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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

3. 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

4. Response to Li and Hopper.

Author

Thomas M., Sakoda L.C., Hoffmeister M., Rosenthal E.A., Lee J.K., van Duijnhoven F.J.B., Platz E.A., Wu A.H., Dampier C.H., de la Chapelle A., Wolk A., Joshi A.D., Burnett-Hartman A., Gsur A., Lindblom A., Castells A., Win A.K., Namjou B., Van Guelpen B., Tangen C.M., He Q., Li C.I., Schafmayer C., Joshu C.E., Ulrich C.M., Bishop D.T., Buchanan D.D., Schaid D., Drew D.A., Muller D.C., Duggan D., Crosslin D.R., Albanes D., Giovannucci E.L., Larson E., Qu F., Mentch F., Giles G.G., Hakonarson H., Hampel H., Stanaway I.B., Figueiredo J.C., Huyghe J.R., Minnier J., Chang-Claude J., Hampe J., Harley J.B., Visvanathan K., Curtis K.R., Offit K., Li L., Le Marchand L., Vodickova L., Gunter M.J., Jenkins M.A., Slattery M.L., Lemire M., Woods M.O., Song M., Murphy N., Lindor N.M., Dikilitas O., Pharoah P.D.P., Campbell P.T., Newcomb P.A., Milne R.L., MacInnis R.J., Castellvi-Bel S., Ogino S., Berndt S.I., Bezieau S., Thibodeau S.N., Gallinger S.J., Zaidi S.H., Harrison T.A., Keku T.O., Hudson T.J., Vymetalkova V., Moreno V., Martin V., Arndt V., Wei W.-Q., Chung W., Su Y.-R., Hayes R.B., White E., Vodicka P., Casey G., Gruber S.B., Schoen R.E., Chan A.T., Potter J.D., Brenner H., Jarvik G.P., Corley D.A., Peters U., Hsu L., Thomas M., Sakoda L.C., Hoffmeister M., Rosenthal E.A., Lee J.K., van Duijnhoven F.J.B., Platz E.A., Wu A.H., Dampier C.H., de la Chapelle A., Wolk A., Joshi A.D., Burnett-Hartman A., Gsur A., Lindblom A., Castells A., Win A.K., Namjou B., Van Guelpen B., Tangen C.M., He Q., Li C.I., Schafmayer C., Joshu C.E., Ulrich C.M., Bishop D.T., Buchanan D.D., Schaid D., Drew D.A., Muller D.C., Duggan D., Crosslin D.R., Albanes D., Giovannucci E.L., Larson E., Qu F., Mentch F., Giles G.G., Hakonarson H., Hampel H., Stanaway I.B., Figueiredo J.C., Huyghe J.R., Minnier J., Chang-Claude J., Hampe J., Harley J.B., Visvanathan K., Curtis K.R., Offit K., Li L., Le Marchand L., Vodickova L., Gunter M.J., Jenkins M.A., Slattery M.L., Lemire M., Woods M.O., Song M., Murphy N., Lindor N.M., Dikilitas O., Pharoah P.D.P., Campbell P.T., Newcomb P.A., Milne R.L., MacInnis R.J., Castellvi-Bel S., Ogino S., Berndt S.I., Bezieau S., Thibodeau S.N., Gallinger S.J., Zaidi S.H., Harrison T.A., Keku T.O., Hudson T.J., Vymetalkova V., Moreno V., Martin V., Arndt V., Wei W.-Q., Chung W., Su Y.-R., Hayes R.B., White E., Vodicka P., Casey G., Gruber S.B., Schoen R.E., Chan A.T., Potter J.D., Brenner H., Jarvik G.P., Corley D.A., Peters U., and Hsu L.

Published
2021

6. Helicobacter pylori infection and the risk of Barrett's oesophagus: a community-based study

Author

Corley, D.A., Kubo, A., Levin, T.R., Block, G., Habel, L., Zhao, W., Leighton, P., Rumore, G., Quesenberry, C., Buffler, P., and Parsonnet, J.

Subjects
Helicobacter infections -- Complications and side effects, Helicobacter infections -- Genetic aspects, Helicobacter infections -- Research, Barrett's esophagus -- Risk factors, Barrett's esophagus -- Development and progression, Barrett's esophagus -- Research, Health
Published
2008

7. Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma

Author

Dong, J., Maj, C., Tsavachidis, S., Ostrom, Q.T., Gharahkhani, P., Anderson, L.A., Wu, A.H., Ye, W., Bernstein, L., Borisov, O., Schröder, J., Chow, W.H., Gammon, M.D., Liu, G., Caldas, C., Pharoah, P.D., Risch, H.A., May, A., Gerges, C., Anders, M., Venerito, M., Schmidt, T., Izbicki, J.R., Hölscher, A.H., Schumacher, B., Vashist, Y., Neuhaus, H., Rösch, T., Knapp, M., Krawitz, P., Böhmer, A., Iyer, P.G., Reid, B.J., Lagergren, J., Shaheen, N.J., Corley, D.A., Gockel, I., Fitzgerald, R.C., Cook, M.B., Whiteman, D.C., Vaughan, T.L., Schumacher, J., Thrift, A.P., Dong, J., Maj, C., Tsavachidis, S., Ostrom, Q.T., Gharahkhani, P., Anderson, L.A., Wu, A.H., Ye, W., Bernstein, L., Borisov, O., Schröder, J., Chow, W.H., Gammon, M.D., Liu, G., Caldas, C., Pharoah, P.D., Risch, H.A., May, A., Gerges, C., Anders, M., Venerito, M., Schmidt, T., Izbicki, J.R., Hölscher, A.H., Schumacher, B., Vashist, Y., Neuhaus, H., Rösch, T., Knapp, M., Krawitz, P., Böhmer, A., Iyer, P.G., Reid, B.J., Lagergren, J., Shaheen, N.J., Corley, D.A., Gockel, I., Fitzgerald, R.C., Cook, M.B., Whiteman, D.C., Vaughan, T.L., Schumacher, J., and Thrift, A.P.

Abstract

Contains fulltext : 229320.pdf (Publisher’s version ) (Closed access), BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored. METHODS: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. RESULTS: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, P(BONF) = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, P(BONF) = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. CONCLUSIONS: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.

Published
2020

8. Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.

Author

Huyghe J.R., Thomas M., Sakoda L.C., Hoffmeister M., Rosenthal E.A., Lee J.K., van Duijnhoven F.J.B., Platz E.A., Wu A.H., Dampier C.H., de la Chapelle A., Wolk A., Joshi A.D., Burnett-Hartman A., Gsur A., Lindblom A., Castells A., Win A.K., Namjou B., Van Guelpen B., Tangen C.M., He Q., Li C.I., Schafmayer C., Joshu C.E., Ulrich C.M., Bishop D.T., Buchanan D.D., Schaid D., Drew D.A., Muller D.C., Duggan D., Crosslin D.R., Albanes D., Giovannucci E.L., Larson E., Qu F., Mentch F., Giles G.G., Hakonarson H., Hampel H., Stanaway I.B., Figueiredo J.C., Minnier J., Chang-Claude J., Hampe J., Harley J.B., Visvanathan K., Curtis K.R., Offit K., Li L., Le Marchand L., Vodickova L., Gunter M.J., Jenkins M.A., Slattery M.L., Lemire M., Woods M.O., Song M., Murphy N., Lindor N.M., Dikilitas O., Pharoah P.D.P., Campbell P.T., Newcomb P.A., Milne R.L., MacInnis R.J., Castellvi-Bel S., Ogino S., Berndt S.I., Bezieau S., Thibodeau S.N., Gallinger S.J., Zaidi S.H., Harrison T.A., Keku T.O., Hudson T.J., Vymetalkova V., Moreno V., Martin V., Arndt V., Wei W.-Q., Chung W., Su Y.-R., Hayes R.B., White E., Vodicka P., Casey G., Gruber S.B., Schoen R.E., Chan A.T., Potter J.D., Brenner H., Jarvik G.P., Corley D.A., Peters U., Hsu L., Huyghe J.R., Thomas M., Sakoda L.C., Hoffmeister M., Rosenthal E.A., Lee J.K., van Duijnhoven F.J.B., Platz E.A., Wu A.H., Dampier C.H., de la Chapelle A., Wolk A., Joshi A.D., Burnett-Hartman A., Gsur A., Lindblom A., Castells A., Win A.K., Namjou B., Van Guelpen B., Tangen C.M., He Q., Li C.I., Schafmayer C., Joshu C.E., Ulrich C.M., Bishop D.T., Buchanan D.D., Schaid D., Drew D.A., Muller D.C., Duggan D., Crosslin D.R., Albanes D., Giovannucci E.L., Larson E., Qu F., Mentch F., Giles G.G., Hakonarson H., Hampel H., Stanaway I.B., Figueiredo J.C., Minnier J., Chang-Claude J., Hampe J., Harley J.B., Visvanathan K., Curtis K.R., Offit K., Li L., Le Marchand L., Vodickova L., Gunter M.J., Jenkins M.A., Slattery M.L., Lemire M., Woods M.O., Song M., Murphy N., Lindor N.M., Dikilitas O., Pharoah P.D.P., Campbell P.T., Newcomb P.A., Milne R.L., MacInnis R.J., Castellvi-Bel S., Ogino S., Berndt S.I., Bezieau S., Thibodeau S.N., Gallinger S.J., Zaidi S.H., Harrison T.A., Keku T.O., Hudson T.J., Vymetalkova V., Moreno V., Martin V., Arndt V., Wei W.-Q., Chung W., Su Y.-R., Hayes R.B., White E., Vodicka P., Casey G., Gruber S.B., Schoen R.E., Chan A.T., Potter J.D., Brenner H., Jarvik G.P., Corley D.A., Peters U., and Hsu L.

