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1.  Association of GWAS-Identified Lung Cancer Susceptibility Loci with Survival Length in Patients with Small-Cell Lung Cancer Treated with Platinum-Based Chemotherapy 
PLoS ONE  2014;9(11):e113574.
Genetic variants have been shown to affect length of survival in cancer patients. This study explored the association between lung cancer susceptibility loci tagged by single-nucleotide polymorphisms (SNPs) identified in the genome-wide association studies and length of survival in small-cell lung cancer (SCLC). Eighteen SNPs were genotyped among 874 SCLC patients and Cox proportional hazards regression was used to examine the effects of genotype on survival length under an additive model with age, sex, smoking status and clinical stage as covariates. We identified 3 loci, 20q13.2 (rs4809957G >A), 22q12.2 (rs36600C >T) and 5p15.33 (rs401681C >T), significantly associated with the survival time of SCLC patients. The adjusted hazard ratio (HR) for patients with the rs4809957 GA or AA genotype was 0.80 (95% CI, 0.66–0.96; P = 0.0187) and 0.73 (95% CI, 0.55–0.96; P = 0.0263) compared with the GG genotype. Using the dominant model, the adjusted HR for patients carrying at least one T allele at rs36600 or rs401681 was 0.78 (95% CI, 0.63–0.96; P = 0.0199) and 1.29 (95% CI, 1.08–1.55; P = 0.0047), respectively, compared with the CC genotype. Stratification analyses showed that the significant associations of these 3 loci were only seen in smokers and male patients. The rs4809957 SNP was only significantly associated with length of survival of patients with extensive-stage but not limited-stage tumor. These results suggest that some of the lung cancer susceptibility loci might also affect the prognosis of SCLC.
doi:10.1371/journal.pone.0113574
PMCID: PMC4240611  PMID: 25415319
2.  Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia 
Lan, Qing | Hsiung, Chao A | Matsuo, Keitaro | Hong, Yun-Chul | Seow, Adeline | Wang, Zhaoming | Hosgood, H Dean | Chen, Kexin | Wang, Jiu-Cun | Chatterjee, Nilanjan | Hu, Wei | Wong, Maria Pik | Zheng, Wei | Caporaso, Neil | Park, Jae Yong | Chen, Chien-Jen | Kim, Yeul Hong | Kim, Young Tae | Landi, Maria Teresa | Shen, Hongbing | Lawrence, Charles | Burdett, Laurie | Yeager, Meredith | Yuenger, Jeffrey | Jacobs, Kevin B | Chang, I-Shou | Mitsudomi, Tetsuya | Kim, Hee Nam | Chang, Gee-Chen | Bassig, Bryan A | Tucker, Margaret | Wei, Fusheng | Yin, Zhihua | Wu, Chen | An, She-Juan | Qian, Biyun | Lee, Victor Ho Fun | Lu, Daru | Liu, Jianjun | Jeon, Hyo-Sung | Hsiao, Chin-Fu | Sung, Jae Sook | Kim, Jin Hee | Gao, Yu-Tang | Tsai, Ying-Huang | Jung, Yoo Jin | Guo, Huan | Hu, Zhibin | Hutchinson, Amy | Wang, Wen-Chang | Klein, Robert | Chung, Charles C | Oh, In-Jae | Chen, Kuan-Yu | Berndt, Sonja I | He, Xingzhou | Wu, Wei | Chang, Jiang | Zhang, Xu-Chao | Huang, Ming-Shyan | Zheng, Hong | Wang, Junwen | Zhao, Xueying | Li, Yuqing | Choi, Jin Eun | Su, Wu-Chou | Park, Kyong Hwa | Sung, Sook Whan | Shu, Xiao-Ou | Chen, Yuh-Min | Liu, Li | Kang, Chang Hyun | Hu, Lingmin | Chen, Chung-Hsing | Pao, William | Kim, Young-Chul | Yang, Tsung-Ying | Xu, Jun | Guan, Peng | Tan, Wen | Su, Jian | Wang, Chih-Liang | Li, Haixin | Sihoe, Alan Dart Loon | Zhao, Zhenhong | Chen, Ying | Choi, Yi Young | Hung, Jen-Yu | Kim, Jun Suk | Yoon, Ho-Il | Cai, Qiuyin | Lin, Chien-Chung | Park, In Kyu | Xu, Ping | Dong, Jing | Kim, Christopher | He, Qincheng | Perng, Reury-Perng | Kohno, Takashi | Kweon, Sun-Seog | Chen, Chih-Yi | Vermeulen, Roel | Wu, Junjie | Lim, Wei-Yen | Chen, Kun-Chieh | Chow, Wong-Ho | Ji, Bu-Tian | Chan, John K C | Chu, Minjie | Li1, Yao-Jen | Yokota, Jun | Li, Jihua | Chen, Hongyan | Xiang, Yong-Bing | Yu, Chong-Jen | Kunitoh, Hideo | Wu, Guoping | Jin, Li | Lo, Yen-Li | Shiraishi, Kouya | Chen, Ying-Hsiang | Lin, Hsien-Chih | Wu, Tangchun | Wu, Yi-Long | Yang, Pan-Chyr | Zhou, Baosen | Shin, Min-Ho | Fraumeni, Joseph F | Lin, Dongxin | Chanock, Stephen J | Rothman, Nathaniel
Nature genetics  2012;44(12):1330-1335.
