Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations.
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ABSTRACT:
SUBMITTER: Wu C
PROVIDER: S-EPMC4212832 | biostudies-literature | 2014 Sep
REPOSITORIES: biostudies-literature
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Project description:We conducted a genome-wide association study (GWAS) and a genome-wide gene-environment interaction analysis of esophageal squamous-cell carcinoma (ESCC) in 2,031 affected individuals (cases) and 2,044 controls with independent validation in 8,092 cases and 8,620 controls. We identified nine new ESCC susceptibility loci, of which seven, at chromosomes 4q23, 16q12.1, 17q21, 22q12, 3q27, 17p13 and 18p11, had a significant marginal effect (P=1.78×10(-39) to P=2.49×10(-11)) and two of which, at 2q22 and 13q33, had a significant association only in the gene-alcohol drinking interaction (gene-environment interaction P (PG×E)=4.39×10(-11) and PG×E=4.80×10(-8), respectively). Variants at the 4q23 locus, which includes the ADH cluster, each had a significant interaction with alcohol drinking in their association with ESCC risk (PG×E=2.54×10(-7) to PG×E=3.23×10(-2)). We confirmed the known association of the ALDH2 locus on 12q24 to ESCC, and a joint analysis showed that drinkers with both of the ADH1B and ALDH2 risk alleles had a fourfold increased risk for ESCC compared to drinkers without these risk alleles. Our results underscore the direct genetic contribution to ESCC risk, as well as the genetic contribution to ESCC through interaction with alcohol consumption.
| S-EPMC3513832 | biostudies-other
Project description:Esophageal squamous cell carcinoma (ESCC) has a high disease burden in sub-Saharan Africa and has a very poor prognosis. Genome-wide association studies (GWASs) of ESCC in predominantly East Asian populations indicate a substantial genetic contribution to its etiology, but no genome-wide studies have been done in populations of African ancestry. Here, we report a GWAS in 1,686 African individuals with ESCC and 3,217 population-matched control individuals to investigate its genetic etiology. We identified a genome-wide-significant risk locus on chromosome 9 upstream of FAM120A (rs12379660, p = 4.58 × 10-8, odds ratio = 1.28, 95% confidence interval = 1.22-1.34), as well as a potential African-specific risk locus on chromosome 2 (rs142741123, p = 5.49 × 10-8) within MYO1B. FAM120A is a component of oxidative stress-induced survival signals, and the associated variants at the FAM120A locus co-localized with highly significant cis-eQTLs in FAM120AOS in both esophageal mucosa and esophageal muscularis tissue. A trans-ethnic meta-analysis was then performed with the African ESCC study and a Chinese ESCC study in a combined total of 3,699 ESCC-affected individuals and 5,918 control individuals, which identified three genome-wide-significant loci on chromosome 9 at FAM120A (rs12379660, pmeta = 9.36 × 10-10), chromosome 10 at PLCE1 (rs7099485, pmeta = 1.48 × 10-8), and chromosome 22 at CHEK2 (rs1033667, pmeta = 1.47 × 10-9). This indicates the existence of both shared and distinct genetic risk loci for ESCC in African and Asian populations. Our GWAS of ESCC conducted in a population of African ancestry indicates a substantial genetic contribution to ESCC risk in Africa.
| S-EPMC10577073 | biostudies-literature
Project description:BackgroundOur previous genome-wide association study (GWAS) identified three independent single nucleotide polymorphisms (SNPs) in human major histocompatibility complex (MHC) region showing association with esophageal squamous cell carcinoma (ESCC). In this study, we increased GWAS sample size on MHC region and performed validation in an independent ESCC cases and normal controls with aim to find additional loci at MHC region showing association with an increased risk to ESCC.MethodsThe 1,077 ESCC cases and 1,733 controls were genotyped using Illumina Human 610-Quad Bead Chip, and 451 cases and 374 controls were genotyped using Illumina Human 660W-Quad Bead Chip. After quality control, the selected SNPs were replicated by TaqMan genotyping assay on another 2,026 ESCC cases and 2,384 normal controls.ResultsBy excluding low quality SNPs in primary GWAS screening, we selected 2,533 SNPs in MHC region for association analysis, and identified 5 SNPs with p <10-4. Further validation analysis in an independent case-control cohort confirmed one of the 5 SNPs (rs911178) that showed significant association with ESCC. rs911178 (PGWAS = 6.125E-04, OR = 0.644 and Preplication = 1.406E-22, OR = 0.489) was located at upstream of SCAND3.ConclusionThe rs911178 (SCAND3 gene) in MHC region is significantly associated with high risk of ESCC. This study not only reveal the potential role of MHC region for the pathogenesis of ESCC, but also provides important clues for the establishment of tools and methods for screening high risk population of ESCC.