Abstract

Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might be

Published
2020

9. No Association Between Vitamin D Status and Risk of Barrett's Esophagus or Esophageal Adenocarcinoma: A Mendelian Randomization Study

Author

Dong, J., Gharahkhani, P., Chow, W.H., Gammon, M.D., Liu, G., Caldas, C., Wu, A.H., Ye, W., Onstad, L., Anderson, L.A., Bernstein, L., Pharoah, P.D., Risch, H.A., Corley, D.A., Fitzgerald, R.C., Iyer, P.G., Reid, B.J., Lagergren, J., Shaheen, N.J., Vaughan, T.L., MacGregor, S., Love, S., Palles, C., Tomlinson, I., Gockel, I., May, A., Gerges, C., Anders, M., Bohmer, A.C., Becker, J., Kreuser, N., Thieme, R., Noder, T., Venerito, M., Veits, L., Schmidt, T., Schmidt, C., Izbicki, J.R., Holscher, A.H., Lang, H., Lorenz, D., Schumacher, B., Mayershofer, R., Vashist, Y., Ott, K., Vieth, M., Weismuller, J., Nothen, M.M., Moebus, S., Knapp, M., Peters, W.H.M., Neuhaus, H., Rosch, T., Ell, C., Jankowski, J., Schumacher, J., Neale, R.E., Whiteman, D.C., Thrift, A.P., Dong, J., Gharahkhani, P., Chow, W.H., Gammon, M.D., Liu, G., Caldas, C., Wu, A.H., Ye, W., Onstad, L., Anderson, L.A., Bernstein, L., Pharoah, P.D., Risch, H.A., Corley, D.A., Fitzgerald, R.C., Iyer, P.G., Reid, B.J., Lagergren, J., Shaheen, N.J., Vaughan, T.L., MacGregor, S., Love, S., Palles, C., Tomlinson, I., Gockel, I., May, A., Gerges, C., Anders, M., Bohmer, A.C., Becker, J., Kreuser, N., Thieme, R., Noder, T., Venerito, M., Veits, L., Schmidt, T., Schmidt, C., Izbicki, J.R., Holscher, A.H., Lang, H., Lorenz, D., Schumacher, B., Mayershofer, R., Vashist, Y., Ott, K., Vieth, M., Weismuller, J., Nothen, M.M., Moebus, S., Knapp, M., Peters, W.H.M., Neuhaus, H., Rosch, T., Ell, C., Jankowski, J., Schumacher, J., Neale, R.E., Whiteman, D.C., and Thrift, A.P.

Abstract

Contains fulltext : 215282.pdf (publisher's version ) (Closed access), BACKGROUND & AIMS: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. RESULTS: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18). CONCLUSIONS: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC.

Published
2019

10. Effect of time to diagnostic testing for breast, cervical, and colorectal cancer screening abnormalities on screening efficacy: A modeling study

Author

Rutter, C.M. (Carolyn), Kim, J.J. (Jane J.), Meester, R.G.S. (Reinier), Sprague, B.L. (Brian), Burger, E.A. (Emily A.), Zauber, A.G. (Ann), Ergun, M.A. (Mehmet Ali), Campos, N.G. (Nicole G.), Doubeni, C.A. (Chyke A.), Trentham-Dietz, A. (Amy), Sy, S., Alagoz, O. (Oguzhan), Stout, N.K. (Natasha), Lansdorp-Vogelaar, I. (Iris), Corley, D.A. (Douglas), Tosteson, A.N.A. (Anna), Rutter, C.M. (Carolyn), Kim, J.J. (Jane J.), Meester, R.G.S. (Reinier), Sprague, B.L. (Brian), Burger, E.A. (Emily A.), Zauber, A.G. (Ann), Ergun, M.A. (Mehmet Ali), Campos, N.G. (Nicole G.), Doubeni, C.A. (Chyke A.), Trentham-Dietz, A. (Amy), Sy, S., Alagoz, O. (Oguzhan), Stout, N.K. (Natasha), Lansdorp-Vogelaar, I. (Iris), Corley, D.A. (Douglas), and Tosteson, A.N.A. (Anna)

Abstract

Background: Patients who receive an abnormal cancer screening result require follow-up for diagnostic testing, but the time to follow-up varies across patients and practices. Methods: We used a simulation study to estimate the change in lifetime screening benefits when time to follow-up for breast, cervical, and colorectal cancers was increased. Estimates were based on four independently developed microsimulation models that each simulated the life course of adults eligible for breast (women ages 50–74 years), cervical (women ages 21–65 years), or colorectal (adults ages 50–75 years) cancer screening. We assumed screening based on biennial mammography for breast cancer, triennial Papanicolaou testing for cervical cancer, and annual fecal immunochemical testing for colorectal cancer. For each cancer type, we simulated diagnostic testing immediately and at 3, 6, and 12 months after an abnormal screening exam. Results: We found declines in screening benefit with longer times to diagnostic testing, particularly for breast cancer screening. Compared to immediate diagnostic testing, testing at 3 months resulted in reduced screening benefit, with fewer undiscounted life years gained per 1,000 screened (breast: 17.3%, cervical: 0.8%, colorectal: 2.0% and 2.7%, from two colorectal cancer models), fewer cancers prevented (cervical: 1.4% fewer, colorectal: 0.5% and 1.7% fewer, respectively), and, for breast and colorectal cancer, a less favorable stage distribution. Conclusions: Longer times to diagnostic testing after an abnormal screening test can decrease screening effectiveness, but the impact varies substantially by cancer type. Impact: Understanding the impact of time to diagnostic testing on screening effectiveness can help inform quality improvement efforts. Cancer Epidemiol Biomarkers Prev; 27(2); 158–64. 2017 AACR.

