L.

Published
2014
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16. Validity of an online 24-h recall tool (myfood24) for dietary assessment in population studies: comparison with biomarkers and standard interviews

Author

Wark, Petra A., Hardie, Laura J., Frost, Gary S., Alwan, Nisreen A., Carter, Michelle, Elliott, Paul, Ford, Heather E., Hancock, Neil, Morris, Michelle A., Mulla, Umme Z., Noorwali, Essra A., Petropoulou, K., Murphy, David, Potter, Gregory D. M., Riboli, Elio, Greenwood, Darren C., and Cade, Janet E.

Published
2018
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17. eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

Author

Wang, Xiaoyu, Gharahkhani, Puya, Levine, David M., Fitzgerald, Rebecca C., Gockel, Ines, Corley, Douglas A., Risch, Harvey A., Bernstein, Leslie, Chow, Wong-Ho, Onstad, Lynn, Shaheen, Nicholas J., Lagergren, Jesper, Hardie, Laura J., Wu, Anna H., Pharoah, Paul D. P., Liu, Geoffrey, Anderson, Lesley A., Iyer, Prasad G., Gammon, Marilie D., Caldas, Carlos, Ye, Weimin, Barr, Hugh, Moayyedi, Paul, Harrison, Rebecca, Watson, R. G. Peter, Attwood, Stephen, Chegwidden, Laura, Love, Sharon B., MacDonald, David, DeCaestecker, John, Prenen, Hans, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Reeh, Matthias, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Tomlinson, Ian, Palles, Claire, Jankowski, Janusz A., Whiteman, David C., MacGregor, Stuart, Schumacher, Johannes, Vaughan, Thomas L., Buas, Matthew F., Dai, James Y., Wang, Xiaoyu, Gharahkhani, Puya, Levine, David M., Fitzgerald, Rebecca C., Gockel, Ines, Corley, Douglas A., Risch, Harvey A., Bernstein, Leslie, Chow, Wong-Ho, Onstad, Lynn, Shaheen, Nicholas J., Lagergren, Jesper, Hardie, Laura J., Wu, Anna H., Pharoah, Paul D. P., Liu, Geoffrey, Anderson, Lesley A., Iyer, Prasad G., Gammon, Marilie D., Caldas, Carlos, Ye, Weimin, Barr, Hugh, Moayyedi, Paul, Harrison, Rebecca, Watson, R. G. Peter, Attwood, Stephen, Chegwidden, Laura, Love, Sharon B., MacDonald, David, DeCaestecker, John, Prenen, Hans, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Reeh, Matthias, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Tomlinson, Ian, Palles, Claire, Jankowski, Janusz A., Whiteman, David C., MacGregor, Stuart, Schumacher, Johannes, Vaughan, Thomas L., Buas, Matthew F., and Dai, James Y.

Abstract

Background: Over 20 susceptibility single-nucleotide poly-morphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability.Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. Results: Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). Conclusions: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach.Impact: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set-based genetic association approach as an alternative method for TWAS analysis.

Published
2022

18. Birth Weight, Head Circumference, and Prenatal Exposure to Acrylamide from Maternal Diet: The European Prospective Mother—Child Study (NewGeneris)

Author

NewGeneris Consortium, Pedersen, Marie, von Stedingk, Hans, Botsivali, Maria, Agramunt, Silvia, Alexander, Jan, Brunborg, Gunnar, Chatzi, Leda, Fleming, Sarah, Fthenou, Eleni, Granum, Berit, Gutzkow, Kristine B., Hardie, Laura J., Knudsen, Lisbeth E., Kyrtopoulos, Soterios A., Mendez, Michelle A., Merlo, Domenico F., Nielsen, Jeanette K., Rydberg, Per, Segerbäck, Dan, Sunyer, Jordi, Wright, John, Törnqvist, Margareta, Kleinjans, Jos C., and Kogevinas, Manolis

Published
2012

19. eQTL Set–Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

Author

Wang, Xiaoyu, primary, Gharahkhani, Puya, additional, Levine, David M., additional, Fitzgerald, Rebecca C., additional, Gockel, Ines, additional, Corley, Douglas A., additional, Risch, Harvey A., additional, Bernstein, Leslie, additional, Chow, Wong-Ho, additional, Onstad, Lynn, additional, Shaheen, Nicholas J., additional, Lagergren, Jesper, additional, Hardie, Laura J., additional, Wu, Anna H., additional, Pharoah, Paul D.P., additional, Liu, Geoffrey, additional, Anderson, Lesley A., additional, Iyer, Prasad G., additional, Gammon, Marilie D., additional, Caldas, Carlos, additional, Ye, Weimin, additional, Barr, Hugh, additional, Moayyedi, Paul, additional, Harrison, Rebecca, additional, Watson, R.G. Peter, additional, Attwood, Stephen, additional, Chegwidden, Laura, additional, Love, Sharon B., additional, MacDonald, David, additional, deCaestecker, John, additional, Prenen, Hans, additional, Ott, Katja, additional, Moebus, Susanne, additional, Venerito, Marino, additional, Lang, Hauke, additional, Mayershofer, Rupert, additional, Knapp, Michael, additional, Veits, Lothar, additional, Gerges, Christian, additional, Weismüller, Josef, additional, Reeh, Matthias, additional, Nöthen, Markus M., additional, Izbicki, Jakob R., additional, Manner, Hendrik, additional, Neuhaus, Horst, additional, Rösch, Thomas, additional, Böhmer, Anne C., additional, Hölscher, Arnulf H., additional, Anders, Mario, additional, Pech, Oliver, additional, Schumacher, Brigitte, additional, Schmidt, Claudia, additional, Schmidt, Thomas, additional, Noder, Tania, additional, Lorenz, Dietmar, additional, Vieth, Michael, additional, May, Andrea, additional, Hess, Timo, additional, Kreuser, Nicole, additional, Becker, Jessica, additional, Ell, Christian, additional, Tomlinson, Ian, additional, Palles, Claire, additional, Jankowski, Janusz A., additional, Whiteman, David C., additional, MacGregor, Stuart, additional, Schumacher, Johannes, additional, Vaughan, Thomas L., additional, Buas, Matthew F., additional, and Dai, James Y., additional

Published
2022
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21. Obesity and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus: A Mendelian Randomization Study

Author

Thrift, Aaron P., Shaheen, Nicholas J., Gammon, Marilie D., Bernstein, Leslie, Reid, Brian J., Onstad, Lynn, Risch, Harvey A., Liu, Geoffrey, Bird, Nigel C., Wu, Anna H., Corley, Douglas A., Romero, Yvonne, Chanock, Stephen J., Chow, Wong-Ho, Casson, Alan G., Levine, David M., Zhang, Rui, Ek, Weronica E., MacGregor, Stuart, Ye, Weimin, Hardie, Laura J., Vaughan, Thomas L., and Whiteman, David C.

