Abstract
Background & Aims: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)—nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations. Methods: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels. Results: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10 –8 . We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%–75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci. Conclusions: We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1455-1466 |
| Number of pages | 12 |
| Journal | Gastroenterology |
| Volume | 156 |
| Issue number | 5 |
| DOIs | |
| State | Published - Apr 2019 |
| Externally published | Yes |
Keywords
- Colon Cancer
- Epidemiology
- Genetic Variants
- Immunology
ASJC Scopus subject areas
- Hepatology
- Gastroenterology
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Large-Scale Genome-Wide Association Study of East Asians Identifies Loci Associated With Risk for Colorectal Cancer. / Lu, Yingchang; Kweon, Sun Seog; Tanikawa, Chizu et al.
In: Gastroenterology, Vol. 156, No. 5, 04.2019, p. 1455-1466.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Large-Scale Genome-Wide Association Study of East Asians Identifies Loci Associated With Risk for Colorectal Cancer
AU - Lu, Yingchang
AU - Kweon, Sun Seog
AU - Tanikawa, Chizu
AU - Jia, Wei Hua
AU - Xiang, Yong Bing
AU - Cai, Qiuyin
AU - Zeng, Chenjie
AU - Schmit, Stephanie L.
AU - Shin, Aesun
AU - Matsuo, Keitaro
AU - Jee, Sun Ha
AU - Kim, Dong Hyun
AU - Kim, Jeongseon
AU - Wen, Wanqing
AU - Shi, Jiajun
AU - Guo, Xingyi
AU - Li, Bingshan
AU - Wang, Nan
AU - Zhang, Ben
AU - Li, Xinxiang
AU - Shin, Min Ho
AU - Li, Hong Lan
AU - Ren, Zefang
AU - Oh, Jae Hwan
AU - Oze, Isao
AU - Ahn, Yoon Ok
AU - Jung, Keum Ji
AU - Conti, David V.
AU - Schumacher, Fredrick R.
AU - Rennert, Gad
AU - Jenkins, Mark A.
AU - Campbell, Peter T.
AU - Hoffmeister, Michael
AU - Casey, Graham
AU - Gruber, Stephen B.
AU - Gao, Jing
AU - Gao, Yu Tang
AU - Pan, Zhi Zhong
AU - Kamatani, Yoichiro
AU - Zeng, Yi Xin
AU - Shu, Xiao Ou
AU - Long, Jirong
AU - Matsuda, Koichi
AU - Zheng, Wei
N1 - Funding Information: Funding The work at Vanderbilt University Medical Center was supported by US National Institutes of Health (NIH) grants R01CA188214, R37CA070867, R01CA124558, R01CA158473, and R01CA148667, as well as Anne Potter Wilson Chair funds from the Vanderbilt University School of Medicine. Sample preparation and genotyping assays at Vanderbilt University were conducted at the Survey and Biospecimen Shared Resources and Vanderbilt Microarray Shared Resource, which are supported in part by the Vanderbilt-Ingram Cancer Center (P30CA068485). Imputation and statistical analyses were performed on servers maintained by the Advanced Computing Center for Research and Education at Vanderbilt University.Studies (grant support) participating in the Asia Colorectal Cancer Consortium include the Shanghai Women's Health Study (US NIH R37CA070867 and UM1CA182910), the Shanghai Men's Health Study (US NIH R01CA082729 and UM1CA173640), the Shanghai Breast and Endometrial Cancer Studies (US NIH R01CA064277 and R01CA092585, contributing only controls), the Shanghai Colorectal Cancer Study 3 (US NIH R37CA070867 and R01CA188214 and Anne Potter Wilson Chair funds), the Guangzhou Colorectal Cancer Study (National Key Scientific and Technological Project 2011ZX09307-001-04; the National Basic Research Program 2011CB504303, contributing only controls; and the Natural Science Foundation of China 81072383, contributing only controls), the Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (grants from Chonnam National University Hwasun Hospital Biomedical Research Institute (HCRI18007), the Japan BioBank Colorectal Cancer Study (grant from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government), the Aichi Colorectal Cancer Study (Grant-in-Aid for Cancer Research, grant for the Third Term Comprehensive Control Research for Cancer, and Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology 17015018 and 221S0001), the Korea–National Cancer Center Colorectal Cancer Study (Basic Science Research Program through the National Research Foundation of Korea 2010-0010276 and 2013R1A1A2A10008260 and National Cancer Center Korea 0910220), and