Published
2018
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12. Reproductive and sex hormonal factors and oesophageal and gastric junction adenocarcinoma: A pooled analysis

Author

Cronin-Fenton, D.P., Murray, Liam, Whiteman, D.C., Cardwell, Christopher, Webb, P.M., Jordan, S.J., Corley, D.A., Sharp, L., Lagergren, J., and Investigators, B.E.A.C.O.N.

Subjects
Adult, Cancer Research, medicine.medical_specialty, Esophageal Neoplasms, Hormone Replacement Therapy, Population, Adenocarcinoma, Gastroenterology, Article, Risk Factors, Internal medicine, Humans, Medicine, Gonadal Steroid Hormones, education, Stomach cancer, Aged, Pregnancy, education.field_of_study, business.industry, Incidence (epidemiology), Case-control study, Odds ratio, Middle Aged, medicine.disease, digestive system diseases, Breast Feeding, Oncology, Case-Control Studies, Female, Esophagogastric Junction, business, Breast feeding
Abstract

Udgivelsesdato: 2010-Jul BACKGROUND: The rapidly rising incidence and the striking male predominance are as yet unexplained features of oesophageal and gastric junction adenocarcinoma. Few and underpowered studies have examined the impact of female reproductive factors on risk of these adenocarcinomas in women. We therefore pooled data on women from four population-based case-control studies to examine the association of female reproductive and sex hormonal factors with oesophageal and gastric junction adenocarcinoma. METHODS: Data on women from case-control studies conducted in Ireland, the United Kingdom (UK), Australia and United States of America (USA) were pooled. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for a range of reproductive factors, adjusted for age, study and major risk factors for oesophageal and gastric junction adenocarcinoma. RESULTS: We included 218 cases and 862 controls. Among parous women, a reduced risk of oesophageal and gastric junction adenocarcinoma was found after breastfeeding (OR=0.58, 95% CI=0.37-0.92) and the risk decreased with increased duration of breastfeeding (>12 months OR=0.42, 95% CI=0.23-0.77). The endogenous reproductive factors such as parity, menstruation, history of pregnancy and the exogenous factors such as use of oral contraceptives and of hormone replacement therapy were not statistically significantly associated with oesophageal and gastric junction adenocarcinoma. CONCLUSION: Our findings suggest that breastfeeding is associated with a decreased risk of oesophageal and gastric junction adenocarcinoma. The potential mechanism of this association warrants further investigation.

Published
2010

13. Race/Ethnicity and Adoption of a Population Health Management Approach to Colorectal Cancer Screening in a Community-Based Healthcare System

Author

Mehta, S.J. (Shivan J.), Jensen, C.D. (Christopher D.), Quinn, V.P. (Virginia P.), Schottinger, J.E. (Joanne E.), Zauber, A. (Ann), Meester, R.G.S. (Reinier), Laiyemo, A.O. (Adeyinka O.), Fedewa, S. (Stacey), Goodman, M. (Michael), Fletcher, R.H. (Robert H.), Levin, T.R. (Theodore R.), Corley, D.A. (Douglas), Doubeni, C.A. (Chyke A.), Mehta, S.J. (Shivan J.), Jensen, C.D. (Christopher D.), Quinn, V.P. (Virginia P.), Schottinger, J.E. (Joanne E.), Zauber, A. (Ann), Meester, R.G.S. (Reinier), Laiyemo, A.O. (Adeyinka O.), Fedewa, S. (Stacey), Goodman, M. (Michael), Fletcher, R.H. (Robert H.), Levin, T.R. (Theodore R.), Corley, D.A. (Douglas), and Doubeni, C.A. (Chyke A.)

Abstract

Background: Screening outreach programs using population health management principles offer services uniformly to all eligible persons, but racial/ethnic colorectal cancer (CRC) screening patterns in such programs are not well known. Objective: To examine the association between race/ethnicity and the receipt of CRC screening and timely follow-up of positive results before and after implementation of a screening program. Design: Retrospective cohort study of screen-eligible individuals at the Kaiser Permanente Northern California community-based integrated healthcare delivery system (2004–2013). Subjects: A total of 868,934 screen-eligible individuals 51–74 years of age at cohort entry, which included 662,872 persons in the period before program implementation (2004–2006), 654,633 during the first 3 years after implementation (2007–2009), and 665,268 in the period from 4 to 7 years (2010–2013) after program implementation. Intervention: A comprehensive system-wide long-term effort to increase CRC that included leadership alignment, goal-setting, and quality assurance through a PHM approach, using mailed fecal immunochemical testing (FIT) along with offering screening at office visits. Main Measures: Differences over time and by race/ethnicity in up-to-date CRC screening (overall and by test type) and timely follow-up of a positive screen. Race/ethnicity categories included non-Hispanic white, non-Hispanic black, Hispanic/Latino, Asian/Pacific Islander, Native American, and multiple races. Key Results: From 2004 to 2013, age/sex-adjusted CRC screening rates increased in all groups, including 35.2 to 81.1 % among whites and 35.6 to 78.0 % among blacks. Screening rates among Hispanics (33.1 to 78.3 %) and Native Americans (29.4 to 74.5 %) remained lower than those for whites both before and after program implementation. Blacks, who had slightly higher rates before program implementation (adjusted rate ratio [RR] = 1.04, 99 % CI: 1.02–1.05), had lower rates after progra