| S-EPMC5426749 | biostudies-literature
Project description:Genetic susceptibility plays an essential role in an individual's risk of esophageal squamous cell carcinoma (ESCC). The aim of this study is to investigate the associations between clusterin (CLU) gene polymorphisms and ESCC risk. We undertook a case-control study to analyze three CLU polymorphisms (gene rs9331888 C>G, rs17466684 A>G and rs1532278 T>C) in an Han Chinese population, by extraction of genomic DNA from the peripheral blood of 642 patients with ESCC and 658 control participants, and performed CLU genotyping using DNA sequencing. The obtained results indicated that overall, no statistically significant association was observed in rs17466684 and rs1532278. However, gene rs9331888 C>G genotype was at increased risk of ESCCs (P=0.037; odds ratio (OR)=1.089, 95% CI: 1.006-1.175). Moreover, rs9331888 G/G genotype ESCCs were more significantly common in patients with tumor size of >5 cm than T allele ESCC and in cases of poor differentiation and lower advanced pathological stage. In conclusion, polymorphism in rs9331888 C>G was observed to be associated with susceptibility of ESCC. Nevertheless, further investigation with a larger sample size is needed to support our results.
| S-EPMC4613044 | biostudies-literature
Project description:Since 2006, genome-wide association studies of schizophrenia have led to the identification of numerous novel risk loci for this disease. However, there remains a geographical imbalance in genome-wide association studies, which to date have primarily focused on Western populations. During the last 6 years, genome-wide association studies in Han Chinese populations have identified both the sharing of susceptible loci across ethnicities and genes unique to Han Chinese populations. Here, we review recent progress in genome-wide association studies of schizophrenia in Han Chinese populations. Researchers have identified and replicated the sharing of susceptible genes, such as within the major histocompatibility complex, microRNA 137 (MIR137), zinc finger protein 804A (ZNF804A), vaccinia related kinase 2 (VRK2), and arsenite methyltransferase (AS3MT), across both European and East Asian populations. Several copy number variations identified in European populations have also been validated in the Han Chinese, including duplications at 16p11.2, 15q11.2-13.1, 7q11.23, and VIPR2 and deletions at 22q11.2, 1q21.1-q21.2, and NRXN1. However, these studies have identified some potential confounding factors, such as genetic heterogeneity and the effects of natural selection on tetraspanin 18 (TSPAN18) or zinc finger protein 323 (ZNF323), which may explain the population differences in genome-wide association studies. In the future, genome-wide association studies in Han Chinese populations should include meta-analyzes or mega-analyses with enlarged sample sizes across populations, deep sequencing, precision medicine treatment, and functional exploration of the risk genes for schizophrenia.
| S-EPMC5552785 | biostudies-literature
Project description: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.
| S-EPMC3315211 | biostudies-literature
Project description:BACKGROUND: Excision repair cross complementing group 5 (ERCC5 or XPG) plays an important role in regulating DNA excision repair; its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity and thus contribute to cancer risk. METHODOLOGY/PRINCIPAL FINDINGS: In a hospital-based case-control study of 1115 esophageal squamous cell carcinoma (ESCC) cases and 1117 cancer-free controls, we genotyped three potentially functional SNPs of ERCC5 (SNPs, rs2296147T>C, rs2094258C>T and rs873601G>A) and estimated crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for their associations with risk of ESCC using unconditional logistic regression models. We also calculated false-positive report probabilities (FPRPs) for significant findings. We found that compared with the TT genotype, ERCC5 rs2296147 C variant genotypes were associated with a significantly lower ESCC risk (CT: adjusted OR?=?0.76, 95% CI?=?0.63-0.93, CT/CC: adjusted OR?=?0.80, 95% CI?=?0.67-0.96); however, this risk was not observed for the other two SNPs (rs2094258C>T and rs873601 G>A), nor in further stratification and haplotype analysis. CONCLUSIONS/SIGNIFICANCES: These findings suggested that ERCC5 polymorphisms may contribute to risk of ESCC in Eastern Chinese populations, but the effect was weak and needs further validation by larger population-based case-control studies.
