Search

There is considerable inconsistency in results regarding the association of dietary glycemic index (GI) and glycemic load (GL) with cancer risk. We therefore conducted this systematic review and dose-response meta-analysis of prospective cohort studies to evaluate the relationship between dietary GI/GL and cancer risk.We searched PubMed and Web of Science for prospective cohort studies of dietary GI/GL in relation to risks of all types of cancer up to 31 March 2021. We used a random-effect model to calculate summary relative risks (RR) and 95% confidence intervals (CI). The certainty of evidence was assessed by the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. This study was registered at PROSPERO (CRD42020215338).Overall, 55 cohorts were included in the meta-analysis. We assessed the relationship between dietary GI or GL and risks of 23 cancer types, including hormone-related cancers, cancers from digestive system, respiratory system, urinary system and other cancer sites. High GI diet increased overall risk of cancer with low certainty of evidence (highest vs lowest categories, n = 3, RR 1.04, 95% CI 1.01-1.07). For site-specific cancers, high GI diet increased risks of lung cancer (highest vs lowest categories, n = 5, RR 1.08, 95% CI 1.01-1.18) and breast cancer (highest vs lowest categories, n = 14, RR 1.05, 95% CI 1.01-1.09), especially for postmenopausal breast cancer (highest vs lowest categories, n = 10, RR 1.06, 95% CI 1.00-1.13), all with low certainty of evidence. Additionally, dietary GI was positively related to risk of bladder cancer with low certainty of evidence (highest vs lowest categories, n = 3, RR 1.23, 95% CI 1.09-1.40), as well as negatively related to ovarian cancer risk with very low certainty of evidence (highest vs lowest categories, n = 4, RR 0.83, 95% CI 0.69-1.00) and lymphoma risk with low certainty of evidence (highest vs lowest categories, n = 2, RR 0.84, 95% CI 0.72-0.98). Besides, we found an inverse association of dietary GL with lung cancer risk with low certainty of evidence (highest vs lowest categories, n = 5, RR 0.87, 95% CI 0.80-0.94).High dietary GI increased overall cancer risk with low certainty of evidence. For site-specific cancers, high GI diet increased the risks of breast cancer with low certainty of evidence and lung cancer with low certainty of evidence. Dietary GL was inversely associated with lung cancer risk with low certainty of evidence.

Aim: To identify patients with colorectal cancer (CRC) who are at a truly higher risk of progression, which is key for individualized approaches to precision therapy. Materials & methods: We developed a predictor associated with progression-free interval (PFI) using The Cancer Genome Atlas CRC methylation data. Results: The risk score was associated with PFI in the whole cohort (p < 0.001). A nomogram consisting of the risk score and other significant clinical features was generated to predict the 3- and 5-year PFI in the whole set (area under the curve: 0.79 and 0.71, respectively). Conclusion: The risk score based on 23 DNA-methylation sites may serve as the basis for improved prediction of progression in patients with CRC in future clinical practice.

The SLC10A1 Ser267Phe (S267F) variant has been reported to severely inhibit hepatitis B virus (HBV) infection and taurocholate transport activity. This study aimed to clarify the effects of this variant on HBV infection and bile acid metabolism. SLC10A1 S267F was genotyped in 2907 HBV-exposed subjects (including HBV persistent carriers and spontaneously recovered subjects) and 1364 unexposed subjects (HBV marker-negative subjects), followed by replication I, comprising 914 exposed subjects and 1123 unexposed subjects, and replication II, comprising 355 children born to HBsAg-positive mothers (226 HBV-infected children and 129 controls). Intriguingly, SLC10A1 AA was observed only in the unexposed group, but not in the exposed group. The SLC10A1 A allele consistently decreased HBV infection risk compared with the G allele (OR = 0.76, 95% CI: 0.64-0.90 in combined samples). In addition, children with the SLC10A1 GA genotype had a reduced risk of perinatal transmission (OR = 0.31, 95% CI: 0.14-0.71). Moreover, unexposed subjects with the SLC10A1 AA genotype exhibited decreased serum total cholesterol and low-density lipoprotein cholesterol compared to those with the GG or GA genotypes (P = 2.975 × 10-4 and 0.004, respectively). The study highlighted the role of the SLC10A1 S267F variant in the loss of the ability to support HBV infection and taurocholate transport activity. Subjects with the AA genotype may escape from HBV infection and present decreased cholesterol levels as a consequence of impaired bile acid uptake.

