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

Author

Wang, Xiaoyu, Gharahkhani, P., Levine, D.M., Fitzgerald, R.C., Gockel, I., Corley, D.A., Risch, H.A., Bernstein, L., Chow, W.H., Onstad, L., Shaheen, N.J., Lagergren, J., Hardie, L.J., Wu, A.H., Pharoah, P.D., Liu, G., Anderson, L.A., Iyer, P.G., Gammon, M.D., Caldas, C., Ye, W., Barr, H., Moayyedi, P., Harrison, R., Watson, R.G.P., Attwood, S., Chegwidden, L., Love, S.B., MacDonald, D., DeCaestecker, J., Prenen, H., Ott, K., Moebus, S., Venerito, M., Lang, H., Mayershofer, R., Knapp, M., Veits, L., Gerges, C., Weismüller, J., Reeh, M., Nöthen, M.M., Izbicki, J.R., Manner, H., Neuhaus, H., Rösch, T., Böhmer, A.C., Hölscher, A.H., Anders, M., Pech, O., Schumacher, B., Schmidt, C., Schmidt, T., Noder, T., Lorenz, D., Vieth, M., May, A., Hess, T., Kreuser, N., Becker, J., Ell, C., Tomlinson, I., Palles, C., Jankowski, J.A., Whiteman, D.C., MacGregor, S., Schumacher, J., Vaughan, T.L., Buas, M.F., Dai, J.Y., Wang, Xiaoyu, Gharahkhani, P., Levine, D.M., Fitzgerald, R.C., Gockel, I., Corley, D.A., Risch, H.A., Bernstein, L., Chow, W.H., Onstad, L., Shaheen, N.J., Lagergren, J., Hardie, L.J., Wu, A.H., Pharoah, P.D., Liu, G., Anderson, L.A., Iyer, P.G., Gammon, M.D., Caldas, C., Ye, W., Barr, H., Moayyedi, P., Harrison, R., Watson, R.G.P., Attwood, S., Chegwidden, L., Love, S.B., MacDonald, D., DeCaestecker, J., Prenen, H., Ott, K., Moebus, S., Venerito, M., Lang, H., Mayershofer, R., Knapp, M., Veits, L., Gerges, C., Weismüller, J., Reeh, M., Nöthen, M.M., Izbicki, J.R., Manner, H., Neuhaus, H., Rösch, T., Böhmer, A.C., Hölscher, A.H., Anders, M., Pech, O., Schumacher, B., Schmidt, C., Schmidt, T., Noder, T., Lorenz, D., Vieth, M., May, A., Hess, T., Kreuser, N., Becker, J., Ell, C., Tomlinson, I., Palles, C., Jankowski, J.A., Whiteman, D.C., MacGregor, S., Schumacher, J., Vaughan, T.L., Buas, M.F., and Dai, J.Y.

Abstract

Item does not contain fulltext, 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. 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