Published
2016
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14. 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

15. BOB CAT: A Large-Scale Review and Delphi Consensus for Management of Barrett's Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia

Author

Bennett, C., Moayyedi, P., Corley, D.A., DeCaestecker, J., Falck-Ytter, Y., Falk, G., Vakil, N., Sanders, S., Vieth, M., Inadomi, J., Aldulaimi, D., Ho, K.Y., Odze, R., Meltzer, S.J., Quigley, E., Gittens, S., Watson, P., Zaninotto, G., Iyer, P.G., Alexandre, L., Ang, Y., Callaghan, J., Harrison, R., Singh, R., Bhandari, P., Bisschops, R., Geramizadeh, B., Kaye, P., Krishnadath, S., Fennerty, M.B., Manner, H., Nason, K.S., Pech, O., Konda, V., Ragunath, K., Rahman, I., Romero, Y., Sampliner, R., Siersema, P.D., Tack, J., Tham, T.C., Trudgill, N., Weinberg, D.S., Wang, J, Wang, K., Wong, J.Y., Attwood, S., Malfertheiner, P., MacDonald, D., Barr, H., Ferguson, M.K., Jankowski, J., Bennett, C., Moayyedi, P., Corley, D.A., DeCaestecker, J., Falck-Ytter, Y., Falk, G., Vakil, N., Sanders, S., Vieth, M., Inadomi, J., Aldulaimi, D., Ho, K.Y., Odze, R., Meltzer, S.J., Quigley, E., Gittens, S., Watson, P., Zaninotto, G., Iyer, P.G., Alexandre, L., Ang, Y., Callaghan, J., Harrison, R., Singh, R., Bhandari, P., Bisschops, R., Geramizadeh, B., Kaye, P., Krishnadath, S., Fennerty, M.B., Manner, H., Nason, K.S., Pech, O., Konda, V., Ragunath, K., Rahman, I., Romero, Y., Sampliner, R., Siersema, P.D., Tack, J., Tham, T.C., Trudgill, N., Weinberg, D.S., Wang, J, Wang, K., Wong, J.Y., Attwood, S., Malfertheiner, P., MacDonald, D., Barr, H., Ferguson, M.K., and Jankowski, J.

Abstract

Item does not contain fulltext, OBJECTIVES: Barrett's esophagus (BE) is a common premalignant lesion for which surveillance is recommended. This strategy is limited by considerable variations in clinical practice. We conducted an international, multidisciplinary, systematic search and evidence-based review of BE and provided consensus recommendations for clinical use in patients with nondysplastic, indefinite, and low-grade dysplasia (LGD). METHODS: We defined the scope, proposed statements, and searched electronic databases, yielding 20,558 publications that were screened, selected online, and formed the evidence base. We used a Delphi consensus process, with an 80% agreement threshold, using GRADE (Grading of Recommendations Assessment, Development and Evaluation) to categorize the quality of evidence and strength of recommendations. RESULTS: In total, 80% of respondents agreed with 55 of 127 statements in the final voting rounds. Population endoscopic screening is not recommended and screening should target only very high-risk cases of males aged over 60 years with chronic uncontrolled reflux. A new international definition of BE was agreed upon. For any degree of dysplasia, at least two specialist gastrointestinal (GI) pathologists are required. Risk factors for cancer include male gender, length of BE, and central obesity. Endoscopic resection should be used for visible, nodular areas. Surveillance is not recommended for <5 years of life expectancy. Management strategies for indefinite dysplasia (IND) and LGD were identified, including a de-escalation strategy for lower-risk patients and escalation to intervention with follow-up for higher-risk patients. CONCLUSIONS: In this uniquely large consensus process in gastroenterology, we made key clinical recommendations for the escalation/de-escalation of BE in clinical practice. We made strong recommendations for the prioritization of future research.

Published
2015

16. Public health impact of achieving 80% colorectal cancer screening rates in the United States by 2018

Author

Meester, R.G.S. (Reinier), Doubeni, C.A. (Chyke A.), Zauber, A.G. (Ann), Goede, S.L. (Luuk), Levin, T.R. (Theodore R.), Corley, D.A. (Douglas), Jemal, A. (Ahmedin), Lansdorp-Vogelaar, I. (Iris), Meester, R.G.S. (Reinier), Doubeni, C.A. (Chyke A.), Zauber, A.G. (Ann), Goede, S.L. (Luuk), Levin, T.R. (Theodore R.), Corley, D.A. (Douglas), Jemal, A. (Ahmedin), and Lansdorp-Vogelaar, I. (Iris)