To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10-18), 6q22.2 (rs9387478, P = 4.14 × 10-10) and 6p21.32 (rs2395185, P = 9.51 × 10-9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.
doi:10.1038/ng.2456
PMCID: PMC4169232  PMID: 23143601
3.  Replication of the 4p16 Susceptibility Locus in Congenital Heart Disease in Han Chinese Populations 
PLoS ONE  2014;9(9):e107411.
Congenital heart disease (CHD) is the most common form of congenital human birth anomalies and a leading cause of perinatal and infant mortality. Some studies including our published genome-wide association study (GWAS) of CHD have indicated that genetic variants may contribute to the risk of CHD. Recently, Cordell et al. published a GWAS of multiple CHD phenotypes in European Caucasians and identified 3 susceptibility loci (rs870142, rs16835979 and rs6824295) for ostium secundum atrial septal defect (ASD) at chromosome 4p16. However, whether these loci at 4p16 confer the predisposition to CHD in Chinese population is unclear. In the current study, we first analyzed the associations between these 3 single nucleotide polymorphisms (SNPs) at 4p16 and CHD risk by using our existing genome-wide scan data and found all of the 3 SNPs showed significant associations with ASD in the same direction as that observed in Cordell’s study, but not with other subtypes- ventricular septal defect (VSD) and ASD combined VSD. As these 3 SNPs were in high linkage disequilibrium (LD) in Chinese population, we selected one SNP with the lowest P value in our GWAS scan (rs16835979) to perform a replication study with additional 1,709 CHD cases with multiple phenotypes and 1,962 controls. The significant association was also observed only within the ASD subgroup, which was heterogeneous from other disease groups. In combined GWAS and replication samples, the minor allele of rs16835979 remained significant association with the risk of ASD (OR = 1.22, 95% CI = 1.08–1.38, P = 0.001). Our findings suggest that susceptibility loci of ASD identified from Cordell’s European GWAS are generalizable to Chinese population, and such investigation may provide new insights into the roles of genetic variants in the etiology of different CHD phenotypes.
doi:10.1371/journal.pone.0107411
PMCID: PMC4162603  PMID: 25215500
4.  The Spatial Analysis on Hemorrhagic Fever with Renal Syndrome in Jiangsu Province, China Based on Geographic Information System 
PLoS ONE  2014;9(9):e83848.
Background
Hemorrhagic fever with renal syndrome (HFRS) is endemic in mainland China, accounting for 90% of total reported cases worldwide, and Jiangsu is one of the most severely affected provinces. In this study, the authors conducted GIS-based spatial analyses in order to determine the spatial distribution of the HFRS cases, identify key areas and explore risk factors for public health planning and resource allocation.
Methods
Interpolation maps by inverse distance weighting were produced to detect the spatial distribution of HFRS cases in Jiangsu from 2001 to 2011. Spatio-temporal clustering was applied to identify clusters at the county level. Spatial correlation analysis was conducted to detect influencing factors of HFRS in Jiangsu.
Results
HFRS cases in Jiangsu from 2001 to 2011 were mapped and the results suggested that cases in Jiangsu were not distributed randomly. Cases were mainly distributed in northeastern and southwestern Jiangsu, especially in Dafeng and Sihong counties. It was notable that prior to this study, Sihong county had rarely been reported as a high-risk area of HFRS. With the maximum spatial size of 50% of the total population and the maximum temporal size of 50% of the total population, spatio-temporal clustering showed that there was one most likely cluster (LLR = 624.52, P<0.0001, RR = 8.19) and one second-most likely cluster (LLR = 553.97, P<0.0001, RR = 8.25), and both of these clusters appeared from 2001 to 2004. Spatial correlation analysis showed that the incidence of HFRS in Jiangsu was influenced by distances to highways, railways, rivers and lakes.
Conclusion
The application of GIS together with spatial interpolation, spatio-temporal clustering and spatial correlation analysis can effectively identify high-risk areas and factors influencing HFRS incidence to lay a foundation for researching its pathogenesis.
doi:10.1371/journal.pone.0083848
PMCID: PMC4160164  PMID: 25207806
5.  Evaluation of functional genetic variants at 6q25.1 and risk of breast cancer in a Chinese population 
Introduction
Single-nucleotide polymorphisms (SNPs) at 6q25.1 that are associated with breast cancer susceptibility have been identified in several genome-wide association studies (GWASs). However, the exact causal variants in this region have not been clarified.
Methods
In the present study, we genotyped six potentially functional single-nucleotide polymorphisms (SNPs) within the CCDC170 and ESR1 gene regions at 6q25.1 and accessed their associations with risk of breast cancer in a study of 1,064 cases and 1,073 cancer-free controls in Chinese women. The biological function of the risk variant was further evaluated by performing laboratory experiments.