Published
2014
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22. Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

Author

Dighe, Shruti G., Chen, Jianhong, Yan, Li, He, Qianchuan, Gharahkhani, Puya, Onstad, Lynn, Levine, David M., Palles, Claire, Ye, Weimin, Gammon, Marilie D., Iyer, Prasad G., Anderson, Lesley A., Liu, Geoffrey, Wu, Anna H., Dai, James Y., Chow, Wong-Ho, Risch, Harvey A., Lagergren, Jesper, Shaheen, Nicholas J., Bernstein, Leslie, Corley, Douglas A., Prenen, Hans, DeCaestecker, John, MacDonald, David, Moayyedi, Paul, Barr, Hugh, Love, Sharon B., Chegwidden, Laura, Attwood, Stephen, Watson, Peter, Harrison, Rebecca, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Gockel, Ines, Vashist, Yogesh, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Ambrosone, Christine B., Moysich, Kirsten B., MacGregor, Stuart, Tomlinson, Ian, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Vaughan, Thomas L., Madeleine, Margaret M., Hardie, Laura J., Buas, Matthew F., Dighe, Shruti G., Chen, Jianhong, Yan, Li, He, Qianchuan, Gharahkhani, Puya, Onstad, Lynn, Levine, David M., Palles, Claire, Ye, Weimin, Gammon, Marilie D., Iyer, Prasad G., Anderson, Lesley A., Liu, Geoffrey, Wu, Anna H., Dai, James Y., Chow, Wong-Ho, Risch, Harvey A., Lagergren, Jesper, Shaheen, Nicholas J., Bernstein, Leslie, Corley, Douglas A., Prenen, Hans, DeCaestecker, John, MacDonald, David, Moayyedi, Paul, Barr, Hugh, Love, Sharon B., Chegwidden, Laura, Attwood, Stephen, Watson, Peter, Harrison, Rebecca, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Gockel, Ines, Vashist, Yogesh, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Ambrosone, Christine B., Moysich, Kirsten B., MacGregor, Stuart, Tomlinson, Ian, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Vaughan, Thomas L., Madeleine, Margaret M., Hardie, Laura J., and Buas, Matthew F.

Abstract

Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS metaanalysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Published
2021

23. A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Author

Ong, Jue Sheng, Dixon-Suen, Suzanne C., Han, Xikun, An, Jiyuan, Fitzgerald, Rebecca, Buas, Matt, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Hardie, Laura J., Bird, Nigel C., Reid, Brian J., Chow, Wong Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Whiteman, David E., Vaughan, Thomas, Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A.M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Liyanage, Upekha, Dusingize, Jean Cluade, Schumacher, Johannes, Gockel, Ines, Böhmer, Anne, Jankowski, Janusz, Palles, Claire, O’Mara, Tracy, Spurdle, Amanda, Law, Matthew H., Iles, Mark M., Pharoah, Paul, Berchuck, Andrew, Zheng, Wei, Thrift, Aaron P., Olsen, Catherine, Neale, Rachel E., Gharahkhani, Puya, Webb, Penelope M., MacGregor, Stuart, other, and, Ong, Jue Sheng, Dixon-Suen, Suzanne C., Han, Xikun, An, Jiyuan, Fitzgerald, Rebecca, Buas, Matt, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Hardie, Laura J., Bird, Nigel C., Reid, Brian J., Chow, Wong Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Whiteman, David E., Vaughan, Thomas, Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A.M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Liyanage, Upekha, Dusingize, Jean Cluade, Schumacher, Johannes, Gockel, Ines, Böhmer, Anne, Jankowski, Janusz, Palles, Claire, O’Mara, Tracy, Spurdle, Amanda, Law, Matthew H., Iles, Mark M., Pharoah, Paul, Berchuck, Andrew, Zheng, Wei, Thrift, Aaron P., Olsen, Catherine, Neale, Rachel E., Gharahkhani, Puya, Webb, Penelope M., MacGregor, Stuart, and other, and

Abstract

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.

Published
2021

24. Birth weight, head circumference, and prenatal exposure to acrylamide from maternal diet: the European prospective mother-child study (NewGeneris)

Author

Pedersen, Marie, Stedingk, Hans von, Botsivali, Maria, Agramunt, Silvia, Alexander, Jan, Brunborg, Gunnar, Chatzi, Leda, Fleming, Sarah, Fthenou, Eleni, Granum, Berit, Gutzkow, Kristine B., Hardie, Laura J., Knudsen, Lisbeth E., Kyrtopoulos, Soterios A., Mendez, Michelle A., Merlo, Domenico F., Nielsen, Jeanette K., Rydberg, Per, Segerback, Dan, Sunyer, Jordi, Wright, John, Tornqvist, Margareta, Kleinjans, Jos C., and Kogevinas, Manolis

Subjects
Birth weight -- Measurement, Acrylamide -- Health aspects, Birth size -- Measurement, Cephalometry -- Methods, Diet -- Physiological aspects, Prenatal influences -- Physiological aspects, Environmental issues, Health
Abstract

Acrylamide is neurotoxic in humans and animals, and is classified as a probable human carcinogen [International Agency for Research on Cancer (IARC) 1994]. Occupational expo-sure and smoking were originally regarded [...]

Published
2012

25. Integrative post-genome-wide association analysis of CDKN2A and TP53 SNPs and risk of esophageal adenocarcinoma

Author

Buas, Matthew F., Levine, David M., Makar, Karen W., Utsugi, Heidi, Onstad, Lynn, Li, Xiaohong, Galipeau, Patricia C., Shaheen, Nicholas J., Hardie, Laura J., Romero, Yvonne, Bernstein, Leslie, Gammon, Marilie D., Casson, Alan G., Bird, Nigel C., Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Corley, Douglas A., Blount, Patricia L., Fitzgerald, Rebecca C., Whiteman, David C., Wu, Anna H., Reid, Brian J., and Vaughan, Thomas L.

Published
2014
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26. eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma.