the Korean Cancer Prevention Study-II Colorectal Cancer Study (National R&D Program for Cancer Control 1631020 and Seoul R&D Program 10526). Funding The work at Vanderbilt University Medical Center was supported by US National Institutes of Health (NIH) grants R01CA188214, R37CA070867, R01CA124558, R01CA158473, and R01CA148667, as well as Anne Potter Wilson Chair funds from the Vanderbilt University School of Medicine. Sample preparation and genotyping assays at Vanderbilt University were conducted at the Survey and Biospecimen Shared Resources and Vanderbilt Microarray Shared Resource, which are supported in part by the Vanderbilt-Ingram Cancer Center (P30CA068485). Imputation and statistical analyses were performed on servers maintained by the Advanced Computing Center for Research and Education at Vanderbilt University. Studies (grant support) participating in the Asia Colorectal Cancer Consortium include the Shanghai Women's Health Study (US NIH R37CA070867 and UM1CA182910), the Shanghai Men's Health Study (US NIH R01CA082729 and UM1CA173640), the Shanghai Breast and Endometrial Cancer Studies (US NIH R01CA064277 and R01CA092585, contributing only controls), the Shanghai Colorectal Cancer Study 3 (US NIH R37CA070867 and R01CA188214 and Anne Potter Wilson Chair funds), the Guangzhou Colorectal Cancer Study (National Key Scientific and Technological Project 2011ZX09307-001-04; the National Basic Research Program 2011CB504303, contributing only controls; and the Natural Science Foundation of China 81072383, contributing only controls), the Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (grants from Chonnam National University Hwasun Hospital Biomedical Research Institute (HCRI18007), the Japan BioBank Colorectal Cancer Study (grant from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government), the Aichi Colorectal Cancer Study (Grant-in-Aid for Cancer Research, grant for the Third Term Comprehensive Control Research for Cancer, and Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology 17015018 and 221S0001), the Korea–National Cancer Center Colorectal Cancer Study (Basic Science Research Program through the National Research Foundation of Korea 2010-0010276 and 2013R1A1A2A10008260 and National Cancer Center Korea 0910220), and the Korean Cancer Prevention Study-II Colorectal Cancer Study (National R&D Program for Cancer Control 1631020 and Seoul R&D Program 10526). Participating studies (grant support) in the GECCO, CORECT, and CCFR genome-wide association study meta-analysis are GECCO (US NIH U01CA137088 and R01CA059045), DALS (US NIH R01CA048998), DACHS (German Federal Ministry of Education and Research BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, 01KH0404, and 01ER0814), HPFS (P01 CA 055075, UM1 CA167552, R01 137178, R01 CA151993, and P50 CA127003), NHS (UM1 CA186107, R01 CA137178, P01 CA87969, R01 CA151993, and P50 CA127003), OFCCR (US NIH U01CA074783), PMH (US NIH R01CA076366), PHS (US NIH R01CA042182), VITAL (US NIH K05CA154337), WHI (US NIH HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C) and PLCO (US NIH Z01CP 010200, U01HG004446, and U01HG 004438). CORECT is supported by the National Cancer Institute as part of the GAME-ON consortium (US NIH U19CA148107), with additional support from National Cancer Institute grants (R01CA81488 and P30CA014089), the National Human Genome Research Institute at the US NIH (T32HG000040), and the National Institute of Environmental Health Sciences at the US NIH (T32ES013678). CCFR is supported by the National Cancer Institute, the US NIH under RFA CA-95-011, and through cooperative agreements with members of the Colon Cancer Family Registry and principal investigators of the Australasian Colorectal Cancer Family Registry (US NIH U01CA097735), the Familial Colorectal Neoplasia Collaborative Group (US NIH U01CA074799; University of Southern California), the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (US NIH U01CA074800), the Ontario Registry for Studies of Familial Colorectal Cancer (US NIH U01CA074783), the Seattle Colorectal Cancer Family Registry (US NIH U01CA074794), and the University of Hawaii Colorectal Cancer Family Registry (US NIH, U01CA074806). The genome-wide association