Results
Breast cancer risk was significantly associated with three SNPs located at 6q25.1—rs9383935 in CCDC170 and rs2228480 and rs3798758 in ESR1—with variant allele attributed odds ratios (ORs) of 1.38 (95% confidence interval (CI): 1.20 to 1.57, P = 2.21 × 10−6), 0.84 (95% CI: 0.72 to 0.98, P = 0.025) and 1.19 (95% CI: 1.04 to 1.37, P = 0.013), respectively. The functional variant rs9383935 is in high linkage disequilibrium (LD) with GWAS-reported top-hit SNP (rs2046210), but only rs9383935 showed a strong independent effect in conditional regression analysis. The rs9383935 risk allele A showed decreased activity of reporter gene in both the MCF-7 and BT-474 breast cancer cell lines, which might be due to an altered binding capacity of miR-27a to the 3′ untranslated region (3′ UTR) sequence of CCDC170. Real-time quantitative reverse transcription PCR confirmed the correlation between rs9383935 genotypes and CCDC170 expression levels.
Conclusions
The results of this study suggest that the functional variant rs9383935, located at the 3′ UTR of CCDC170, may be one candidate of the causal variants at 6q25.1 that modulate the risk of breast cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0422-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-014-0422-x
PMCID: PMC4303231  PMID: 25116933
6.  Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4 
Nature genetics  2012;44(11):1231-1235.
Prostate cancer risk–associated variants have been reported in populations of European descent, African-Americans and Japanese using genome-wide association studies (GWAS). To systematically investigate prostate cancer risk–associated variants in Chinese men, we performed the first GWAS in Han Chinese. In addition to confirming several associations reported in other ancestry groups, this study identified two new risk-associated loci for prostate cancer on chromosomes 9q31.2 (rs817826, P = 5.45 × 10−14) and 19q13.4 (rs103294, P = 5.34 × 10−16) in 4,484 prostate cancer cases and 8,934 controls. The rs103294 marker at 19q13.4 is in strong linkage equilibrium with a 6.7-kb germline deletion that removes the first six of seven exons in LILRA3, a gene regulating inflammatory response, and was significantly associated with the mRNA expression of LILRA3 in T cells (P < 1 × 10−4). These findings may advance the understanding of genetic susceptibility to prostate cancer.
doi:10.1038/ng.2424
PMCID: PMC4116636  PMID: 23023329
7.  Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus–related hepatocellular carcinoma 
Nature genetics  2012;45(1):72-75.
To identify genetic susceptibility loci for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in the Chinese population, we carried out a genome-wide association study (GWAS) in 2,514 chronic HBV carriers (1,161 HCC cases and 1,353 controls) followed by a 2-stage validation among 6 independent populations of chronic HBV carriers (4,319 cases and 4,966 controls). The joint analyses showed that HCC risk was significantly associated with two independent loci: rs7574865 at STAT4, Pmeta = 2.48 × 10−10, odds ratio (OR) = 1.21; and rs9275319 at HLA-DQ, Pmeta = 2.72 × 10−17, OR = 1.49. The risk allele G at rs7574865 was significantly associated with lower mRNA levels of STAT4 in both the HCC tissues and nontumor tissues of 155 individuals with HBV-related HCC (Ptrend = 0.0008 and 0.0002, respectively). We also found significantly lower mRNA expression of STAT4 in HCC tumor tissues compared with paired adjacent nontumor tissues (P = 2.33 × 10−14).
doi:10.1038/ng.2483
PMCID: PMC4105840  PMID: 23242368
8.  Evaluation of the Impact of Hepatitis B Vaccination in Adults in Jiangsu Province, China 
PLoS ONE  2014;9(6):e101501.
Hepatitis B immunization programs for newborns, children, and adolescents in China have shown remarkable results. To establish whether there would be any benefit in extending the program to cover older individuals, we examined both the epidemiology of hepatitis B virus (HBV) infection and the coverage of hepatitis B vaccinations among adults born before routine vaccinations were implemented. We then evaluated the impact of hepatitis B vaccination in adults aged 20–59 years. A large-scale cross-sectional epidemiological survey of HBV infection was performed in the province of Jiangsu, south-east China, between September 2009 and March 2010. A total of 86,732 adults aged 20–59 years were included, of which 8,615 (9.9%, 95% CI = 9.7–10.1%) were HBsAg sero-positive. Self-reported vaccination status suggested that the coverage was approximately 23.7% (95% CI = 23.4–24.0%). It was shown that higher HBV vaccination coverage was associated with a lower rate of HBsAg seropositivity among adults. There was a negative correlation between hepatitis B vaccination coverage and HBsAg prevalence (correlation coefficient = −0.805, p = 0.016), which might demonstrate the combined effects of vaccination and pre-vaccination HBsAg screening. In the unvaccinated group, the HBsAg-positive rate had an obvious upward trend with age growing among 20–39 year-olds (Trend χ2 = 22.605, P<0.001), while the vaccinated group showed no such trend (Trend χ2 = 3.462, P = 0.063). Overall, hepatitis B vaccination in adults might reduce the rate of HBsAg positivity. Therefore, routine immunization of adults aged 20–39 years should be seriously considered.
doi:10.1371/journal.pone.0101501
PMCID: PMC4076282  PMID: 24979048
9.  Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls 
Human Molecular Genetics  2013;22(12):2539-2550.