Author

Xiaoyu Wang, Gharahkhani, Puya, Levine, David M., Fitzgerald, Rebecca C., Gockel, Ines, Corley, Douglas A., Risch, Harvey A., Bernstein, Leslie, Wong-Ho Chow, Onstad, Lynn, Shaheen, Nicholas J., Lagergren, Jesper, Hardie, Laura J., Wu, Anna H., Pharoah, Paul D. P., Liu, Geoffrey, Anderson, Lesley A., Iyer, Prasad G., Gammon, Marilie D., and Caldas, Carlos

Abstract

Background: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. Results: Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). Conclusions: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach. [ABSTRACT FROM AUTHOR]

Published
2022
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27. Additional file 1 of Maternal iodine status, intrauterine growth, birth outcomes and congenital anomalies in a UK birth cohort

Author

Snart, Charles Jonathan Peter, Threapleton, Diane Erin, Keeble, Claire, Taylor, Elizabeth, Waiblinger, Dagmar, Reid, Stephen, Nisreen A. Alwan, Mason, Dan, Rafaq Azad, Cade, Janet Elizabeth, Simpson, Nigel A. B., Meadows, Sarah, McKillion, Amanda, Santorelli, Gillian, Waterman, Amanda H., Zimmermann, Michael, Stewart, Paul M., Wright, John, Mon-Williams, Mark, Greenwood, Darren Charles, and Hardie, Laura J.

Abstract

Additional file 1: Table S1. Details of socioeconomic position categories and maternal education levels. Table S2. Details of model covariates, sample exclusions, sensitivity analyses and subgroup analyses for each of the different outcomes. Table S3. Pairwise correlations between each of the growth measures. Table S4. Predicted estimates (continuous outcomes) and percent at the threshold (binary outcomes) (99% CIs) at the 25th, 50th and 75th centiles of iodine concentration and p-overall* for ‘average’ participants†. Figure S1. A directed acyclic graph used to identify confounders and competing exposures in the association between maternal iodine concentration and birth or pregnancy outcomes. Figure S2. Flow chart of participant inclusions and exclusions. Figure S3. Estimated APGAR score at 1 minute and percent with congenital anomalies, using imputed datasets for the full sample. Figure S4. Estimated biparietal diameter, femur length and abdominal circumference, from ultrasound scans at 34 weeks’ gestation, across the range of maternal I:Cr concentrations using imputed datasets for the full sample. Figure S5. Estimated birthweight centile in all participants, sensitivity analysis and subgroups. Figure S6. Estimated birthweight in grams in all participants, sensitivity analysis and subgroups. Figure S7. Probability of being small for gestational age in all participants, sensitivity analysis and subgroups. Figure S8. Probability of low birthweight in all participants, sensitivity analysis and subgroups. Figure S9. Apgar score at 5 minutes after birth in all participants, sensitivity analysis and subgroups. Figure S10. Estimated head circumference at birth in all participants, sensitivity analysis and subgroups. Figure S11. Estimated head circumference from 34 week ultrasound scan in all participants, sensitivity analysis and subgroups. Figure S12. Estimated weight from 34 week ultrasound scan in all participants, sensitivity analysis and subgroups. Figure S13. Probability of preterm birth in all participants, sensitivity analysis and subgroups. Figure S14. Probability of congenital anomalies in all participants, sensitivity analysis and subgroups.

Published
2020
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29. Prenatal and Postpartum Maternal Iodide Intake from Diet and Supplements, Urinary Iodine and Thyroid Hormone Concentrations in a Region of the United Kingdom with Mild-to-Moderate Iodine Deficiency

Author

Threapleton, Diane E., primary, Waiblinger, Dagmar, additional, Snart, Charles J.P., additional, Taylor, Elizabeth, additional, Keeble, Claire, additional, Ashraf, Samina, additional, Bi, Shazia, additional, Ajjan, Ramzi, additional, Azad, Rafaq, additional, Hancock, Neil, additional, Mason, Dan, additional, Reid, Stephen, additional, Cromie, Kirsten J., additional, Alwan, Nisreen A., additional, Zimmermann, Michael, additional, Stewart, Paul M., additional, Simpson, Nigel A.B., additional, Wright, John, additional, Cade, Janet E., additional, Hardie, Laura J., additional, and Greenwood, Darren C., additional

Published
2021
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30. Germline Genetic Contributions to Risk for Esophageal Adenocarcinoma, Barrett’s Esophagus, and Gastroesophageal Reflux

Author

Ek, Weronica E., Levine, David M., D’Amato, Mauro, Pedersen, Nancy L., Magnusson, Patrik K. E., Bresso, Francesca, Onstad, Lynn E., Schmidt, Peter T., Törnblom, Hans, Nordenstedt, Helena, Romero, Yvonne, Chow, Wong-Ho, Murray, Liam J., Gammon, Marilie D., Liu, Geoffrey, Bernstein, Leslie, Casson, Alan G., Risch, Harvey A., Shaheen, Nicholas J., Bird, Nigel C., Reid, Brian J., Corley, Douglas A., Hardie, Laura J., Ye, Weimin, Wu, Anna H., Zucchelli, Marco, Spector, Tim D., Hysi, Pirro, Vaughan, Thomas L., Whiteman, David C., and MacGregor, Stuart

Published
2013
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31. Germline variation in the insulin-like growth factor pathway and risk of Barrett’s esophagus and esophageal adenocarcinoma

Author

Dighe, Shruti G, primary, Chen, Jianhong, additional, Yan, Li, additional, He, Qianchuan, additional, Gharahkhani, Puya, additional, Onstad, Lynn, additional, Levine, David M, additional, Palles, Claire, additional, Ye, Weimin, additional, Gammon, Marilie D, additional, Iyer, Prasad G, additional, Anderson, Lesley A, additional, Liu, Geoffrey, additional, Wu, Anna H, additional, Dai, James Y, additional, Chow, Wong-Ho, additional, Risch, Harvey A, additional, Lagergren, Jesper, additional, Shaheen, Nicholas J, additional, Bernstein, Leslie, additional, Corley, Douglas A, additional, Prenen, Hans, additional, deCaestecker, John, additional, MacDonald, David, additional, Moayyedi, Paul, additional, Barr, Hugh, additional, Love, Sharon B, additional, Chegwidden, Laura, additional, Attwood, Stephen, additional, Watson, Peter, additional, Harrison, Rebecca, additional, Ott, Katja, additional, Moebus, Susanne, additional, Venerito, Marino, additional, Lang, Hauke, additional, Mayershofer, Rupert, additional, Knapp, Michael, additional, Veits, Lothar, additional, Gerges, Christian, additional, Weismüller, Josef, additional, Gockel, Ines, additional, Vashist, Yogesh, additional, Nöthen, Markus M, additional, Izbicki, Jakob R, additional, Manner, Hendrik, additional, Neuhaus, Horst, additional, Rösch, Thomas, additional, Böhmer, Anne C, additional, Hölscher, Arnulf H, additional, Anders, Mario, additional, Pech, Oliver, additional, Schumacher, Brigitte, additional, Schmidt, Claudia, additional, Schmidt, Thomas, additional, Noder, Tania, additional, Lorenz, Dietmar, additional, Vieth, Michael, additional, May, Andrea, additional, Hess, Timo, additional, Kreuser, Nicole, additional, Becker, Jessica, additional, Ell, Christian, additional, Ambrosone, Christine B, additional, Moysich, Kirsten B, additional, MacGregor, Stuart, additional, Tomlinson, Ian, additional, Whiteman, David C, additional, Jankowski, Janusz, additional, Schumacher, Johannes, additional, Vaughan, Thomas L, additional, Madeleine, Margaret M, additional, Hardie, Laura J, additional, and Buas, Matthew F, additional