| S-EPMC3406052 | biostudies-literature
Project description:ERCC2 is indispensable for nucleotide excision repair pathway, and its functional polymorphisms may be associated with cancer risk. In a large case-control study of 1126 esophageal squamous cell carcinomas (ESCC) patients and 1131 controls, we genotyped two SNPs in ERCC2 (rs238406 G > T and rs13181 T > G) and assessed their associations with ESCC risk. We found a significantly elevated ESCC risk associated with the rs238406 T variant genotypes (adjusted OR = 1.30 and 1.24, 95% CI = 1.02-1.66 and 1.03-1.49 for TG and TG/TT, respectively, compared with GG), particularly in the subgroup of those smoked more than 16 pack-years. Multivariate logistic regression analysis suggested a possible multiplicative gene-environment interaction between rs238406 genotypes and smoking (Pinteraction = 0.026) on ESCC risk. Although no significant risk associations were observed for rs13181, further mini meta-analysis with our and 18 other published studies of 5,012 cases and 8,238 controls found evidence of an association between the rs13181 variant G allele and esophageal cancer risk (TG/GG vs. TT, OR = 1.17; 95% CI = 1.02-1.33). Interestingly, we consistently found a significant correlation between variant genotypes of these two SNPs and ERCC2 mRNA expression. These findings suggest that potentially functional SNPs in ERCC2 may contribute to ESCC risk.
| S-EPMC4160711 | biostudies-literature
Project description:BackgroundGrowing evidence suggested that B- and T-lymphocyte attenuator (BTLA) polymorphisms raised the susceptibility to a wide range of cancers. This study aimed to evaluate whether BTLA variants were related to the risk of esophageal squamous cell carcinoma (ESCC).MethodsA total of 721 ESCC patients and 1208 matched non-cancer controls were included in this research, and four tagging BTLA polymorphisms (rs2171513 G > A, rs3112270 A > G, rs1982809 G > A, and rs16859629 T > C) were selected and genotyped using SNPscan™ Assays.ResultsIn the present study, no significant relationship between BTLA polymorphisms and ESCC was observed. However, stratified analyses suggested that the variant of BTLA rs3112270 A > G reduced the risk of ESCC in the male subgroup (AG vs AA: adjusted OR = 0.78, 95% CI = 0.61-0.99, P = .042), BMI < 24 kg/m2 subgroup (AG vs AA: adjusted OR = 0.72, 95% CI = 0.55-0.93, P = .012; AG/GG vs AA: adjusted OR = 0.77, 95% CI = 0.60-0.98, P = .032), and ever drinking subgroup (AG vs AA: adjusted OR = 0.61, 95% CI = 0.38-0.97, P = .037). But when stratified by BMI ≥ 24 kg/m2 , the rs3112270 A > G polymorphism increased the susceptibility to ESCC (GG vs AA: adjusted OR = 1.91, 95% CI = 1.02-3.59, P = .045). Besides, we demonstrated that BTLA rs2171513 G > A polymorphism was protective of ESCC in the ever drinking subgroup (GA/AA vs GG: adjusted OR = 0.62, 95% CI = 0.39-0.97, P = .037).ConclusionTaken together, our initial investigation postulated that the rs3112270 A > G and rs2171513 G > A variants in the BTLA gene are candidates for the risk of ESCC, which might be helpful for the early diagnosis and treatment of ESCC.
| S-EPMC7307356 | biostudies-literature
Project description:Phospholipase C epsilon 1 (PLCE1) (an effector of Ras) belonging to the phospholipase family plays crucial roles in carcinogenesis and progression of several cancers, including squamous cell carcinoma of the head and neck (SCCHN). A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus in genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) that share similar risk factors with SCCHN. Therefore, we investigated the association between potentially functional SNPs in PLCE1 and susceptibility to SCCHN.We genotyped three potentially functional SNPs (rs2274223A/G, rs3203713A/G and rs11599672T/G) of PLCE1 in 1,098 SCCHN patients and 1,090 controls matched by age and sex in a non-Hispanic white population.Although none of three SNPs was alone significantly associated with overall risk of SCCHN, their combined effects of risk alleles (rs2274223G, rs3203713G and rs11599672G) were found to be associated with risk of SCCHN in a locus-dose effect manner (Ptrend=0.046), particularly for non-oropharyngeal tumors (Ptrend=0.017); specifically, rs2274223 was associated with a significantly increased risk (AG vs. AA: adjusted OR=1.29, 95% CI=1.01-1.64; AG/GG vs. AA: adjusted OR=1.30, 95% CI=1.03-1.64), while rs11599672 was associated with a significantly decreased risk (GG vs. TT: adjusted OR=0.54, 95% CI=0.34-0.86; TG/GG vs. TT: adjusted OR=0.76, 95% CI=0.61-0.95).Our findings suggest that PLCE1 variants may have an effect on risk of SCCHN associated with tobacco and alcohol exposure, particularly for those tumors arising at non-oropharyngeal sites. These findings, although need to be validated by larger studies, are consistent with those in esophageal and gastric cancers.
| S-EPMC3142535 | biostudies-literature