Abstract

BACKGROUND The National Colorectal Cancer Roundtable, a national coalition of public, private, and voluntary organizations, has recently announced an initiative to increase colorectal cancer (CRC) screening rates in the United States to 80% by 2018. The authors evaluated the potential public health benefits of achieving this goal. METHODS The authors simulated the 1980 through 2030 United States population of individuals aged 50 to 100 years using microsimulation modeling. Test-specific historical screening rates were based on National Health Interview Survey data for 1987 through 2013. The effects of increasing screening rates from approximately 58% in 2013 to 80% in 2018 were compared to a scenario in which the screening rate remained approximately constant. The outcomes were cancer incidence and mortality rates and numbers of CRC cases and deaths during short-term follow-up (2013-2020) and extended follow-up (2013-2030). RESULTS Increasing CRC screening rates to 80% by 2018 would reduce CRC incidence rates by 17% and mortality rates by 19% during short-term follow-up and by 22% and 33%, respectively, during extended follow-up. These reductions would amount to a total of 277,000 averted new cancers and 203,000 averted CRC deaths from 2013 through 2030. CONCLUSIONS Achieving the goal of increasing the uptake of CRC screening in the United States to 80% by 2018 may have a considerable public health impact by averting approximately 280,000 new cancer cases and 200,000 cancer deaths within <20 years. Cancer 2015;121:2281-2285.© 2015 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Published
2015
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17. Variation in adenoma detection rate and the lifetime benefits and cost of colorectal cancer screening: A microsimulation model

Author

Meester, R.G.S. (Reinier), Doubeni, C.A. (Chyke A.), Lansdorp-Vogelaar, I. (Iris), Jensen, C.D. (Christopher D.), Meulen, M.P. (Miriam) van der, Levin, T.R. (Theodore R.), Quinn, V.P. (Virginia P.), Schottinger, J.E. (Joanne E.), Zauber, A.G. (Ann), Corley, D.A. (Douglas), Ballegooijen, M. (Marjolein) van, Meester, R.G.S. (Reinier), Doubeni, C.A. (Chyke A.), Lansdorp-Vogelaar, I. (Iris), Jensen, C.D. (Christopher D.), Meulen, M.P. (Miriam) van der, Levin, T.R. (Theodore R.), Quinn, V.P. (Virginia P.), Schottinger, J.E. (Joanne E.), Zauber, A.G. (Ann), Corley, D.A. (Douglas), and Ballegooijen, M. (Marjolein) van

Abstract

Copyright

Published
2015
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18. Colorectal cancer deaths attributable to nonuse of screening in the United States

Author

Meester, R.G.S. (Reinier), Doubeni, C.A. (Chyke A.), Lansdorp-Vogelaar, I. (Iris), Goede, S.L. (S. Lucas), Levin, T.R. (Theodore R.), Quinn, V.P. (Virginia P.), Ballegooijen, M. (Marjolein) van, Corley, D.A. (Douglas), Zauber, A.G. (Ann), Meester, R.G.S. (Reinier), Doubeni, C.A. (Chyke A.), Lansdorp-Vogelaar, I. (Iris), Goede, S.L. (S. Lucas), Levin, T.R. (Theodore R.), Quinn, V.P. (Virginia P.), Ballegooijen, M. (Marjolein) van, Corley, D.A. (Douglas), and Zauber, A.G. (Ann)

Abstract

Purpose: Screening is a major contributor to colorectal cancer (CRC) mortality reductions in the United States but is underused. We estimated the fraction of CRC deaths attributable to nonuse of screening to demonstrate the potential benefits from targeted interventions. Methods: The established microsimulation screening analysis colon model was used to estimate the population attributable fraction (PAF) in people aged ≥50years. The model incorporates long-term patterns and effects of screening by age and type of screening test. PAF for 2010 was estimated using currently available data on screening uptake. PAF was also projected assuming constant future screening rates to incorporate lagged effects from past increases in screening uptake. We also computed PAF using Levin's formula to gauge how this simpler approach differs from the model-based approach. Results: There were an estimated 51,500 CRC deaths in 2010, about 63% (N ~ 32,200) of which were attributable to nonscreening. The PAF decreases slightly to 58% in 2020. Levin's approach yielded a considerably more conservative PAF of 46% (N ~ 23,600) for2010. Conclusions: Most of the current United States CRC deaths are attributable to nonscreening. This underscores the potential benefits of increasing screening uptake in the population. Traditional m

Published
2015
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19. Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus

Author

Palles, C. (Claire), Chegwidden, L. (Laura), Li, X. (Xinzhong), Findlay, J.M. (John M.), Farnham, G. (Garry), Castro Giner, F. (Francesc), Peppelenbosch, M.P. (Maikel), Kovac, M. (Michal), Adams, C.L. (Claire), Prenen, H. (Hans), Briggs, S. (Sarah), Harrison, R. (Rebecca), Sanders, S. (Scott), Macdonald, D.R.W. (David), Haigh, K. (Katharina), Tucker, A.T. (Art), Love, S. (Sharon), Nanji, M. (Manoj), Decaestecker, J. (John), Ferry, D.R. (David), Rathbone, B. (Barrie), Hapeshi, J. (Julie), Barr, H. (Hugh), Moayyedi, P. (Paul), Watson, P. (Peter), Zietek, B. (Barbara), Maroo, N. (Neera), Gay, L. (Laura), Underwood, T. (Tim), Boulter, L. (Lisa), McMurtry, H. (Hugh), Monk, A.B. (Alastair), Patel, P. (Poulam), Ragunath, K. (Krish), Al Dulaimi, D. (David), Murray, I. (Iain), Koss, C. (Clara), Veitch, A. (Andrew), Trudgill, N. (Nigel), Nwokolo, C. (Chuka), Rembacken, B., Atherfold, P. (Paul), Green, E.K. (Elaine K), Ang, Y. (Yeng), Kuipers, E.J. (Ernst), Chow, W. (Wu), Paterson, S. (Stuart), Kadri, S. (Sudarshan), Beales, I. (Ian), Grimley, C. (Charles), Mullins, P. (Paul), Beckett, C. (Conrad), Farrant, M. (Mark), Dixon, A. (Andrew), Kelly, S. (Sean), Johnson, M. (Matthew), Wajed, S. (Shahjehan), Dhar, A. (Archana), Sawyer, E.J. (Elinor), Roylance, R. (Rebecca), Onstad, L. (Lynn), Gammon, M.D. (Marilie), Corley, D.A. (Douglas), Shaheen, N. (Nazima), Bird, N.C. (Nigel), Hardie, B.G.S. (Bruce), Reid, B.J. (Brian), Ye, W. (Weimin), Liu, G. (Geoffrey), Romero, Y. (Yvonne), Bernstein, L. (Leslie), Wu, A.H. (Anna H.), Casson, A.G. (Alan), Fitzgerald, R.C. (Rebecca), Whiteman, D.C. (David C.), Risch, H. (Harvey), Levine, D.M. (David M.), Vaughan, T.L. (Thomas), Verhaar, A.P. (Auke), Van Den Brande, J. (Jan), Toxopeus, E.L.A. (Eelke), Spaander, M.C.W. (Manon), Wijnhoven, B.P.L. (Bas), Laan, L.J.W. (Luc) van der, Krishnadath, K.K. (Kausilia), Wijmenga, C. (Cisca), Trynka, G. (Gosia), McManus, R. (Ross), Reynolds, J.V. (John V.), O'Sullivan, J. (Jacintha), Macmathuna, P. (Padraic), McGarrigle, S.A. (Sarah A.), Kelleher, D. (Dermot), Vermeire, S. (Séverine), Cleynen, I. (Isabelle), Bisschops, R. (Raf), Tomlinson, I.P. (Ian), Jankowski, J.A. (Janusz Antoni), Palles, C. (Claire), Chegwidden, L. (Laura), Li, X. (Xinzhong), Findlay, J.M. (John M.), Farnham, G. (Garry), Castro Giner, F. (Francesc), Peppelenbosch, M.P. (Maikel), Kovac, M. (Michal), Adams, C.L. (Claire), Prenen, H. (Hans), Briggs, S. (Sarah), Harrison, R. (Rebecca), Sanders, S. (Scott), Macdonald, D.R.W. (David), Haigh, K. (Katharina), Tucker, A.T. (Art), Love, S. (Sharon), Nanji, M. (Manoj), Decaestecker, J. (John), Ferry, D.R. (David), Rathbone, B. (Barrie), Hapeshi, J. (Julie), Barr, H. (Hugh), Moayyedi, P. (Paul), Watson, P. (Peter), Zietek, B. (Barbara), Maroo, N. (Neera), Gay, L. (Laura), Underwood, T. (Tim), Boulter, L. (Lisa), McMurtry, H. (Hugh), Monk, A.B. (Alastair), Patel, P. (Poulam), Ragunath, K. (Krish), Al Dulaimi, D. (David), Murray, I. (Iain), Koss, C. (Clara), Veitch, A. (Andrew), Trudgill, N. (Nigel), Nwokolo, C. (Chuka), Rembacken, B., Atherfold, P. (Paul), Green, E.K. (Elaine K), Ang, Y. (Yeng), Kuipers, E.J. (Ernst), Chow, W. (Wu), Paterson, S. (Stuart), Kadri, S. (Sudarshan), Beales, I. (Ian), Grimley, C. (Charles), Mullins, P. (Paul), Beckett, C. (Conrad), Farrant, M. (Mark), Dixon, A. (Andrew), Kelly, S. (Sean), Johnson, M. (Matthew), Wajed, S. (Shahjehan), Dhar, A. (Archana), Sawyer, E.J. (Elinor), Roylance, R. (Rebecca), Onstad, L. (Lynn), Gammon, M.D. (Marilie), Corley, D.A. (Douglas), Shaheen, N. (Nazima), Bird, N.C. (Nigel), Hardie, B.G.S. (Bruce), Reid, B.J. (Brian), Ye, W. (Weimin), Liu, G. (Geoffrey), Romero, Y. (Yvonne), Bernstein, L. (Leslie), Wu, A.H. (Anna H.), Casson, A.G. (Alan), Fitzgerald, R.C. (Rebecca), Whiteman, D.C. (David C.), Risch, H. (Harvey), Levine, D.M. (David M.), Vaughan, T.L. (Thomas), Verhaar, A.P. (Auke), Van Den Brande, J. (Jan), Toxopeus, E.L.A. (Eelke), Spaander, M.C.W. (Manon), Wijnhoven, B.P.L. (Bas), Laan, L.J.W. (Luc) van der, Krishnadath, K.K. (Kausilia), Wijmenga, C. (Cisca), Trynka, G. (Gosia), McManus, R. (Ross), Reynolds, J.V. (John V.), O'Sullivan, J. (Jacintha), Macmathuna, P. (Padraic), McGarrigle, S.A. (Sarah A.), Kelleher, D. (Dermot), Vermeire, S. (Séverine), Cleynen, I. (Isabelle), Bisschops, R. (Raf), Tomlinson, I.P. (Ian), and Jankowski, J.A. (Janusz Antoni)

