Journal
NATURE GENETICS
Volume 50, Issue 3, Pages 338-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41588-018-0045-8
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Funding
- National Key Research and Development Plan Program [2016YFC1302702, 2016YFC1302701, 2016YFC1302703]
- National Program for Support of Top-notch Young Professionals, National Natural Science Foundation of China [81171878, 81222038]
- Fok Ying Tung Foundation for Young Teachers in the Higher Education Institutions of China [131038]
- Program for HUST Academic Frontier Youth Team
- National Key Research and Development Plan Program [2016YFC1302702, 2016YFC1302701, 2016YFC1302703]
- National Program for Support of Top-notch Young Professionals, National Natural Science Foundation of China [81171878, 81222038]
- Fok Ying Tung Foundation for Young Teachers in the Higher Education Institutions of China [131038]
- Program for HUST Academic Frontier Youth Team
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Genome-wide association studies have identified common variants associated with risk of esophageal squamous cell carcinoma (ESCC). However, these common variants cannot explain all heritability of ESCC. Here we report an exome-wide interrogation of 3,714 individuals with ESCC and 3,880 controls for low-frequency susceptibility loci, with two independent replication samples comprising 7,002 cases and 8,757 controls. We found six new susceptibility loci in CCHCR1, TCN2, TNXB, LTA, CYP26B1 and FASN (P = 7.77 x 10(-24) to P = 1.49 x 10(-11)), and three low-frequency variants had relatively high effect size (odds ratio > 1.5). Individuals with the rs138478634-GA genotype had significantly lower levels of serum all-trans retinoic acid, an anticancer nutrient, than those with the rs138478634-GG genotype (P = 0.0004), most likely due to an enhanced capacity of variant CYP26B1 to catabolize this agent. These findings emphasize the important role of rare coding variants in the development of ESCC.
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