Hongbing Shen

A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese

Lung cancer is the leading cause of cancer-related deaths worldwide. To identify genetic factors that modify the risk of lung cancer in individuals of Chinese ancestry, we performed a genome-wide association scan in 5,408 subjects (2,331 individuals with lung cancer (cases) and 3,077 controls) followed by a two-stage validation among 12,722 subjects (6,313 cases and 6,409 controls). The combined analyses identified six well-replicated SNPs with independent effects and significant lung cancer associations (P < 5.0 × 10−8) located in TP63 (rs4488809 at 3q28, P = 7.2 × 10−26), TERT-CLPTM1L (rs465498 and rs2736100 at 5p15.33, P = 1.2 × 10−20 and P = 1.0 × 10−27, respectively), MIPEP-TNFRSF19 (rs753955 at 13q12.12, P = 1.5 × 10−12) and MTMR3-HORMAD2-LIF (rs17728461 and rs36600 at 22q12.2, P = 1.1 × 10−11 and P = 6.2 × 10−13, respectively). Two of these loci (13q12.12 and 22q12.2) were newly identified in the Chinese population. These results suggest that genetic variants in 3q28, 5p15.33, 13q12.12 and 22q12.2 may contribute to the susceptibility of lung cancer in Han Chinese.

XRCC1 Polymorphisms and Cancer Risk: A Meta-analysis of 38 Case-Control Studies

Several potential functional polymorphisms (Arg194Trp, Arg280His, Arg399Gln) in the DNA base excision repair gene X-ray repair cross-complementing group 1 (XRCC1) have been implicated in cancer risk. Our meta-analysis on total of 11,957 cancer cases and 14,174 control subjects from 38 published case-control studies showed that the odds ratio (OR) for the variant genotypes (Trp/Trp + Arg/Trp) of the Arg194Trp polymorphism, compared with the wild-type homozygote (Arg/Arg), was 0.89 [95% confidence interval (95% CI), 0.81-0.98] for all tumor types without between-study heterogeneity. Similarly, the overall risk for the combined variant genotypes (His/His + Arg/His) of the Arg280His, compared with the wild homozygote (Arg/Arg), was 1.19 (95% CI, 1.00-1.42). However, there was no main effect in either recessive or dominant modeling for the Arg399Gln, and the variant Gln/Gln homozygote was not associated with overall cancer risk (OR, 1.01; 95% CI, 0.90-1.14). The analyses suggest that XRCC1 Arg194Trp, Arg280His polymorphisms may be biomarkers of cancer susceptibility and a single larger study with thousands of subjects and tissue-specific biochemical and biological characterization is warranted to further evaluate potential gene-to-gene and gene-to-environment interactions on XRCC1 polymorphisms and cancer risk.

Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations

Esophageal squamous-cell carcinoma (ESCC) is one of the most prevalent cancers worldwide and occurs at a relatively high frequency in China. To identify genetic susceptibility loci for ESCC, we conducted a genome-wide association study on 2,031 individuals with ESCC (cases) and 2,044 controls of Chinese descent using 666,141 autosomal SNPs. We evaluated promising associations in an additional 6,276 cases and 6,165 controls of Chinese descent from different areas of China. We identified seven susceptibility loci on chromosomes 5q11, 6p21, 10q23, 12q24 and 21q22 (ranging from P = 7.48 × 10−12 to P = 2.44 × 10−31); among these loci, 5q11, 6p21 and 21q22 were newly identified. Three variants in high linkage disequilibrium on 12q24 confer their risks to ESCC in a gene-lifestyle interaction manner, with more pronounced risk enhancement seen in tobacco and alcohol users. Furthermore, the identified variants had a cumulative association with ESCC risk (Ptrend = 7.92 × 10−56). These findings highlight the involvement of multiple genetic loci and gene-environment interaction in the development of esophageal cancer.

A genome-wide association study identifies new susceptibility loci for non-cardia gastric cancer at 3q13.31 and 5p13.1

Gastric cancer, including the cardia and non-cardia types, is the second leading cause of cancer-related deaths worldwide. To identify genetic risk variants for non-cardia gastric cancer, we performed a genome-wide association study in 3,279 individuals (1,006 with non-cardia gastric cancer and 2,273 controls) of Chinese descent. We replicated significant associations in an additional 6,897 subjects (3,288 with non-cardia gastric cancer and 3,609 controls). We identified two new susceptibility loci for non-cardia gastric cancer at 5p13.1 (rs13361707 in the region including PTGER4 and PRKAA1; odds ratio (OR) = 1.41; P = 7.6 × 10−29) and 3q13.31 (rs9841504 in ZBTB20; OR = 0.76; P = 1.7 × 10−9). Imputation analyses also confirmed previously reported associations of rs2294008 and rs2976392 on 8q24, rs4072037 on 1q22 and rs13042395 on 20p13 with non-cardia gastric cancer susceptibility in the Han Chinese population.

Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions

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 six new ESCC susceptibility loci, of which four, at chromosomes 4q23, 16q12.1, 22q12 and 3q27 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.

Genome-wide association study identifies five loci associated with susceptibility to pancreatic cancer in Chinese populations.

Pancreatic cancer has the lowest survival rate among human cancers, and there are no effective markers for its screening and early diagnosis. To identify genetic susceptibility markers for this cancer, we carried out a genome-wide association study on 981 individuals with pancreatic cancer (cases) and 1,991 cancer-free controls of Chinese descent using 666,141 autosomal SNPs. Promising associations were replicated in an additional 2,603 pancreatic cancer cases and 2,877 controls recruited from 25 hospitals in 16 provinces or cities in China. We identified five new susceptibility loci at chromosomes 21q21.3, 5p13.1, 21q22.3, 22q13.32 and 10q26.11 (P = 2.24 × 10−13 to P = 4.18 × 10−10) in addition to 13q22.1 previously reported in populations of European ancestry. These results advance our understanding of the development of pancreatic cancer and highlight potential targets for the prevention or treatment of this cancer.