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

Author

Dighe, S.G., Chen, J., Yan, L., He, Q., Gharahkhani, P., Onstad, L., Levine, D.M., Palles, C., Ye, W., Gammon, M.D., Iyer, P.G., Anderson, L.A., Liu, G., Wu, A.H., Dai, J.Y., Chow, W.H., Risch, H.A., Lagergren, J., Shaheen, N.J., Bernstein, L., Corley, D.A., Prenen, H., DeCaestecker, J., MacDonald, D., Moayyedi, P., Barr, H., Love, S.B., Chegwidden, L., Attwood, S., Watson, P., Harrison, R., Ott, K., Moebus, S., Venerito, M., Lang, H., Mayershofer, R., Knapp, M., Veits, L., Gerges, C., Weismüller, J., Gockel, I., Vashist, Y., Nöthen, M.M., Izbicki, J.R., Manner, H., Neuhaus, H., Rösch, T., Böhmer, A.C., Hölscher, A.H., Anders, M., Pech, O., Schumacher, B., Schmidt, C., Schmidt, T., Noder, T., Lorenz, D., Vieth, M., May, A., Hess, T., Kreuser, N., Becker, J., Ell, C., Ambrosone, C.B., Moysich, K.B., MacGregor, S., Tomlinson, I., Whiteman, D.C., Jankowski, J., Schumacher, J., Vaughan, T.L., Madeleine, M.M., Hardie, L.J., Buas, M.F., Dighe, S.G., Chen, J., Yan, L., He, Q., Gharahkhani, P., Onstad, L., Levine, D.M., Palles, C., Ye, W., Gammon, M.D., Iyer, P.G., Anderson, L.A., Liu, G., Wu, A.H., Dai, J.Y., Chow, W.H., Risch, H.A., Lagergren, J., Shaheen, N.J., Bernstein, L., Corley, D.A., Prenen, H., DeCaestecker, J., MacDonald, D., Moayyedi, P., Barr, H., Love, S.B., Chegwidden, L., Attwood, S., Watson, P., Harrison, R., Ott, K., Moebus, S., Venerito, M., Lang, H., Mayershofer, R., Knapp, M., Veits, L., Gerges, C., Weismüller, J., Gockel, I., Vashist, Y., Nöthen, M.M., Izbicki, J.R., Manner, H., Neuhaus, H., Rösch, T., Böhmer, A.C., Hölscher, A.H., Anders, M., Pech, O., Schumacher, B., Schmidt, C., Schmidt, T., Noder, T., Lorenz, D., Vieth, M., May, A., Hess, T., Kreuser, N., Becker, J., Ell, C., Ambrosone, C.B., Moysich, K.B., MacGregor, S., Tomlinson, I., Whiteman, D.C., Jankowski, J., Schumacher, J., Vaughan, T.L., Madeleine, M.M., Hardie, L.J., and Buas, M.F.

Abstract

Contains fulltext : 235640.pdf (Publisher’s version ) (Closed access), 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 meta-analysis. 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

3. TP53 and progression from Barrett's metaplasia to oesophageal adenocarcinoma in a UK population cohort

Author

Murray, L., Sedo, A., Scott, M., McManus, D., Sloan, J.M., Hardie, L.J., Forman, D., and Wild, C.P.

Subjects
Barrett's esophagus -- Research, Barrett's esophagus -- Physiological aspects, Barrett's esophagus -- Diagnosis, Barrett's esophagus -- Development and progression, Immunohistochemistry -- Evaluation, Immunohistochemistry -- Usage, Biological markers -- Evaluation, Biological markers -- Usage, Health
Published
2006

10. BIOMONITORING STUDIES OF MYCOTOXINS EXPOSURE AND ITS ASSOCIATION WITH TYPICAL FOOD CONSUMPTION IN SWEDISH ADULTS

Author

Olsen M., Hardie L.J., Solfrizzo M., Kotova N., Warensjö Lemming E., Turner P.C., Gambacorta L., and Wallin S.

Subjects
human biomonitoring, concurrent exposure, mycotoxins, food and beverages, urinary biomarkers, diet
Abstract

It is well known that mycotoxin producing moulds may contaminate numerous agricultural commodities either before harvest or during storage. Various foods may therefore be contaminated with a range of mycotoxins. Consequently, consumers are generally exposed to more than one mycotoxin at the same time. The aim of our studies was to determine the possible associations between mycotoxin exposure and diet as well as concurrent exposure to mycotoxins in randomly selected Swedish adults, aged 18-80 years. The participants took part in the Swedish national dietary survey "Riksmaten 2010-11" and urinary samples were collected on average 19 days after the 4-day web-based diet record. In the first study, total urinary deoxynivalenol (DON), i.e. free DON and the DON-glucuronide, was measured using immunoaffinity enrichment and LCMS quantification. In the second study, concurrent mycotoxin exposure was analysed using a multi-biomarker LC-MS/MS method. The first study showed that exposure of DON among the adult population was very common (>90%) with levels ranging from non-detectable (nd) to 65.8 ng DON/ml urine and a median level of 2.9 ng/ml. Furthermore, urinary DON (ng/mg creatinine) was associated with the intake (gram/day) of total cereal grain as well as with whole grain. DON was also significantly associated with breakfast cereals and porridge (p

Published
2015

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

Author

Thrift, A.P., Risch, H.A., Onstad, L., Shaheen, N.J., Casson, A.G., Bernstein, L., Corley, D.A., Levine, D.M., Chow, W-H., Reid, B.J., Romero, Y., Hardie, L.J., Liu, G., Wu, A.H., Bird, N.C., Gammon, M.D., Ye, W., Whiteman, D.C., and Vaughan, T.L.

