We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS)1,2,3 of esophageal squamous cell carcinoma (ESCC) in individuals of Chinese ancestry (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.82–0.88; P = 7.72 × 10−20) and rs1642764 at 17p13.1 (per-allele OR = 0.88, 95% CI = 0.85–0.91; P = 3.10 × 10−13). rs7447927 is a synonymous SNP in TMEM173, and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR = 1.33, 95% CI = 1.22–1.46; P = 1.99 × 10−10). Our joint analysis identifies new ESCC susceptibility loci overall as well as a new locus unique to the population in the Taihang Mountain region at high risk of ESCC.
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This work was funded by the National High-Tech Research and Development Program of China (2009AA022706 to D.L.), the National Basic Research Program of China (2011CB504303 to D.L. and W.T.) and the National Natural Science Foundation of China (30721001 to D.L., Q.Z. and Z.L.).
We thank all the subjects and their family members whose contributions made this work possible; medical students from Zhengzhou University, Xinxiang Medical University, Zhengzhou Medical School and the Henan University of Science and Technology for sample and data collections; Q.C. Kan (The First Affiliated Hospital of Zhengzhou University) and Y. Xing (Xinxiang Medical University) for organizing field work for sample collection and finding financial support for the study; the Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, China, for genotyping; and W. Huang (Health Department of Henan Province) for field work organization.
This work was supported by the Invitation Team of the Ministry of Education (2008IRTSTHN010), the National Natural Science Foundation of China (81071783), 863 High-Tech Key Projects (2012AA02A209, 2012AA02A503 and 2012AA02A201), Innovation Scientists and Technicians Troop Construction Projects of Henan Province (3047), the Key Disciplines Revitalization Plan of Zhengzhou University (20132016) and the Collaborative Innovation Center for Esophageal Cancer Research of Henan Province (20132016).
The Shanghai Men's Health Study (SMHS) was supported by NCI extramural research grant R01 CA82729. The Shanghai Women's Health Study (SWHS) was supported by NCI extramural research grant R37 CA70837 and, in part, for biological sample collection, by NCI intramural research program contract NO2-CP-11010 with Vanderbilt University. The studies would not be possible without continuing support and devotion from the study participants and the staff of SMHS and SWHS.
The Singapore Chinese Health Study (SCHS) was supported by NCI extramural research grants R01 CA55069, R35 CA53890, R01 CA80205 and R01 CA144034. We are indebted to the contributions of M.C. Yu and H.-P. Lee in the establishment of this cohort. The study would not be possible without the assistance in identifying cancer cases through database linkage provided by the Ministry of Health in Singapore. We are indebted to the study subjects for their continuing participation and to the staff of SCHS for their support.
The Shanxi Upper Gastrointestinal Cancer Genetics Project was supported by NCI intramural research program contract NO2-SC-66211 with the Shanxi Cancer Hospital and Institute.
The Nutrition Intervention Trials (NIT) was supported by NCI intramural research program contracts NO1-SC-91030 and HHSN261200477001C with the Cancer Institute and Hospital of the Chinese Academy of Medical Sciences.
This research was supported in part by the intramural research program of the US NIH/NCI, the Division of Cancer Epidemiology and Genetics, and the Center for Cancer Research.
This project was funded in part with federal funds from the US NIH/NCI under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government.
Integrated supplementary information
Supplementary Figures 1–9 and Supplementary Tables 1–9
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Genes & Immunity (2019)