Published
2020
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32. Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases

Author

An, Jiyuan, Gharahkhani, Puya, Law, Matthew H., Ong, Jue Sheng, Han, Xikun, Olsen, Catherine M., Neale, Rachel E., Lai, John, Vaughan, Tom L., Böhmer, Anne C., Jankowski, Janusz, Fitzgerald, Rebecca C., Schumacher, Johannes, Palles, Claire, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Murray, Liam J., Reid, Brian J., Chow, Wong Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A.M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Whiteman, David C., MacGregor, Stuart, other, and, An, Jiyuan, Gharahkhani, Puya, Law, Matthew H., Ong, Jue Sheng, Han, Xikun, Olsen, Catherine M., Neale, Rachel E., Lai, John, Vaughan, Tom L., Böhmer, Anne C., Jankowski, Janusz, Fitzgerald, Rebecca C., Schumacher, Johannes, Palles, Claire, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Bird, Nigel C., Hardie, Laura J., Murray, Liam J., Reid, Brian J., Chow, Wong Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H., Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Furlotte, N. A., Hinds, D. A., Huber, K. E., Kleinman, A., Litterman, N. K., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A.M., Pitts, S. J., Sathirapongsasuti, J. Fah, Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H., Whiteman, David C., MacGregor, Stuart, and other, and

Abstract

Gastroesophageal reflux disease (GERD) is caused by gastric acid entering the esophagus. GERD has high prevalence and is the major risk factor for Barrett’s esophagus (BE) and esophageal adenocarcinoma (EA). We conduct a large GERD GWAS meta-analysis (80,265 cases, 305,011 controls), identifying 25 independent genome-wide significant loci for GERD. Several of the implicated genes are existing or putative drug targets. Loci discovery is greatest with a broad GERD definition (including cases defined by self-report or medication data). Further, 91% of the GERD risk-increasing alleles also increase BE and/or EA risk, greatly expanding gene discovery for these traits. Our results map genes for GERD and related traits and uncover potential new drug targets for these conditions.

Published
2019

34. Validity of an online 24-hour recall tool (myfood24) 1 for dietary assessment in 2 population studies: comparison with biomarkers and standard interviews

Author

Wark, Petra, Hardie, Laura J., Frost, Gary, Alwan, Nisreen, Carter, Michelle, Elliott, Paul, Ford, Heather E., Hancock, Neil, Morris, Michelle, Mulla, Umme Z., Noorwali, Essra A., Petropoulou, Katrina, Murphy, David, Potter, Gregory D.M., Riboli, Elio, Greenwood, Darren C., and Cade, Janet

Abstract

Background: Online dietary assessment tools can reduce administrative costs and facilitate repeated dietary assessment during follow-up in large-scale studies. However, information on bias due to measurement error of such tools is limited. We developed an online 24-hour recall (myfood24) and compared its performance with a traditional interviewer-administered multiple-pass 24-hour recall, assessing both against biomarkers. Methods: Metabolically stable adults were recruited and completed the new online dietary recall, an interviewer-based multiple pass recall and a suite of reference measures. Longer-term dietary intake was estimated from up to 3 x 24-hour recalls taken 2 weeks apart. Estimated intake of protein, potassium and sodium were compared with urinary biomarker concentrations. Estimated total sugar intake was compared with a predictive biomarker and estimated energy intake compared with energy expenditure measured by accelerometry and calorimetry. Nutrient intakes were also compared to those derived from an interviewer-administered multiple-pass 24-hour recall. Results: Biomarker samples were received from 212 participants on at least one occasion. Both self-reported dietary assessment tools led to attenuation compared to biomarkers. The online tools resulted in attenuation factors around 0.2 to 0.3 and partial correlation coefficients reflecting ranking intakes, of approximately 0.3 to 0.4. This was broadly similar to the more administratively burdensome interviewer-based tool. Other nutrient estimates derived from myfood24 were around 10-20% lower than from the interviewer-based tool, with wide limits of agreement. Intra-class correlation coefficients were approximately 0.4 to 0.5 indicating consistent moderate agreement. Conclusions: Our findings show that, whilst results from both measures of self-reported diet are attenuated compared to biomarker measures, the myfood24 online 24-hour recall is comparable to the more time-consuming and costly interviewer-based 24-hour recall across a range of measures.

Published
2018

35. Validation of the Oxford WebQ Online 24-Hour Dietary Questionnaire Using Biomarkers

Author

Greenwood, Darren C, primary, Hardie, Laura J, primary, Frost, Gary S, primary, Alwan, Nisreen A, primary, Bradbury, Kathryn E, primary, Carter, Michelle, primary, Elliott, Paul, primary, Evans, Charlotte E L, primary, Ford, Heather E, primary, Hancock, Neil, primary, Key, Timothy J, primary, Liu, Bette, primary, Morris, Michelle A, primary, Mulla, Umme Z, primary, Petropoulou, Katerina, primary, Potter, Gregory D M, primary, Riboli, Elio, primary, Young, Heather, primary, Wark, Petra A, primary, and Cade, Janet E, primary

Published
2019
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36. A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization.

Author

Ong, Jue-Sheng, Dixon-Suen, Suzanne C., Han, Xikun, An, Jiyuan, Esophageal Cancer Consortium, Fitzgerald, Rebecca, Buas, Matt, Gammon, Marilie D., Corley, Douglas A., Shaheen, Nicholas J., Hardie, Laura J., Bird, Nigel C., Reid, Brian J., Chow, Wong-Ho, Risch, Harvey A., Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, and Wu, Anna H.