study work was supported by a National Cancer Institute grant (US NIH U01CA122839). OFCCR was supported by a GL2 grant from the Ontario Research Fund, Canadian Institutes of Health Research, and a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. ASTERISK was funded by a Regional Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique, and the Ligue Régionale Contre le Cancer (LRCC). The authors thank all study participants and the research staff of all parent studies for their contributions and commitment to this project. The authors thank Vanderbilt staff members Jing He for data processing and analyses and Marshal Younger for editing and preparing the manuscript. Author contributions: Wei Zheng conceived and directed the Asia Colorectal Cancer Consortium and the Shanghai-Vanderbilt Colorectal Cancer Genetics Project. Koichi Matsuda, Chizu Tanikawa, and Yoichiro Kamatani directed the BioBank Japan Colorectal Cancer Study. Wei Zheng, Xiao-Ou Shu, and Yong-Bing Xiang directed the Shanghai Study. Wei-Hua Jia, Zefang Ren, Yi-Xin Zeng, and Zhi-Zhong Pan directed the Guangzhou Colorectal Cancer Study. Keitaro Matsuo and Isao Oze directed the Aichi Colorectal Cancer Study. Dong-Hyun Kim and Yoon-Ok Ahn directed the KCPS-II Colorectal Cancer Study. Sun-Seog Kweon and Min-Ho Shin directed the Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (HCES-CRC). Aesun Shin, Jae Hwan Oh, and Jeongseon Kim directed the Korea-NCC (National Cancer Center) Colorectal Cancer Study. Keum Ji Jung and Sun Ha Jee directed the Seoul Colorectal Cancer Study. Stephanie L. Schmit, David V. Conti, Stephen B. Gruber, Fredrick R. Schumacher, Gad Rennert, Graham Casey, Mark A. Jenkins, Peter T. Campbell, and Michael Hoffmeister were involved in genetic association analyses in European populations. Qiuyin Cai directed laboratory operations. Jiajun Shi and Nan Wang performed the genotyping experiments. Yingchang Lu performed the statistical and bioinformatics analyses. Wanqing Wen and Bingshan Li contributed to the statistical analyses and data interpretation. Yingchang Lu, Wanqing Wen, and Jirong Long managed the data. Yingchang Lu, Wanqing Wen, and Xingyi Guo performed the expression analysis. Yingchang Lu and Wei Zheng wrote the manuscript with significant contributions from Xiao-Ou Shu, Qiuyin Cai, Jirong Long, Wanqing Wen, and Chenjie Zeng. All authors contributed to data and biological sample collection in the original studies included in this project and to manuscript revision. All authors have reviewed and approved the content of the article. Funding The work at Vanderbilt University Medical Center was supported by US National Institutes of Health (NIH) grants R01CA188214, R37CA070867, R01CA124558, R01CA158473, and R01CA148667, as well as Anne Potter Wilson Chair funds from the Vanderbilt University School of Medicine. Sample preparation and genotyping assays at Vanderbilt University were conducted at the Survey and Biospecimen Shared Resources and Vanderbilt Microarray Shared Resource, which are supported in part by the Vanderbilt-Ingram Cancer Center (P30CA068485). Imputation and statistical analyses were performed on servers maintained by the Advanced Computing Center for Research and Education at Vanderbilt University. Studies (grant support) participating in the Asia Colorectal Cancer Consortium include the Shanghai Women's Health Study (US NIH R37CA070867 and UM1CA182910), the Shanghai Men's Health Study (US NIH R01CA082729 and UM1CA173640), the Shanghai Breast and Endometrial Cancer Studies (US NIH R01CA064277 and R01CA092585, contributing only controls), the Shanghai Colorectal Cancer Study 3 (US NIH R37CA070867 and R01CA188214 and Anne Potter Wilson Chair funds), the Guangzhou Colorectal Cancer Study (National Key Scientific and Technological Project 2011ZX09307-001-04; the National Basic Research Program 2011CB504303, contributing only controls; and the Natural Science Foundation of China 81072383, contributing only controls), the Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (grants from Chonnam National University Hwasun Hospital Biomedical Research Institute (HCRI18007), the Japan BioBank Colorectal Cancer Study (grant from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government), the