In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of <0.0015. Eight of the 70 SNPs showed a significantly different association with breast cancer risk by estrogen receptor (ER) status at P < 0.05. With the exception of rs2046210 at 6q25.1, the seven other SNPs showed a stronger association with ER-positive than ER-negative cancer. This study replicated all five genetic risk variants initially identified in Asians and provided evidence for associations of breast cancer risk in the East Asian population with nearly half of the genetic risk variants initially reported in GWASs conducted in European descendants. Taken together, these common genetic risk variants explain ∼10% of excess familial risk of breast cancer in Asian populations.
doi:10.1093/hmg/ddt089
PMCID: PMC3658167  PMID: 23535825
10.  A genetic variant in pseudogene E2F3P1 contributes to prognosis of hepatocellular carcinoma 
Journal of Biomedical Research  2014;28(3):194-200.
ABSTRACT
Certain pseudogenes may regulate their protein-coding cousins by competing for miRNAs and play an active biological role in cancer. However, few studies have focused on the association of genetic variations in pseudogenes with cancer prognosis. We selected six potentially functional single nucleotide polymorphisms (SNPs) in cancer-related pseudogenes, and performed a case-only study to assess the association between those SNPs and the prognosis of hepatocellular carcinoma (HCC) in 331 HBV-positive HCC patients without surgical treatment. Log-rank test and Cox proportional hazard models were used for survival analysis. We found that the A allele of rs9909601 in E2F3P1 was significantly associated with a better prognosis compared with the G allele [adjusted hazard ratio (HR)  =  0.69, 95% confidence interval (CI)  =  0.56–0.86, P  =  0.001]. Additionally, this protective effect was more predominant for patients without chemotherapy and transcatheter hepatic arterial chemoembolization (TACE) treatment. Interestingly, we also detected a statistically significant multiplicative interaction between genotypes of rs9909601 and chemotherapy or TACE status on HCC survival (P for multiplicative interaction < 0.001). These findings indicate that rs9909601 in the pseudogene E2F3P1 may be a genetic marker for HCC prognosis in Chinese.
doi:10.7555/JBR.28.20140052
PMCID: PMC4085556  PMID: 25013402
pseudogene; E2F3P1; SNP; hepatocellular carcinoma (HCC); prognosis
11.  A Genetic Variant in Primary miR-378 Is Associated with Risk and Prognosis of Hepatocellular Carcinoma in a Chinese Population 
PLoS ONE  2014;9(4):e93707.
Background
MiR-378 has been reported to be related to cell survival, tumor growth and angiogenesis and may participate in hepatocellular carcinoma (HCC) development and prognosis. Genetic variants in primary miR-378 (pri-miR-378) may impact miR-378 expression and contribute to HCC risk and survival. This study aimed to assess the associations between a genetic variant in primary miR-378 and HCC susceptibility and prognosis.
Methods
We conducted a case-control study to analyze the association of rs1076064 in pri-miR-378 with hepatocellular carcinoma risk in 1300 HCC patients with positive hepatitis B virus (HBV) and 1344 HBV carriers. Then, we evaluated the correlation between the polymorphism and hepatocellular carcinoma prognosis in 331 HCC patients at either intermediate or advanced stage without surgical treatment.
Results
The variant genotypes of rs1076064 were associated with a decreased HCC risk in HBV carriers [Adjusted odds ratio (OR) = 0.90, 95% confidence intervals (CI) = 0.81–1.00, P = 0.047]. Moreover, HCC patients with the variant genotypes were associated with a better survival [Adjusted hazard ratio (HR) = 0.70, 95% CIs = 0.59–0.83, P<0.0001 in an additive genetic model]. The reporter gene assay showed that the variant G allele of rs1076064 exerted higher promoter activity than the A allele.
Conclusions
These findings indicate that rs1076064 may be a biomarker for HCC susceptibility and prognosis through altering pri-miR-378 transcription.
doi:10.1371/journal.pone.0093707
PMCID: PMC3994025  PMID: 24751683
12.  Genetic Variants at 10p11 Confer Risk of Tetralogy of Fallot in Chinese of Nanjing 
PLoS ONE  2014;9(3):e89636.
A recent genome-wide association study (GWAS) has identified a new subset of susceptibility loci of Tetralogy of Fallot (TOF), one form of cyanotic congenital heart disease (CHD), on chromosomes 10p11, 10p14, 12q24, 13q31, 15q13 and 16q12 in Europeans. In the current study, we conducted a case-control study in a Chinese population including 1,010 CHD cases [atrial septal defect (ASD), ventricular septal defect (VSD) and TOF] and 1,962 controls to evaluate the associations of these loci with risk of CHD. We found that rs2228638 in NRP1 on 10p11 was significantly increased the risk of TOF (OR = 1.52, 95% CI = 1.13–2.04, P = 0.006), but not in other subgroups including ASD and VSD. In addition, no significant associations were observed between the other loci and the risk of ASD, VSD or TOF. Our results suggested that the genetic variants on 10p11 may serve as candidate markers for TOF susceptibility in Chinese population.
doi:10.1371/journal.pone.0089636
PMCID: PMC3940663  PMID: 24594544
13.  Stability SCAD: a powerful approach to detect interactions in large-scale genomic study 
BMC Bioinformatics  2014;15:62.
Background
Evidence suggests that common complex diseases may be partially due to SNP-SNP interactions, but such detection is yet to be fully established in a high-dimensional small-sample (small-n-large-p) study. A number of penalized regression techniques are gaining popularity within the statistical community, and are now being applied to detect interactions. These techniques tend to be over-fitting, and are prone to false positives. The recently developed stability least absolute shrinkage and selection operator (SLASSO) has been used to control family-wise error rate, but often at the expense of power (and thus false negative results).