A genome-wide association study in Chinese men identifies three risk loci for non-obstructive azoospermia

Non-obstructive azoospermia (NOA) is one of the most severe forms of male infertility. Its pathophysiology is largely unknown, and few genetic influences have been defined. To identify common variants contributing to NOA in Han Chinese men, we performed a three-stage genome-wide association study of 2,927 individuals with NOA and 5,734 controls. The combined analyses identified significant (P < 5.0 × 10−8) associations between NOA risk and common variants near PRMT6 (rs12097821 at 1p13.3: odds ratio (OR) = 1.25, P = 5.7 × 10−10), PEX10 (rs2477686 at 1p36.32: OR = 1.39, P = 5.7 × 10−12) and SOX5 (rs10842262 at 12p12.1: OR = 1.23, P = 2.3 × 10−9). These findings implicate genetic variants at 1p13.3, 1p36.32 and 12p12.1 in the etiology of NOA in Han Chinese men.

Association analyses identify multiple new lung cancer susceptibility loci and their interactions with smoking in the Chinese population

To find additional susceptibility loci for lung cancer, we tested promising associations from our previous genome-wide association study (GWAS) of lung cancer in the Chinese population in an extended validation sample size of 7,436 individuals with lung cancer (cases) and 7,483 controls. We found genome-wide significant (P < 5.0 × 10−8) evidence for three additional lung cancer susceptibility loci at 10p14 (rs1663689, close to GATA3, P = 2.84 × 10−10), 5q32 (rs2895680 in PPP2R2B-STK32A-DPYSL3, P = 6.60 × 10−9) and 20q13.2 (rs4809957 in CYP24A1, P = 1.20 × 10−8). We also found consistent associations for rs247008 at 5q31.1 (IL3-CSF2-P4HA2, P = 7.68 × 10−8) and rs9439519 at 1p36.32 (AJAP1-NPHP4, P = 3.65 × 10−6). Four of these loci showed evidence for interactions with smoking dose (P = 1.72 × 10−10, P = 5.07 × 10−3, P = 6.77 × 10−3 and P = 4.49 × 10−2 for rs2895680, rs4809957, rs247008 and rs9439519, respectively). These results advance our understanding of lung cancer susceptibility and highlight potential pathways that integrate genetic variants and smoking in the development of lung cancer.

DNA repair gene XPC genotypes/haplotypes and risk of lung cancer in a Chinese population

DNA repair is central to normal cellular functions, and polymorphisms of DNA repair genes may cause variation in DNA repair capacity in the general population. Newly identified polymorphisms of xeroderma pigmentosum group C (XPC), one of the nucleotide excision repair genes, were shown to contribute to genetic susceptibility to cancer. In this study, we hypothesized that 2 exonic variants C499T and A939C and their haplotypes in XPC are associated with lung cancer risk. To test this hypothesis, we performed a case‐control study of 320 histologically confirmed lung cancer patients and 322 age and sex frequency‐matched cancer‐free controls in a Chinese population. Multivariate logistic regression analyses revealed that the risks [adjusted odds ratios (ORs) and 95% confidence intervals (CIs)] associated with the XPC variant genotypes were 1.57 (95% CI = 1.13–2.19) for 499CT/TT and 1.21 (95% CI = 0.87–1.69) for 939AC/CC compared with the 499CC and 939AA wild‐type homozygotes, respectively. Individuals with both putative risk genotypes (499CT/TT and 939AC/CC) had a greater risk of lung cancer (adjusted OR = 2.37; 95% CI = 1.33–4.21) compared with individuals with both wild‐type genotypes (499CC and 939AA). When we performed the haplotype analysis and assumed the XPC 499T and 939C as risk alleles, the adjusted ORs increased as the number of variants in the haplotype genotypes increased (ptrend < 0.001). In the stratified analysis, the greatest risk was found in smokers having the combined variant genotypes (adjusted OR = 7.36; 95% CI = 3.19–17.00) compared with nonsmokers having both wild‐type genotypes and in smokers with 2 or 3 haplotype variants (adjusted OR = 7.27; 95% CI = 3.37–15.68) compared with nonsmokers having 0 haplotype variant. These findings indicate that XPC exonic variants may contribute to the risk of lung cancer in the Chinese population, and these variant genotypes may modulate the risk of lung cancer associated with smoking.

New loci associated with chronic hepatitis B virus infection in Han Chinese

Chronic hepatitis B virus (HBV) infection is a challenging global health problem. To identify genetic loci involved in chronic HBV infection, we designed a three-phase genome-wide association study in Han Chinese populations. The discovery phase included 951 HBV carriers (cases) and 937 individuals who had naturally cleared HBV infection (controls) and was followed by independent replications with a total of 2,248 cases and 3,051 controls and additional replications with 1,982 HBV carriers and 2,622 controls from the general population. We identified two new loci associated with chronic HBV infection: rs3130542 at 6p21.33 (near HLA-C, odds ratio (OR) = 1.33, P = 9.49 × 10−14) and rs4821116 at 22q11.21 (in UBE2L3, OR = 0.82, P = 1.71 × 10−12). Additionally, we replicated the previously identified associations of HLA-DP and HLA-DQ variants at 6p21.32 with chronic HBV infection. These findings highlight the importance of HLA-C and UBE2L3 in the clearance of HBV infection in addition to HLA-DP and HLA-DQ.