Abstract

Background & Aims Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. Methods We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. Results We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10-11) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10-9). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10-9). Conclusions We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

Published
2015
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20. 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

21. Improvement of gastroesophageal reflux symptoms after radiofrequency energy: a randomized, sham-controlled trial

Author

Corley, D.A., Katz, P., Wo, J.M., Stefan, A., Patti, M., Rothstein, R., Edmundowicz, S., Kline, M., Mason, R., and Wolfe, M.

Abstract

Background & Aims: Gastroesophageal reflux disease is a prevalent disorder that often requires long-term medical therapy or surgery. The United States Food and Drug Administration recently cleared new endoluminal gastroesophageal reflux disease treatments; however, no controlled trials exist. Methods: We randomly assigned 64 gastroesophageal reflux disease patients to radiofrequency energy delivery to the gastroesophageal junction (35 patients) or to a sham procedure (29 patients). Principal outcomes were reflux symptoms and quality of life. Secondary outcomes were medication use and esophageal acid exposure. After 6 months, interested sham patients crossed over to active treatment. Results: At 6 months, active treatment significantly and substantially improved patients' heartburn symptoms and quality of life. More active vs. sham patients were without daily heartburn symptoms (n = 19 [61%] vs. n = 7 [33%]; P = 0.05), and more had a >50% improvement in their gastroesophageal reflux disease quality of life score (n = 19 [61%] vs. n = 6 [30%]; P = 0.03). Symptom improvements persisted at 12 months after treatment. At 6 months, there were no differences in daily medication use after a medication withdrawal protocol (n = 17 [55%] vs. n = 14 [61%]; P = 0.67) or in esophageal acid exposure times. There were no perforations or deaths. Conclusions: Radiofrequency energy delivery significantly improved gastroesophageal reflux disease symptoms and quality of life compared with a sham procedure, but it did not decrease esophageal acid exposure or medication use at 6 months. This procedure represents a new option for selected symptomatic gastroesophageal reflux disease patients who are intolerant of, or desire an alternative to, traditional medical therapies.

Published
2003
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22. The Stretta procedure for the treatment of GERD: 6 and 12 month follow-up of the U.S. open label trial

Author

Triadafilopoulos, G., DiBaise, J.K., Nostrant, T.T., Stollman, N.H., Anderson, P.K., Wolfe, M.M., Rothstein, R.I., Wo, J.M., Corley, D.A., Patti, M.G., Antignano, L.V., Goff, J.S., Edmundowicz, S.A., Castell, D.O., Rabine, J.C., Kim, M.S., and Utley, D.S.

Abstract

Background: This multicenter prospective study investigated the longer-term (12 month) safety and efficacy of radiofrequency energy delivery for the treatment of GERD. Methods: A prospective study was conducted of 118 patients with chronic heartburn and/or regurgitation who required antisecretory medication daily and had demonstrated pathologic esophageal acid exposure, a sliding hiatal hernia (=<2 cm), and esophagitis (=< grade 2). RF energy was delivered with the Stretta catheter and thermocouple-controlled generator to create thermal lesions below the mucosa at the gastroesophageal junction. GERD symptom scores, quality of life (SF-36), and medication use were assessed at 0, 1, 4, 6, and 12 months; esophageal acid exposure, motility, and endoscopy were assessed at 0 and 6 months. Results: Seventy-two men and 46 women were treated. At 12 months, 94 patients were available for follow-up. There were improvements after 12 months in the median heartburn score (4 to 1, p = 0.0001), GERD score (27 to 9, p = 0.0001), satisfaction (1 to 4, p = 0.0001), mental SF-36 (46.3 to 55.4, p < 0.0001), and physical SF-36 (40.9 to 53.1, p = 0.0001); proton pump inhibitor requirement fell from 88.1% to 30% of patients. Esophageal acid exposure improved significantly (10.2% to 6.4%, p = 0.0001). There were 10 (8.6%) complications, none of which required therapeutic intervention. Conclusion: The Stretta procedure significantly improves GERD symptoms, quality of life, and esophageal acid exposure and eliminates the need for antisecretory medication in the majority of patients at 12 months. (Gastrointest Endosc 2002;55:149-56.)

Published
2002
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