Results
Here, we propose an alternative stability selection procedure known as stability smoothly clipped absolute deviation (SSCAD). Briefly, this method applies a smoothly clipped absolute deviation (SCAD) algorithm to multiple sub-samples, and then identifies cluster ensemble of interactions across the sub-samples. The proposed method was compared with SLASSO and two kinds of traditional penalized methods by intensive simulation. The simulation revealed higher power and lower false discovery rate (FDR) with SSCAD. An analysis using the new method on the previously published GWAS of lung cancer confirmed all significant interactions identified with SLASSO, and identified two additional interactions not reported with SLASSO analysis.
Conclusions
Based on the results obtained in this study, SSCAD presents to be a powerful procedure for the detection of SNP-SNP interactions in large-scale genomic data.
doi:10.1186/1471-2105-15-62
PMCID: PMC3984751  PMID: 24580776
Genome-wide association study (GWAS); Interaction; Least absolute shrinkage and selection operator (LASSO); Penalized logistic regression; Smoothly clipped absolute deviation (SCAD); Stability selection
14.  Population Aging and Migrant Workers: Bottlenecks in Tuberculosis Control in Rural China 
PLoS ONE  2014;9(2):e88290.
Background
Tuberculosis is a serious global health problem. Its paradigms are shifting through time, especially in rapidly developing countries such as China. Health providers in China are at the forefront of the battle against tuberculosis; however, there are few empirical studies on health providers' perspectives on the challenges they face in tuberculosis control at the county level in China. This study was conducted among health providers to explore their experiences with tuberculosis control in order to identify bottlenecks and emerging challenges in controlling tuberculosis in rural China.
Methods
A qualitative approach was used. Semi-structured, in-depth interviews were conducted with 17 health providers working in various positions within the health system of one rural county (ZJG) of China. Data were analyzed based on thematic content analysis using MAXQDA 10 qualitative data analysis software.
Results
Health providers reported several problems in tuberculosis control in ZJG county. Migrant workers and the elderly were repeatedly documented as the main obstacles in effective tuberculosis control in the county. At a personal level, doctors showed their frustration with the lack of new drugs for treating tuberculosis patients, and their opinions varied regarding incentives for referring patients.
Conclusion
The results suggest that several problems still remain for controlling tuberculosis in rural China. Tuberculosis control efforts need to make reaching the most vulnerable populations a priority and encourage local health providers to adopt innovative practices in the local context based on national guidelines to achieve the best results. Considerable changes in China's National Tuberculosis Control Program are needed to tackle these emerging challenges faced by health workers at the county level.
doi:10.1371/journal.pone.0088290
PMCID: PMC3912209  PMID: 24498440
15.  Genetic Variations in the Flanking Regions of miR-101-2 Are Associated with Increased Risk of Breast Cancer 
PLoS ONE  2014;9(1):e86319.
Genetic variants in human microRNA (miRNA) genes may alter mature miRNA processing and/or target selection, and likely contribute to cancer susceptibility and disease progression. Previous studies have suggested that miR-101 may play important roles in the development of cancer by regulating key tumor-associated genes. However, the role of single nucleotide polymorphisms (SNPs) of miR-101 in breast cancer susceptibility remains unclear. In this study, we genotyped 11 SNPs of the miR-101 genes (including miR-101-1 and miR-101-2) in a case-control study of 1064 breast cancer cases and 1073 cancer-free controls. The results revealed that rs462480 and rs1053872 in the flank regions of pre-miR-101-2 were significantly associated with increased risk of breast cancer (rs462480 AC/CC vs AA: adjusted OR = 1.182, 95% CI: 1.030–1.357, P = 0.017; rs1053872 CG/GG vs CC: adjusted OR = 1.179, 95% CI: 1.040–1.337, P = 0.010). However, the remaining 9 SNPs were not significantly associated with risk of breast cancer. Additionally, combined analysis of the two high-risk SNPs revealed that subjects carrying the variant genotypes of rs462480 and rs1053872 had increased risk of breast cancer in a dose-response manner (Ptrend = 0.002). Compared with individuals with “0–1” risk allele, those carrying “2–4” risk alleles had 1.29-fold risk of breast cancer. In conclusion, these findings suggested that the SNPs rs462480 and rs1053872 residing in miR-101-2 gene may have a solid impact on genetic susceptibility to breast cancer, which may improve our understanding of the potential contribution of miRNA SNPs to cancer pathogenesis.
doi:10.1371/journal.pone.0086319
PMCID: PMC3901682  PMID: 24475105
16.  Spatio-Temporal Trends and Risk Factors for Shigella from 2001 to 2011 in Jiangsu Province, People's Republic of China 
PLoS ONE  2014;9(1):e83487.
Objective
This study aimed to describe the spatial and temporal trends of Shigella incidence rates in Jiangsu Province, People's Republic of China. It also intended to explore complex risk modes facilitating Shigella transmission.
Methods
County-level incidence rates were obtained for analysis using geographic information system (GIS) tools. Trend surface and incidence maps were established to describe geographic distributions. Spatio-temporal cluster analysis and autocorrelation analysis were used for detecting clusters. Based on the number of monthly Shigella cases, an autoregressive integrated moving average (ARIMA) model successfully established a time series model. A spatial correlation analysis and a case-control study were conducted to identify risk factors contributing to Shigella transmissions.