Abstract

Background & Aims\ud \ud Risks for some cancers increase with height. We investigated the relationship between height and risk of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE).\ud Methods\ud \ud We analyzed epidemiologic and genome-wide genomic data from individuals of European ancestry in the Barrett's and Esophageal Adenocarcinoma Consortium, from 999 cases of EAC, 2061 cases of BE, and 2168 population controls. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for associations between height and risks of EAC and BE. We performed a Mendelian randomization analysis to estimate an unconfounded effect of height on EAC and BE using a genetic risk score derived from 243 genetic variants associated with height as an instrumental variable.\ud Results\ud \ud Height was associated inversely with EAC (per 10-cm increase in height: OR, 0.70; 95% CI, 0.62–0.79 for men and OR, 0.57; 95% CI 0.40–0.80 for women) and BE (per 10-cm increase in height: OR, 0.69; 95% CI, 0.62–0.77 for men and OR, 0.61; 95% CI, 0.48–0.77 for women). The risk estimates were consistent across strata of age, education level, smoking, gastroesophageal reflux symptoms, body mass index, and weight. Mendelian randomization analysis yielded results quantitatively similar to those from the conventional epidemiologic analysis.\ud Conclusions\ud \ud Height is associated inversely with risks of EAC and BE. Results from the Mendelian randomization study showed that the inverse association observed did not result from confounding factors. Mechanistic studies of the effect of height on EAC and BE are warranted; height could have utility in clinical risk stratification.

Published
2014

12. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus

Author

Su, Z., Gay, L.J., Strange, A., Palles, C., Band, G., Whiteman, D.C., Lescai, F., Langford, C., Nanji, M., Edkins, S., van der Winkel, A., Levine, D., Sasieni, P., Bellenguez, C., Howarth, K., Freeman, C., Trudgill, N., Tucker, A.T., Pirinen, M., Peppelenbosch, M.P., van der Laan, L.J.W., Kuipers, E.J., Drenth, J.P.H., Peters, W.H., Reynolds, J.V., Kelleher, D.P., McManus, R., Grabsch, H., Prenen, H., Bisschops, R., Krishnadath, K., Siersema, P.D., van Baal, J.W.P.M., Middleton, M., Petty, R., Gillies, R., Burch, N., Bhandari, P., Paterson, S., Edwards, C., Penman, I., Vaidya, K., Ang, Y., Murray, I., Patel, P., Ye, W., Mullins, P., Wu, A.H., Bird, N.C., Dallal, H., Shaheen, N.J., Murray, L.J., Koss, K., Bernstein, L., Romero, Y., Hardie, L.J., Zhang, R., Winter, H., Corley, D.A., Panter, S., Risch, H.A., Reid, B.J., Sargeant, I., Gammon, M.D., Smart, H., Dhar, A., McMurtry, H., Ali, H., Liu, G., Casson, A.G., Chow, W.-H., Rutter, M., Tawil, A., Morris, D., Nwokolo, C., Isaacs, P., Rodgers, C., Ragunath, K., MacDonald, C., Haigh, C., Monk, D., Davies, G., Wajed, S., Johnston, D., Gibbons, M., Cullen, S., Church, N., Langley, R., Griffin, M., Alderson, D., Deloukas, P., Hunt, S.E., Gray, E., Dronov, S., Potter, S.C., Tashakkori-Ghanbaria, A., Anderson, M., Brooks, C., Blackwell, J.M., Bramon, E., Brown, M.A., Casas, J.P., Corvin, A., Duncanson, A., Markus, H.S., Mathew, C.G., Palmer, C.N.A., Plomin, R., Rautanen, A., Sawcer, S.J., Trembath, R.C., Viswanathan, A.C., Wood, N., Trynka, G., Wijmenga, C., Cazier, J.-B., Atherfold, P., Nicholson, A.M., Gellatly, N.L., Glancy, D., Cooper, S.C., Cunningham, D., Lind, T., Hapeshi, J., Ferry, D., Rathbone, B., Brown, J., Love, S., Attwood, S., MacGregor, S., Watson, P., Sanders, S., Ek, W., Harrison, R.F., Moayyedi, P., de Caestecker, J., Barr, H., Stupka, E., Vaughan, T.L., Peltonen, L., Spencer, C.C.A., Tomlinson, I., Donnelly, P., Jankowski, J.A.Z., Genetics, E.A., and Consor, W.T.C.C.