Subjects
CANCER susceptibility, VITAMIN D, BASAL cell carcinoma, OVARIAN cancer
Abstract

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible. Studies of the genetic association between vitamin D and cancer risk have typically been underpowered. Here the authors analyse this using Mendelian Randomisation with more than 70 vitamin D variants obtained from the UK Biobank and large-scale data from various consortia, confirming null associations between vitamin D and most cancers. [ABSTRACT FROM AUTHOR]

Published
2021
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37. Micronuclei in Cord Blood Lymphocytes and Associations with Biomarkers of Exposure to Carcinogens and Hormonally Active Factors, Gene Polymorphisms, and Gene Expression: The NewGeneris Cohort

Author

Merlo, Domenico Franco, Agramunt, Silvia, Anna, Lívia, Besselink, Harrie, Botsivali, Maria, Brady, Nigel J., Ceppi, Marcello, Chatzi, Leda, Chen, Bowang, Decordier, Ilse, Farmer, Peter B., Fleming, Sarah, Fontana, Vincenzo, Försti, Asta, Fthenou, Eleni, Gallo, Fabio, Georgiadis, Panagiotis, Gmuender, Hans, Godschalk, Roger W., Granum, Berit, Hardie, Laura J., Hemminki, Kari, Hochstenbach, Kevin, Knudsen, Lisbeth E., Kogevinas, Manolis, Kovács, Katalin, Kyrtopoulos, Soterios A., Løvik, Martinus, Nielsen, Jeanette K., Nygaard, Unni Cecilie, Pedersen, Marie, Rydberg, Per, Schoket, Bernadette, Segerbäck, Dan, Singh, Rajinder, Sunyer, Jordi, Törnqvist, Margareta, van Loveren, Henk, van Schooten, Frederik J., Vande Loock, Kim, von Stedingk, Hans, Wright, John, Kleinjans, Jos C, Kirsch Volders, Micheline, van Delft, Joost H. M., Marcos, R., Anderson, D., Stagi, E., Lukács, V., Mijal, R., Nomark, E., RS: GROW - Oncology, RS: NUTRIM - R4 - Gene-environment interaction, RS: GROW - R1 - Prevention, Farmacologie en Toxicologie, Promovendi ODB, Toxicogenomics, and Cell Genetics

Subjects
medicine.medical_specialty, Genotype, Health, Toxicology and Mutagenesis, Biomarkers, Carcinogens, Child, Cohort Studies, DNA Adducts, Europe, Female, Fetal Blood, Gene Expression Profiling, Gene Expression Regulation, Hormones, Humans, Leukemia, Malondialdehyde, Micronucleus Tests, Pregnancy, Prenatal Exposure Delayed Effects, T-Lymphocytes, Public Health, Environmental and Occupational Health, Embaràs, Environmental Health and Occupational Health, Sang -- Malalties, Single-nucleotide polymorphism, Genome-wide association study, EPHX1, Biology, Internal medicine, VDP::Midical sciences: 700::Clinical medical sciences: 750::Paediatrics: 760, medicine, CALUX, Toxicology and Mutagenesis, Leucèmia en els infants, Carcinogen, Cancer, Regulation of gene expression, Environmental and Occupational Health, VDP::Medisinske fag: 700::Klinisk medisinske fag: 750::Pediatri: 760, Toxicologia genètica, Gene expression profiling, Endocrinology, Health, Micronucleus test, Immunology, Children's Health, Public Health
Abstract

Background: Leukemia incidence has increased in recent decades among European children, suggesting that early-life environmental exposures play an important role in disease development. Objectives: We investigated the hypothesis that childhood susceptibility may increase as a result of in utero exposure to carcinogens and hormonally acting factors. Using cord blood samples from the NewGeneris cohort, we examined associations between a range of biomarkers of carcinogen exposure and hormonally acting factors with micronuclei (MN) frequency as a proxy measure of cancer risk. Associations with gene expression and genotype were also explored. Methods: DNA and protein adducts, gene expression profiles, circulating hormonally acting factors, and GWAS (genome-wide association study) data were investigated in relation to genomic damage measured by MN frequency in lymphocytes from 623 newborns enrolled between 2006 and 2010 across Europe. Results: Malondialdehyde DNA adducts (M1dG) were associated with increased MN frequency in binucleated lymphocytes (MNBN), and exposure to androgenic, estrogenic, and dioxin-like compounds was associated with MN frequency in mononucleated lymphocytes (MNMONO), although no monotonic exposure–outcome relationship was observed. Lower frequencies of MNBN were associated with a 1-unit increase expression of PDCD11, LATS2, TRIM13, CD28, SMC1A, IL7R, and NIPBL genes. Gene expression was significantly higher in association with the highest versus lowest category of bulky and M1dG–DNA adducts for five and six genes, respectively. Gene expression levels were significantly lower for 11 genes in association with the highest versus lowest category of plasma AR CALUX® (chemically activated luciferase expression for androgens) (8 genes), ERα CALUX® (for estrogens) (2 genes), and DR CALUX® (for dioxins). Several SNPs (single-nucleotide polymorphisms) on chromosome 11 near FOLH1 significantly modified associations between androgen activity and MNBN frequency. Polymorphisms in EPHX1/2 and CYP2E1 were associated with MNBN. Conclusion: We measured in utero exposure to selected environmental carcinogens and circulating hormonally acting factors and detected associations with MN frequency in newborns circulating T lymphocytes. The results highlight mechanisms that may contribute to carcinogen-induced leukemia and require further research. Citation: Merlo DF, Agramunt S, Anna L, Besselink H, Botsivali M, Brady NJ, Ceppi M, Chatzi L, Chen B, Decordier I, Farmer PB, Fleming S, Fontana V, Försti A, Fthenou E, Gallo F, Georgiadis P, Gmuender H, Godschalk RW, Granum B, Hardie LJ, Hemminki K, Hochstenbach K, Knudsen LE, Kogevinas M, Kovács K, Kyrtopoulos SA, Løvik M, Nielsen JK, Nygaard UC, Pedersen M, Rydberg P, Schoket B, Segerbäck D, Singh R, Sunyer J, Törnqvist M, van Loveren H, van Schooten FJ, Vande Loock K, von Stedingk H, Wright J, Kleinjans JC, Kirsch-Volders M, van Delft JHM, NewGeneris Consortium. 2014. Micronuclei in cord blood lymphocytes and associations with biomarkers of exposure to carcinogens and hormonally active factors, gene polymorphisms, and gene expression: The NewGeneris Cohort. Environ Health Perspect 122:193–200; http://dx.doi.org/10.1289/ehp.1206324

Published
2014
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38. Bulky DNA adducts in cord blood, maternal fruit-and-vegetable consumption, and birth weight in a European mother-child study (NewGeneris)

Author

Pedersen, Marie, Schoket, Bernadette, Godschalk, Roger W., Wright, John, von Stedingk, Hans, Tornqvist, Margareta, Sunyer, Jordi, Nielsen, Jeanette K., Merlo, Domenico F., Mendez, Michelle A., Meltzer, Helle M., Lukacs, Viktoria, Landstrom, Anette, Kyrtopoulos, Soterios A., Kovacs, Katalin, Knudsen, Lisbeth E., Haugen, Margaretha, Hardie, Laura J., Gutzkow, Kristine B., Fleming, Sarah, Fthenou, Eleni, Farmer, Peter B., Espinosa, Aina, Chatzi, Leda, Brunborg, Gunnar, Brady, Nigel J., Botsivali, Maria, Arab, Khelifa, Anna, Livia, Alexander, Jan, Agramunt, Silvia, Kleinjans, Jos C., Segerback, Dan, and Kogevinas, Manolis