Results
The far southwestern and northwestern areas of Jiangsu were the most infected. A cluster was detected in southwestern Jiangsu (LLR = 11674.74, P<0.001). The time series model was established as ARIMA (1, 12, 0), which predicted well for cases from August to December, 2011. Highways and water sources potentially caused spatial variation in Shigella development in Jiangsu. The case-control study confirmed not washing hands before dinner (OR = 3.64) and not having access to a safe water source (OR = 2.04) as the main causes of Shigella in Jiangsu Province.
Conclusion
Improvement of sanitation and hygiene should be strengthened in economically developed counties, while access to a safe water supply in impoverished areas should be increased at the same time.
doi:10.1371/journal.pone.0083487
PMCID: PMC3885411  PMID: 24416167
17.  A Genetic Variant in the Promoter Region of miR-106b-25 Cluster Predict Clinical Outcome of HBV-Related Hepatocellular Carcinoma in Chinese 
PLoS ONE  2014;9(1):e85394.
Background
MiR-106b-25 cluster, hosted in intron 13 of MCM7, may play integral roles in diverse processes including immune response, tumorigenesis and progression. A single nucleotide polymorphism (SNP), rs999885, is located in the promoter region of MCM7. Our previous study showed that the A to G base change of rs999885 may provide an increased risk for HCC in HBV persistent carriers by altering the expression of the miR-106b-25 cluster. However, it is unknown whether rs999885 is associated with prognosis of intermediate or advanced HBV-related hepatocellular carcinoma (HCC) patients.
Methods
The SNP, rs999885, was genotyped by using the TaqMan allelic discrimination Assay in 414 intermediate or advanced HCC patients. Log-rank test and Cox proportional hazard models were used for survival analysis.
Results
The variant genotypes of rs999885 were associated with a significantly decreased risk of death for intermediate or advanced HCC [additive model: adjusted hazard ratio (HR)  = 0.76,95% confidence intervals (CI)  = 0.59–0.97]. Further stepwise regression analysis suggested that rs999885 was an independently protective factor for the prognosis of HCC in the final model (additive model: adjusted HR  = 0.72, 95% CI  = 0.56–0.91, P = 0.007).
Conclusions
These findings indicate that the A to G base change of rs999885 may provide a protective effect on the prognosis of intermediate or advanced HCC in Chinese.
doi:10.1371/journal.pone.0085394
PMCID: PMC3885710  PMID: 24416400
18.  Genome-Wide Association Study of Survival in Patients with Pancreatic Adenocarcinoma 
Gut  2012;63(1):10.1136/gutjnl-2012-303477.
Objective
Survival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma.
Design
We analyzed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1,005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (P≤10−5) were advanced to a joint analysis with 363 additional patients from China (ChinaPC).
Results
In the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21, and 1p36.13, tagged by rs12362504 (P=1.63×10−7), rs981621 (P=1.65×10−7), and rs16861827 (P=3.75×10−7), respectively. One-hundred thirty-one SNPs with P ≤ 10−5 were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; P=1.72×10−7) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The hazard ratio (95% CI) for death was 0.74 (0.66–0.84) in PanScan I, 0.79 (0.65–0.97) in ChinaPC, and 0.76 (0.68–0.84) in the joint analysis.
Conclusion
Germline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.
doi:10.1136/gutjnl-2012-303477
PMCID: PMC3816124  PMID: 23180869
Pancreatic cancer; GWAS; single nucleotide polymorphism; SET binding factor 2
19.  Genetic variants at 10q23.33 are associated with plasma lipid levels in a Chinese population 
Journal of Biomedical Research  2012;28(1):53-58.
Plasma lipid abnormalities are implicated in the pathogenic process of type 2 diabetes. The IDE-KIF11-HHEX gene cluster on chromosome 10q23.33 has been identified as a susceptibility locus for type 2 diabetes. We hypothesized that genetic variants at 10q23.33 may be associated with plasma lipid concentrations. Seven tagging single nucleotide polymorphisms (SNPs: rs7923837, rs2488075, rs947591, rs11187146, rs5015480, rs4646957 and rs1111875) at 10q23.33 were genotyped in 3,281 subjects from a Han Chinese population, using the TaqMan OpenArray and Sequenom MassARRAY platforms. Multiple linear regression analyses showed that SNP rs7923837 in the 3′-flanking region of HHEX was significantly associated with triglyceride levels (P = 0.019, 0.031 mmol/L average decrease per minor G allele) and that rs2488075 and rs947591 in the downstream region of HHEX were significantly associated with total cholesterol levels (P = 0.041, 0.058 mmol/L average decrease per minor C allele and P = 0.018, 0.063 mmol/L average decrease per minor A allele, respectively). However, the other four SNPs (rs11187146, rs5015480, rs4646957 and rs1111875) were not significantly associated with any plasma lipid concentrations in this Chinese population. Our data suggest that genetic variants in the IDE-KIF11-HHEX gene cluster at 10q23.33 may partially explain the variation of plasma lipid levels in the Han Chinese population. Further studies are required to confirm these findings in other populations.
doi:10.7555/JBR.27.20120091
PMCID: PMC3904175  PMID: 24474964
cholesterol; triglycerides; polymorphism; genetic; iDE-KIF11-HHEX
20.  Evaluation of Five Candidate Genes from GWAS for Association with Oligozoospermia in a Han Chinese Population 
PLoS ONE  2013;8(11):e80374.