Subjects
digestive system diseases
Abstract

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined = 4.09 × 10−9; odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13–1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined = 2.74 × 10−10; OR = 1.14, 95% CI = 1.10–1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

Published
2012

13. Methylene blue but not indigo carmine causes DNA damage to colonocytes in vitro and in vivo at concentrations used in clinical chromoendoscopy

Author

Davies, J., Burke, D., Olliver, J.R., Hardie, L.J., Wild, C.P., and Routledge, M.N.

Subjects
Colonoscopy -- Management, Colonoscopy -- Usage, Dyes and dyeing -- Usage, Dyes and dyeing -- Health aspects, Dyes and dyeing -- Analysis, Gastrointestinal mucosa -- Research, Gastrointestinal mucosa -- Abnormalities, DNA -- Research, DNA -- Health aspects, Company business management, Health
Published
2007

29. DNA damage levels are raised in Barrett's oesophageal mucosa relative to the squamous epithelium of the oesophagus.

Author

Olliver, J.R., Hardie, L.J., Dexter, S., Chalmers, D., and Wild, C.P.

Subjects
*DNA damage, *DNA, *BIOCHEMICAL genetics, *GENETIC mutation, *ESOPHAGUS, *ADENOCARCINOMA
Abstract

Barrett's oesophagus (BE) is a pre-malignant metaplastic tissue predisposing to oesophageal adenocarcinoma (EC), and gastro-oesophageal reflux is a risk factor for both conditions. Reflux of acid and bile can cause mucosal injury and initiate chronic inflammation. These processes can induce DNA damage, possibly via an oxidative stress mechanism, thus increasing the likelihood of progression from Barrett's metaplasia to dysplasia and finally carcinoma. The comet assay was optimized for the detection of DNA damage (strand breaks and alkali-labile sites) in oesophageal biopsies, including incorporation of the DNA repair enzyme Fapy-DNA glycosylase (Fpg). Fpg allows the detection of 8-hydroxy-2-deoxyguanosine (8-OHdG) sites, a known pro-mutagenic DNA lesion. BE patients were recruited from BE surveillance clinics and oesophageal biopsies collected at endoscopy. Comet analysis revealed significantly increased ( p <0.001) DNA damage in Barrett's epithelium compared with matched squamous epithelium, with median % tail DNA values of 25.1% (first to third quartile 21.7-29.6%) and 18.6% (first to third quartile 16.9-21.4%), respectively. The median % tail DNA was up to 70% higher in the matched BE tissue compared with squamous epithelium from the same patient. Fpg sensitive sites were demonstrated in both tissue types at similar levels. The raised level of DNA damage in the premalignant BE may contribute to the accumulation of genetic alterations occurring during progression to EC. Understanding these underlying mechanisms provides a basis for cancer prevention strategies in BE patients. [ABSTRACT FROM AUTHOR]

Published
2003
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32. CHROMOENDOSCOPY WITH METHYLENE BLUE IN BARRETT'S OESOPHAGUS: ADDING INSULT TO INJURY?

Author

Olliver, J.R., Wild, C.P., Sahay, P., Dexter, S.P.L., and Hardie, L.J.