Subjects
Birth weight -- Genetic aspects, Fetal blood -- Genetic aspects -- Physiological aspects, Birth size -- Genetic aspects, Pregnant women -- Food and nutrition -- Health aspects -- Genetic aspects, Polycyclic aromatic hydrocarbons -- Genetic aspects -- Physiological aspects, Environmental issues, Health
Abstract

Background: Tobacco-smoke, airborne, and dietary exposures to polycyclic aromatic hydrocarbons (PAHs) have been associated with reduced prenatal growth. Evidence from biomarker-based studies of low-exposed populations is limited. Bulky DNA adducts in cord blood reflect the prenatal effective dose to several genotoxic agents including PAHs. OBJECTIVES: We estimated the association between bulky DNA adduct levels and birth weight in a multicenter study and examined modification of this association by maternal intake of fruits and vegetables during pregnancy. Methods: Pregnant women from Denmark, England, Greece, Norway, and Spain were recruited in 2006--2010. Adduct levels were measured by the [sup.32]P-postlabeling technique in white blood cells from 229 mothers and 612 newborns. Maternal diet was examined through questionnaires. Results: Adduct levels in maternal and cord blood samples were similar and positively correlated (median, 12.1 vs. 11.4 adducts in [10.sup.8]nucleotides; Spearman rank correlation coefficient = 0.66, p < 0.001). Cord blood adduct levels were negatively associated with birth weight, with an estimated difference in mean birth weight of -129 g (95% CI: -233, -25 g) for infants in the highest versus lowest tertile of adducts. The negative association with birth weight was limited to births in Norway, Denmark, and England, the countries with the lowest adduct levels, and was more pronounced in births to mothers with low intake of fruits and vegetables (-248 g; 95% CI: -405, -92 g) compared with those with high intake (-58 g; 95% CI: -206, 90 g). Conclusions: Maternal exposure to genotoxic agents that induce the formation of bulky DNA adducts may affect intrauterine growth. Maternal fruit and vegetable consumption may be protective., Introduction Environmental exposures in utero may have adverse effects on health both immediately and in later life. Measurement of biomarkers in cord blood improves exposure assessment and may improve our [...]

Published
2013
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42. Large scale meta-analysis identifies new genetic risk loci for esophageal adenocarcinoma (EA) and the first EA risk locus independent of Barrett’s esophagus

Author

Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Tomlinson, Ian, Gockel, Ines, Palles, Claire, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Bohmer, Anne C., Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismuller, Josef, Nothen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, deCaestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, RG Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Tomlinson, Ian, Gockel, Ines, Palles, Claire, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Bohmer, Anne C., Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismuller, Josef, Nothen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, deCaestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, RG Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, and Schumacher, Johannes

Abstract

SUMMARY Background: Esophageal adenocarcinoma (EA) represents one of the fastest rising oncological diseases in western countries. Barrett’s Esophagus (BE) is the premalignant precursor of EA. However, only a subset of BE patients develop EA, which complicates the clinical management in the absence of valid predictors. Methods: Within an international consortium of groups involved in the genetics of BE/EA, we performed the first meta-analysis of all genome-wide association studies (GWAS) available (>10,000 BE/EA patients, >17,000 controls, all of European descent). The entire GWAS-data set was also analyzed using bioinformatics approaches in order to identify pathophysiologically relevant cellular pathways. Findings: We identified nine new disease loci for BE/EA (P<5×10-8) and thereby doubled the number of known risk loci. The strongest new risk locus implicates CFTR as BE/EA risk gene. Mutations in CFTR cause cystic fibrosis (CF), the most common recessive disorder in Europeans. Gastroesophageal reflux (GER) belongs to the phenotypic CF-spectrum and represents the main risk factor for BE/EA. Thus, the CFTR locus may trigger a common GER-mediated pathophysiology. The strongest disease pathways identified (P<10-6) belong to muscle cell differentiation and to mesenchyme development/differentiation, which fit with current pathophysiological BE/EA concepts. Furthermore, for the first time we identified an EA-specific association (P=1·6×10-8) near HTR3C/ABCC5 which is independent of BE development (P=0·45). Interpretation: The identified disease loci and pathways reveal new insights into the etiology of BE and EA. Furthermore, the EA-specific association at HTR3C/ABCC5 may constitute a novel genetic marker for the prediction of transition from BE to EA. Funding: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council of UK, Cambridge NIHR biomedical researc

Published
2017

43. Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Author

Gharahkhani, Puya, Fitzgerald, Rebecca C, Vaughan, Thomas L, Palles, Claire, Gockel, Ines, Tomlinson, Ian, Buas, Matthew F, May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Böhmer, Anne C, Izbicki, Jakob R, Hölscher, Arnulf H, Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismüller, Josef, Nöthen, Markus M, Barrett's And Esophageal Adenocarcinoma Consortium (BEACON), Esophageal Adenocarcinoma GenEtics Consortium (EAGLE), Wellcome Trust Case Control Consortium 2 (WTCCC2), Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, De Caestecker, John, Harrison, Rebecca, Love, Sharon B, MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, RG Peter, Iyer, Prasad G, Anderson, Lesley A, Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J, Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A, Wu, Anna H, Ye, Weimin, Bird, Nigel C, Shaheen, Nicholas J, Gammon, Marilie D, Corley, Douglas A, Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert HM, Neuhaus, Horst, Rösch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C, Jankowski, Janusz, Schumacher, Johannes, Fitzgerald, Rebecca [0000-0002-3434-3568], Caldas, Carlos [0000-0003-3547-1489], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
Risk, Barrett Esophagus, Esophageal Neoplasms, Humans, Adenocarcinoma, Polymorphism, Single Nucleotide, digestive system diseases, Genome-Wide Association Study
Abstract

BACKGROUND: Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. METHODS: We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p

Published
2016

45. Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

Author

Ek, Weronica E, Lagergren, Katarina, Cook, Michael, Wu, Anna H, Abnet, Christian C, Levine, David, Chow, Wong-Ho, Bernstein, Leslie, Risch, Harvey A, Shaheen, Nicholas J, Bird, Nigel C, Corley, Douglas A, Hardie, Laura J, Fitzgerald, Rebecca C, Gammon, Marilie D, Romero, Yvonne, Liu, Geoffrey, Ye, Weimin, Vaughan, Thomas L, MacGregor, Stuart, Whiteman, David C, Westberg, Lars, Lagergren, Jesper, Ek, Weronica E, Lagergren, Katarina, Cook, Michael, Wu, Anna H, Abnet, Christian C, Levine, David, Chow, Wong-Ho, Bernstein, Leslie, Risch, Harvey A, Shaheen, Nicholas J, Bird, Nigel C, Corley, Douglas A, Hardie, Laura J, Fitzgerald, Rebecca C, Gammon, Marilie D, Romero, Yvonne, Liu, Geoffrey, Ye, Weimin, Vaughan, Thomas L, MacGregor, Stuart, Whiteman, David C, Westberg, Lars, and Lagergren, Jesper