Background
Oligozoospermia is one of the severe forms of idiopathic male infertility. However, its pathology is largely unknown, and few genetic factors have been defined. Our previous genome-wide association study (GWAS) has identified four risk loci for non-obstructive azoospermia (NOA).
Objective
To investigate the potentially functional genetic variants (including not only common variants, but also less-common and rare variants) of these loci on spermatogenic impairment, especially oligozoospermia.
Design, Setting, and Participants
A total of 784 individuals with oligozoospermia and 592 healthy controls were recruited to this study from March 2004 and January 2011.
Measurements
We conducted a two-stage study to explore the association between oligozoospermia and new makers near NOA risk loci. In the first stage, we used next generation sequencing (NGS) in 96 oligozoospermia cases and 96 healthy controls to screen oligozoospermia-susceptible genetic variants. Next, we validated these variants in a large cohort containing 688 cases and 496 controls by SNPscan for high-throughput Single Nucleotide Polymorphism (SNP) genotyping.
Results and Limitations
Totally, we observed seven oligozoospermia associated variants (rs3791185 and rs2232015 in PRMT6, rs146039840 and rs11046992 in Sox5, rs1129332 in PEX10, rs3197744 in SIRPA, rs1048055 in SIRPG) in the first stage. In the validation stage, rs3197744 in SIRPA and rs11046992 in Sox5 were associated with increased risk of oligozoospermia with an odds ratio (OR) of 4.62 (P  =  0.005, 95%CI 1.58-13.4) and 1.82 (P  =  0.005, 95%CI 1.01-1.64), respectively. Further investigation in larger populations and functional characterizations are needed to validate our findings.
Conclusions
Our study provides evidence of independent oligozoospermia risk alleles driven by variants in the potentially functional regions of genes discovered by GWAS. Our findings suggest that integrating sequence data with large-scale genotyping will serve as an effective strategy for discovering risk alleles in the future.
doi:10.1371/journal.pone.0080374
PMCID: PMC3841155  PMID: 24303009
21.  Pathway analyses identify TGFBR2 as potential breast cancer susceptibility gene: results from a consortium study among Asians 
Background
The transforming growth factor beta (TGF-β) signaling pathway plays a significant role in the carcinogenic process of breast cancer.
Methods
We systematically evaluated associations of common variants in TGF-β signaling pathway genes with breast cancer risk using a multi-stage, case-control study among Asian women.
Results
In the first stage, 341 single nucleotide polymorphisms (SNPs) with minor allele frequencies ≥ 0.05 across 11 genes were evaluated among 2,926 cases and 2,380 controls recruited as a part of the Shanghai Breast Cancer Genetics Study (SBCGS). In the second stage, 20 SNPs with promising associations were evaluated among an additional 1,890 cases and 2,000 controls from the SBCGS. One variant, TGFBR2 rs1078985, had highly consistent and significant associations with breast cancer risk among participants in both study stages, as well as promising results from in silico analysis. Additional genotyping was performed among 2,475 cases and 2,343 controls from the SBCGS, as well as among 5,077 cases and 5,384 controls from six studies in the Asian Breast Cancer Consortium (Stage III). Pooled analysis of all data indicated that minor allele homozygotes (AA) of TGFBR2 rs1078985 had a 24% reduced risk of breast cancer compared to major allele carriers (AG or GG) (OR: 0.76, 95% CI: 0.65–0.89, P=8.42×10−4).
Conclusion
These findings support a role for common genetic variation in TGF-β signaling pathway genes, specifically in TGFBR2, in breast cancer susceptibility.
Impact
These findings may provide new insights into the etiology of breast cancer as well as future potential therapeutic targets.
doi:10.1158/1055-9965.EPI-12-0118
PMCID: PMC3810157  PMID: 22539603
TGF-β signaling pathway; breast cancer risk; genetic variation; polymorphism
22.  Genetic variants in RAN, DICER and HIWI of microRNA biogenesis genes and risk of cervical carcinoma in a Chinese population 
Objective
Recent evidence indicates that dysregulation of microRNA (miRNA) biogenesis is implicated in cancer development and progression. Based on the important role of miRNA biogenesis genes in carcinogenesis, we hypothesized that genetic variations of the miRNA biogenesis genes may modulate susceptibility to cervical cancer.
Methods
We identified three single nucleotide polymorphisms (SNPs) located in the 3'-untranslated regions (3'-UTR) of of miRNA biogenesis key genes (rs1057035 in DICER, rs3803012 in RAN and rs10773771 in HIWI) and genotyped these SNPs in a case-control study of 1,486 cervical cancer cases and 1,549 cancer-free controls in Chinese women.
Results
Logistic regression analyses showed that no significant associations were observed between the three SNPs and cervical cancer risk [rs3803012 in RAN AG/GG vs. AA adjusted OR =1.104, 95% confidence interval (CI): 0.859-1.419; rs1057035 in DICER CT/CC vs. TT adjusted OR =0.962, 95% CI: 0.805-1.149; rs10773771 in HIWI CT/CC vs. TT adjusted OR =0.963, 95% CI: 0.826-1.122].
