Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies
Open Access
- 8 February 2012
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 21 (9), 2132-2141
- https://doi.org/10.1093/hmg/dds029
Abstract
Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10−8, and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19–1.40) and P= 7.63 × 10−10. An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.This publication has 34 references indexed in Scilit:
- Improved imputation of common and uncommon SNPs with a new reference setNature Genetics, 2011
- Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1Nature Genetics, 2011
- Genome-wide association study identifies three new melanoma susceptibility lociNature Genetics, 2011
- Cancer incidence and mortality in China, 2006Chinese Journal of Cancer Research, 2011
- A map of human genome variation from population-scale sequencingNature, 2010
- A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinomaNature Genetics, 2010
- Replication of a genome‐wide case–control study of esophageal squamous cell carcinomaInternational Journal of Cancer, 2008
- A common coding variant in CASP8 is associated with breast cancer riskNature Genetics, 2007
- Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversibleNature Genetics, 2006
- Mapping Trait Loci by Use of Inferred Ancestral Recombination GraphsAmerican Journal of Human Genetics, 2006