Abstract

The strong male predominance in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remains inadequately explained, but sex hormones might be involved. We hypothesized that single nucleotide polymorphisms (SNPs) in the androgen pathway influence risk of developing BE and EAC. This genetic-epidemiological analysis included 14 studies from Australia, Europe and North America. Polymorphisms in 16 genes coding for the androgen pathway were analyzed using a gene-based approach: versatile gene-based test association study. This method evaluates associations between a trait and all SNPs within a specific gene rather than each SNP marker individually as in a conventional GWAS. The data were stratified for sex, body-mass index, waist-to-hip ratio, tobacco smoking and gastroesophageal reflux status. Included were data from 1,508 EAC patients, 2,383 BE patients and 2,170 control participants. SNPs within the gene CYP17A1 were associated with risk of BE in the sexes combined (p = 0.002) and in males (p = 0.003), but not in females separately (p = 0.3). This association was found in tobacco smokers (p = 0.003) and in BE patients without reflux (p = 0.004), but not in nonsmokers (p = 0.2) or those with reflux (p = 0.036). SNPs within JMJD1C were associated with risk of EAC in females (p = 0.001). However, none of these associations replicated in a subsequent sample. Fourteen other genes studied did not reach statistically significant levels of association with BE, EAC or the combination of BE and EAC, after correcting for the number of genes included in the analysis. In conclusion, genetic variants in the androgen-related genes CYP17A1 and JMJD1C might be associated with risk of BE and EAC, respectively, but replication data with larger sample sizes are needed.

Published
2016
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46. Large scale meta-analysis identifies new genetic risk loci for esophageal adenocarcinoma (EA) and the first EA risk locus independent of Barrett’s esophagus

Author

Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Tomlinson, Ian, Gockel, Ines, Palles, Claire, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Bohmer, Anne C., Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismuller, Josef, Nothen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, deCaestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, RG Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Gharahkhani, Puya, Fitzgerald, Rebecca C., Vaughan, Thomas L., Tomlinson, Ian, Gockel, Ines, Palles, Claire, Buas, Matthew F., May, Andrea, Gerges, Christian, Anders, Mario, Becker, Jessica, Kreuser, Nicole, Noder, Tania, Venerito, Marino, Veits, Lothar, Schmidt, Thomas, Manner, Hendrik, Schmidt, Claudia, Hess, Timo, Bohmer, Anne C., Izbicki, Jakob R., Holscher, Arnulf H., Lang, Hauke, Lorenz, Dietmar, Schumacher, Brigitte, Hackelsberger, Andreas, Mayershofer, Rupert, Pech, Oliver, Vashist, Yogesh, Ott, Katja, Vieth, Michael, Weismuller, Josef, Nothen, Markus M., Attwood, Stephen, Barr, Hugh, Chegwidden, Laura, deCaestecker, John, Harrison, Rebecca, Love, Sharon B., MacDonald, David, Moayyedi, Paul, Prenen, Hans, Watson, RG Peter, Iyer, Prasad G., Anderson, Lesley A., Bernstein, Leslie, Chow, Wong-Ho, Hardie, Laura J., Lagergren, Jesper, Liu, Geoffrey, Risch, Harvey A., Wu, Anna H., Ye, Weimin, Bird, Nigel C., Shaheen, Nicholas J., Gammon, Marilie D., Corley, Douglas A., Caldas, Carlos, Moebus, Susanne, Knapp, Michael, Peters, Wilbert H. M., Neuhaus, Horst, Rosch, Thomas, Ell, Christian, MacGregor, Stuart, Pharoah, Paul, Whiteman, David C., Jankowski, Janusz, and Schumacher, Johannes

Abstract

SUMMARY Background: Esophageal adenocarcinoma (EA) represents one of the fastest rising oncological diseases in western countries. Barrett’s Esophagus (BE) is the premalignant precursor of EA. However, only a subset of BE patients develop EA, which complicates the clinical management in the absence of valid predictors. Methods: Within an international consortium of groups involved in the genetics of BE/EA, we performed the first meta-analysis of all genome-wide association studies (GWAS) available (>10,000 BE/EA patients, >17,000 controls, all of European descent). The entire GWAS-data set was also analyzed using bioinformatics approaches in order to identify pathophysiologically relevant cellular pathways. Findings: We identified nine new disease loci for BE/EA (P<5×10-8) and thereby doubled the number of known risk loci. The strongest new risk locus implicates CFTR as BE/EA risk gene. Mutations in CFTR cause cystic fibrosis (CF), the most common recessive disorder in Europeans. Gastroesophageal reflux (GER) belongs to the phenotypic CF-spectrum and represents the main risk factor for BE/EA. Thus, the CFTR locus may trigger a common GER-mediated pathophysiology. The strongest disease pathways identified (P<10-6) belong to muscle cell differentiation and to mesenchyme development/differentiation, which fit with current pathophysiological BE/EA concepts. Furthermore, for the first time we identified an EA-specific association (P=1·6×10-8) near HTR3C/ABCC5 which is independent of BE development (P=0·45). Interpretation: The identified disease loci and pathways reveal new insights into the etiology of BE and EA. Furthermore, the EA-specific association at HTR3C/ABCC5 may constitute a novel genetic marker for the prediction of transition from BE to EA. Funding: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council of UK, Cambridge NIHR biomedical researc

Published
2016

47. In Utero Exposure to Compounds with Dioxin-like Activity and Birth Outcomes

Author

Vafeiadi, Marina Agramunt, Silvia Pedersen, Marie Besselink, Harrie Chatzi, Leda Fthenou, Eleni Fleming, Sarah and Hardie, Laura J. Wright, John Knudsen, Lisbeth E. Nielsen, Jeanette K. S. Sunyer, Jordi Carreras, Ramon Brunborg, Gunnar Gutzkow, Kristine B. Nygaard, Unni C. Lovik, Martinus and Kyrtopoulos, Soterios A. Segerback, Dan Merlo, Domenico F. and Kleinjans, Jos C. Vrijheid, Martine Kogevinas, Manolis and NewGeneris Consortium

Abstract

Background: Maternal exposure to dioxins and dioxin-like compounds may affect fetal growth and development. We evaluated the association between in utero dioxin-like activity and birth outcomes in a prospective European mother-child study. Methods: We measured dioxin-like activity in maternal and cord blood plasma samples collected at delivery using the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR CALUX) bioassay in 967 mother-child pairs, in Denmark, Greece, Norway, Spain, and England. Multiple linear regression models were used to investigate the associations with birth weight, gestational age, and head circumference. Results: Plasma dioxin-like activity was higher in maternal sample than in cord samples. Birth weight was lower with medium (-58 g [95% confidence interval (CI) = -176 to 62]) and high (-82 g [-216 to 53]) tertiles of exposure (cord blood) compared with the lowest tertile. Gestational age was shorter by approximately half a week in the highest compared with the lowest (-0.4 weeks [95% CI = -0.8 to -0.1]). This association was stronger in boys than in girls, although the statistical evidence for interaction was weak (P = 0.22). Analysis based on CALUX-toxic equivalents expressed per milliliter of plasma showed similar trends. We found no association between dioxin-like activity in maternal plasma and birth outcomes. Conclusions: Results from this international general population study suggest an association between low-level prenatal dioxin-like activity and shorter gestational age, particularly in boys, with weaker associations for birth weight.