Conclusions
The findings did not suggest that genetic variants in the 3'-UTR of RAN, DICER and HIWI of miRNA biogenesis genes were associated with the risk of cervical cancer in this Chinese population.
doi:10.3978/j.issn.1000-9604.2013.10.03
PMCID: PMC3828428  PMID: 24255581
miRNA biogenesis gene; genetic variant; cervical cancer
23.  Weighted SNP Set Analysis in Genome-Wide Association Study 
PLoS ONE  2013;8(9):e75897.
Genome-wide association studies (GWAS) are popular for identifying genetic variants which are associated with disease risk. Many approaches have been proposed to test multiple single nucleotide polymorphisms (SNPs) in a region simultaneously which considering disadvantages of methods in single locus association analysis. Kernel machine based SNP set analysis is more powerful than single locus analysis, which borrows information from SNPs correlated with causal or tag SNPs. Four types of kernel machine functions and principal component based approach (PCA) were also compared. However, given the loss of power caused by low minor allele frequencies (MAF), we conducted an extension work on PCA and used a new method called weighted PCA (wPCA). Comparative analysis was performed for weighted principal component analysis (wPCA), logistic kernel machine based test (LKM) and principal component analysis (PCA) based on SNP set in the case of different minor allele frequencies (MAF) and linkage disequilibrium (LD) structures. We also applied the three methods to analyze two SNP sets extracted from a real GWAS dataset of non-small cell lung cancer in Han Chinese population. Simulation results show that when the MAF of the causal SNP is low, weighted principal component and weighted IBS are more powerful than PCA and other kernel machine functions at different LD structures and different numbers of causal SNPs. Application of the three methods to a real GWAS dataset indicates that wPCA and wIBS have better performance than the linear kernel, IBS kernel and PCA.
doi:10.1371/journal.pone.0075897
PMCID: PMC3786949  PMID: 24098741
24.  Genetic variant in fat mass and obesity-associated gene associated with type 2 diabetes risk in Han Chinese 
BMC Genetics  2013;14:86.
Background
Genome-wide association study (GWAS) has identified that rs8050136 C/A polymorphism in fat mass and obesity-associated gene (FTO) was associated with the risk of type 2 diabetes (T2D) in Europeans. But this association was abolished after adjustment for body mass index (BMI), suggesting that the effect of rs8050136 on T2D risk might be mediated by BMI in Europeans. However, the findings in subsequent studies were inconsistent among Asian populations. To determine whether rs8050136 polymorphism in FTO is independently associated with the risk of T2D in Chinese, we conducted a case–control study with 2,925 T2D patients and 3,281 controls in Han Chinese.
Results
Logistic regression revealed that the A allele of rs8050136 was significantly associated with an increased risk of T2D, independent of BMI (odds ratio (OR) = 1.17, 95% confidence interval (95% CI) = 1.03-1.32, p = 0.016). Meta-analysis containing 10 reported studies and our data with a total of 15,819 cases and 18,314 controls further confirmed the association between rs8050136 polymorphism and T2D risk in East Asians (OR = 1.13, 95% CI = 1.07-1.19).
Conclusions
Our findings indicate that the genetic variant in FTO may contribute to T2D risk in Han Chinese and rs8050136 polymorphism may be a genetic marker for T2D susceptibility.
doi:10.1186/1471-2156-14-86
PMCID: PMC3848839  PMID: 24053193
Fat mass and obesity-associated Gene; Genome-wide association study; Genetic susceptibility; Single nucleotide polymorphism; Type 2 diabetes
25.  Genome-Wide Association Study of Prognosis in Advanced Non–Small Cell Lung Cancer Patients Receiving Platinum-Based Chemotherapy 
Purpose
Genetic variation may influence chemotherapy response and overall survival in cancer patients.
Experimental design
We conducted a genome-wide scan in 535 advanced-stage non–small cell lung cancer (NSCLC) patients from two independent cohorts (307 from Nanjing and 228 from Beijing). A replication was carried out on an independent cohort of 340 patients from Southeastern China followed by a second validation on 409 patients from the Massachusetts General Hospital (Boston, MA).
Results
Consistent associations with NSCLC survival were identified for five single-nucleotide polymorphisms (SNP) in Chinese populations with P values ranging from 3.63 × 10−5 to 4.19 × 10−7 in the additive genetic model. The minor allele of three SNPs (rs7629386 at 3p22.1, rs969088 at 5p14.1, and rs3850370 at 14q24.3) were associated with worse NSCLC survival while 2 (rs41997 at 7q31.31 and rs12000445 at 9p21.3) were associated with better NSCLC survival. In addition, rs7629386 at 3p22.1 (CTNNB1) and rs3850370 at 14q24.3 (SNW1-ALKBH1-NRXN3) were further replicated in the Caucasian population.
Conclusion
In this three-stage genome-wide association studies, we identified five SNPs as markers for survival of advanced-stage NSCLC patients treated with first-line platinum-based chemotherapy in Chinese Han populations. Two of these SNPs, rs7629386 and rs3850370, could also be markers for survival among Caucasian patients.
doi:10.1158/1078-0432.CCR-12-1202
PMCID: PMC3723686  PMID: 22872573

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