Subjects
ENDOSCOPY, METHYLENE blue, METAPLASIA
Abstract

Chromoendoscopy with methylene blue (MB) is increasingly being applied during endoscopic examination of Barrett's oesophagus (BO). MB selectively stains specialised intestinal metaplasia as it is specifically absorbed by the goblet cells characterising this tissue. Experimental studies show that photosensitisation of MB with visible light stimulates the formation of singlet oxygen species leading to the generation of single strand breaks and oxidative alterations to guanine residues of which the promutagenic DNA adduct, 8-hydroxydeoxyguanosine (8-OHdG) predominates. We hypothesised that the application of MB to the oesophagus followed by exposure to endoscopic light may stimulate high levels of DNA damage in BO. Biopsies were collected before and after MB exposure from immediately adjacent sites within BO mucosa from 15 patients. Biopsies were subject to DNA damage analysis using the comet assay to detect strand breaks and alkali-labile sites. In addition the enzyme Fapy-DNA glycosylase (FpG) was incorporated into the assay to allow the detection of FpG sensitive sites, including 8-OHdG. For every patient studied, DNA damage levels increased (range 6.0-71.9%) following MB chromoendoscopy. Statistical comparison of matched biopsies revealed a significant difference (p < 0.005) in the DNA damage level before (28.8% (24.6-32.4%), median percentage tail DNA (1st-3rd quartile)) compared to after chromoendoscopy (36.5% (32.1-42.7%)). Following MB chromoendoscopy the percentage of cells with highly damage DNA attributable to FpG sensitive sites, approximately doubled. Barrett's mucosa is a recognised preneoplastic tissue, which exhibits many genetic and epigenetic alterations. Exposing this and any associated dysplasia to further promutagenic DNA damage, via MB chromoendoscopy warrants caution as it could potentially accelerate the carcinogenic process. [ABSTRACT FROM AUTHOR]

Published
2003

33. The role of antioxidant vitamins in the progression of Barrett's oesophagus to adenocarcinoma.

Author

Fountoulakis, A., Martin, I.G., White, K., Hardie, L.J., Sue-Ling, H.M., and Wild, C.P.

Subjects
VITAMIN C, CANCER patients, SQUAMOUS cell carcinoma
Abstract

Aims: The sharp increase in the incidence of oesophageal adenocarcinoma over a relatively short period of time indicates that environmental factors are involved in the aetiology and epidemiological data suggest that dietary antioxidants might have a protective effect against the development of the disease. The aim of this study was to measure tissue and plasma levels of vitamin C and ascorbic acid in patients with Barrett's oesophagus. Methods: Blood samples and endoscopic biopsies from squamous, Barrett's, and gastric mucosa were obtained from consecutive patients participating in a surveillance programme. Vitamin levels were measured by high performance liquid chromatography and mean values were compared by a two-tailed unpaired t-test. Results: Forty-two male and 15 female volunteers were recruited. Histology of the Barrett's epithelium revealed nine cases with gastric metaplasia, 45 with intestinal metaplasia and three with dysplasia. The mean values ± SD) of ascorbic acid in squamous, Barrett's and gastric mucosa were 111.1 (± 51.1), 86.9 (± 38) and 75.8 (± 35.8) µg g[sup -1], respectively. The difference between the mean values in squamous and Barrett's mucosa was statistically significant (P = 0.02). The difference between Barrett's and gastric mucosa was not significant. There was also a statistically significant difference between the mean plasma levels of ascorbic acid in male [mean = 7.51 (± 3.7) µg mL[sup -1]] and female [mean = 10.14 (± 4.2) µg mL[sup -1] patients (P = 0.04). A trend towards a decrease in the mean plasma levels of ascorbic acid was noted between patients with gastric metaplasia, intestinal metaplasia and dysplasia (10.57 versus 7.98 versus 4.56 µg mL[sup -1]) but this failed to reach statistical significance due to the small number of patients in each subgroup. Similar results were obtained for the tissue and plasma levels of vitamin C. Conclusions: These results suggest... [ABSTRACT FROM AUTHOR]

Published
2001

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