Published
2014

48. Micronuclei in Cord Blood Lymphocytes and Associations with Biomarkers of Exposure to Carcinogens and Hormonally Active Factors, Gene Polymorphisms, and Gene Expression: The NewGeneris Cohort

Author

Merlo, Domenico Franco Agramunt, Silvia Anna, Livia and Besselink, Harrie Botsivali, Maria Brady, Nigel J. Ceppi, Marcello Chatzi, Leda Chen, Bowang Decordier, Ilse and Farmer, Peter B. Fleming, Sarah Fontana, Vincenzo Foersti, Asta Fthenou, Eleni Gallo, Fabio Georgiadis, Panagiotis and Gmuender, Hans Godschalk, Roger W. Granum, Berit Hardie, Laura J. Hemminki, Kari Hochstenbach, Kevin Knudsen, Lisbeth E. Kogevinas, Manolis Kovacs, Katalin Kyrtopoulos, Soterios A. Lovik, Martinus Nielsen, Jeanette K. Nygaard, Unni Cecilie Pedersen, Marie Rydberg, Per Schoket, Bernadette and Segerback, Dan Singh, Rajinder Sunyer, Jordi Tornqvist, Margareta van Loveren, Henk van Schooten, Frederik J. vande Loock, Kim von Stedingk, Hans Wright, John Kleinjans, Jos C. and Kirsch-Volders, Micheline van Delft, Joost H. M. NewGeneris Consortium

Abstract

Background: Leukemia incidence has increased in recent decades among European children, -suggesting that early-life environmental exposures play an important role in disease development. Objectives: We investigated the hypothesis that childhood susceptibility may increase as a result of in utero exposure to carcinogens and hormonally acting factors. Using cord blood samples from the NewGeneris cohort, we examined associations between a range of biomarkers of carcinogen exposure and hormonally acting factors with micronuclei (MN) frequency as a proxy measure of cancer risk. Associations with gene expression and genotype were also explored. Methods: DNA and protein adducts, gene expression profiles, circulating hormonally acting factors, and GWAS (genome-wide association study) data were investigated in relation to genomic damage measured by MN frequency in lymphocytes from 623 newborns enrolled between 2006 and 2010 across Europe. Results: Malondialdehyde DNA adducts (M(1)dG) were associated with increased MN frequency in binucleated lymphocytes (MNBN), and exposure to androgenic, estrogenic, and dioxin-like compounds was associated with MN frequency in mononucleated lymphocytes (MNMONO), although no monotonic exposure-outcome relationship was observed. Lower frequencies of MNBN were associated with a 1-unit increase expression of PDCD11, LATS2, TRIM13, CD28, SMC1A, IL7R, and NIPBL genes. Gene expression was significantly higher in association with the highest versus lowest category of bulky and M(1)dG-DNA adducts for five and six genes, respectively. Gene expression levels were significantly lower for 11 genes in association with the highest versus lowest category of plasma AR CALUX (R) (chemically activated luciferase expression for androgens) (8 genes), ER alpha CALUX (R) (for estrogens) (2 genes), and DR CALUX (R) (for dioxins). Several SNPs (single-nucleotide polymorphisms) on chromosome 11 near FOLH1 significantly modified associations between androgen activity and MNBN frequency. Polymorphisms in EPHX1/ 2 and CYP2E1 were associated with MNBN. Conclusion: We measured in utero exposure to selected environmental carcinogens and circulating hormonally acting factors and detected associations with MN frequency in newborns circulating T lymphocytes. The results highlight mechanisms that may contribute to carcinogen-induced leukemia and require further research.

Published
2014

49. Maternal diet, prenatal exposure to dioxin-like compounds and birth outcomes in a European prospective mother-child study (NewGeneris)

Author

Papadopoulou, Eleni Kogevinas, Manolis Botsivali, Maria and Pedersen, Marie Besselink, Harrie Mendez, Michelle A. and Fleming, Sarah Hardie, Laura J. Knudsen, Lisbeth E. Wright, John Agramunt, Silvia Sunyer, Jordi Granum, Berit and Gutzkow, Kristine B. Brunborg, Gunnar Alexander, Jan and Meltzer, Helle Margrete Brantsaeter, Anne Lise Sarri, Katerina and Chatzi, Leda Merlo, Domenico F. Kleinjans, Jos C. and Haugen, Margaretha

Abstract

Maternal diet can result in exposure to environmental contaminants including dioxins which may influence foetal growth. We investigated the association between maternal diet and birth outcomes by defining a dioxin-rich diet. We used validated food frequency questionnaires to assess the diet of pregnant women from Greece, Spain, United Kingdom, Denmark and Norway and estimated plasma dioxin-like activity by the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR-CALUX (R)) bioassay in 604 maternal blood samples collected at delivery. We applied reduced rank regression to identify a dioxin-rich dietary pattern based on dioxin-like activity (DR-CALUX (R)) levels in maternal plasma, and calculated a dioxin-diet score as an estimate of adherence to this dietary pattern. In the five country population, dioxin-diet score was characterised by high consumption of red and white meat, lean and fatty fish, low-fat dairy and low consumption of salty snacks and high-fat cheese, during pregnancy. The upper tertile of the dioxin-diet score was associated with a change in birth weight of -121 g (95% confidence intervals: -232, -10 g) compared to the lower tertile after adjustment for con-founders. A small non-significant reduction in gestational age was also observed (-1.4 days, 95% CI: -3.8, 1.0 days). Our results suggest that maternal diet might contribute to the exposure of the foetus to dioxins and dioxin-like compounds and may be related to reduced birth weight. More studies are needed to develop updated dietary guidelines for women of reproductive age, aiming to the reduction of dietary exposure to persistent organic pollutants as dioxins and dioxin-like compounds. (C) 2014 Elsevier B.V. All rights reserved.

Published
2014

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