Aichi Colorectal Cancer Study (Grant-in-Aid for Cancer Research, grant for the Third Term Comprehensive Control Research for Cancer, and Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology 17015018 and 221S0001), the Korea–National Cancer Center Colorectal Cancer Study (Basic Science Research Program through the National Research Foundation of Korea 2010-0010276 and 2013R1A1A2A10008260 and National Cancer Center Korea 0910220), and the Korean Cancer Prevention Study-II Colorectal Cancer Study (National R&D Program for Cancer Control 1631020 and Seoul R&D Program 10526). Participating studies (grant support) in the GECCO, CORECT, and CCFR genome-wide association study meta-analysis are GECCO (US NIH U01CA137088 and R01CA059045), DALS (US NIH R01CA048998), DACHS (German Federal Ministry of Education and Research BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, 01KH0404, and 01ER0814), HPFS (P01 CA 055075, UM1 CA167552, R01 137178, R01 CA151993, and P50 CA127003), NHS (UM1 CA186107, R01 CA137178, P01 CA87969, R01 CA151993, and P50 CA127003), OFCCR (US NIH U01CA074783), PMH (US NIH R01CA076366), PHS (US NIH R01CA042182), VITAL (US NIH K05CA154337), WHI (US NIH HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C) and PLCO (US NIH Z01CP 010200, U01HG004446, and U01HG 004438). CORECT is supported by the National Cancer Institute as part of the GAME-ON consortium (US NIH U19CA148107), with additional support from National Cancer Institute grants (R01CA81488 and P30CA014089), the National Human Genome Research Institute at the US NIH (T32HG000040), and the National Institute of Environmental Health Sciences at the US NIH (T32ES013678). CCFR is supported by the National Cancer Institute, the US NIH under RFA CA-95-011, and through cooperative agreements with members of the Colon Cancer Family Registry and principal investigators of the Australasian Colorectal Cancer Family Registry (US NIH U01CA097735), the Familial Colorectal Neoplasia Collaborative Group (US NIH U01CA074799; University of Southern California), the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (US NIH U01CA074800), the Ontario Registry for Studies of Familial Colorectal Cancer (US NIH U01CA074783), the Seattle Colorectal Cancer Family Registry (US NIH U01CA074794), and the University of Hawaii Colorectal Cancer Family Registry (US NIH, U01CA074806). The genome-wide association study work was supported by a National Cancer Institute grant (US NIH U01CA122839). OFCCR was supported by a GL2 grant from the Ontario Research Fund, Canadian Institutes of Health Research, and a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. ASTERISK was funded by a Regional Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique, and the Ligue Régionale Contre le Cancer (LRCC). Publisher Copyright: © 2019 AGA Institute
PY - 2019/4
Y1 - 2019/4
N2 - Background & Aims: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)—nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations. Methods: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels. Results: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10 –8 . We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%–75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci. Conclusions: We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.
AB - Background & Aims: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)—nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations. Methods: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels. Results: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10 –8 . We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%–75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci. Conclusions: We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.
KW - Colon Cancer
KW - Epidemiology
KW - Genetic Variants
KW - Immunology
UR - http://www.scopus.com/inward/record.url?scp=85063365207&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063365207&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2018.11.066
DO - 10.1053/j.gastro.2018.11.066
M3 - Article
C2 - 30529582
AN - SCOPUS:85063365207
VL - 156
SP - 1455
EP - 1466
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 5
ER -