Genome-wide association studies (GWASs) have identified approximately 100 colorectal cancer (CRC) risk loci. However, the causal genes in these loci have not been systematically interrogated. We conducted a high-throughput RNA-interference functional screen to identify the genes essential for proliferation in the CRC risk loci of Asian populations. We found that ATF1, located in the 12q13.12 region, functions as an oncogene that facilitates cell proliferation; ATF1 has the most significant effect of the identified genes and promotes CRC xenograft growth by affecting cell apoptosis. Next, by integrating a fine-mapping analysis, a two-stage affected-control study consisting of 6,213 affected individuals and 10,388 controls, and multipronged experiments, we elucidated that two risk variants, dbSNP: rs61926301 and dbSNP: rs7959129, that located in the ATF1 promoter and first intron, respectively, facilitate a promoter-enhancer interaction, mediated by the synergy of SP1 and GATA3, to upregulate ATF1 expression, thus synergistically predisposing to CRC risk (OR = 1.77, 95% CI = 1.42–2.21, p = 3.16 × 10(−7); P(multiplicative-interaction) = 1.20 × 10(−22); P(additive-interaction) = 6.50 × 10(−3)). Finally, we performed RNA-seq and ChIP-seq assays in CRC cells treated with ATF1 overexpression in order to dissect the target programs of ATF1. Results showed that ATF1 activates a subset of genes, including BRAF, NRAS, MYC, BIRC2, DAAM1, MAML2, STAT1, ID1, and NKD2, related to apoptosis, Wnt, TGF-β, and MAPK pathways, and these effects could cooperatively increase the risk of CRC. These findings reveal the clinical potential of ATF1 in CRC development and illuminate a promoter-enhancer interaction module between the ATF1 regulatory elements dbSNP: rs61926301 and dbSNP: rs7959129, and they bring us closer to understanding the molecular drivers of cancer.

Bisphenol A (BPA), a common endocrine disrupter, can be activated by cytochrome P450 (CYP) metabolizing enzymes and might influence the development of breast cancer (BC). We hypothesized that BPA could interact with CYP genes, synergistically contributing to the BC risk.Urinary BPA was measured in a total of 302 newly diagnosed BC patients and 302 healthy controls by ultra-high performance liquid chromatography-high resolution mass spectrometry. A set of seven CYP gene polymorphisms was genotyped by using the Sequenom MassARRAY system. A multivariate logistic regression model was used to assess the associations of BPA and BPA-SNP interaction with BC risk.BC patients had a higher urinary BPA concentration than healthy individuals (P 0.001). Each 1-unit increase in log-transformed urinary BPA was associated with a 54 % increased BC risk [95 % confidence interval (CI), 1.34-1.77, P 0.001]. Individuals with the CYP19A1 rs1902580 GA + AA genotype showed a significantly higher BC risk than those with the GG genotype (OR = 1.45, 95 % CI, 1.01-2.09, P 0.05). A significant BPA-CYP17A1 rs743572 interaction was found to be associated with a higher risk of BC (PThe positive association of BPA exposure with BC risk might be modified by CYP17A1 rs743572, providing evidence for the interaction effect of environment-genes on the etiology of BC.

Despite the successes of genome-wide association study (GWAS) in identifying breast cancer (BC) risk-associated variants, only a small fraction of the heritability can be explained. The greatest challenge in the post-GWAS is to identify causal variants and underlying mechanisms responsible for BC susceptibility. In this study, we integrated functional genomic data from ENCODE ChIP-seq, ANNOVAR, and the TRANSFAC matrix to identify potentially regulatory variants with modulating FOXA1-binding affinity across the whole genome, and then conducted a two-stage case-control study including 2164 cases and 2382 controls to investigate the associations between candidate SNPs and BC susceptibility. We identified a BC susceptibility SNP, rs6506689 G>T, with an odds ratio (OR) of 1.23 (95% confidence interval = 1.07-1.40, P = 0.003) under a dominant model in the combined study. Biological assays indicated that the germline G>T variation at rs6506689 creates a FOXA1-binding site and up-regulates the expression of RAB31, thus playing an important role in the development of BC. Our results highlight the importance of regulatory genetic variants in the development of BC by influencing TF-DNA interaction and provide critical insights to pinpoint causal genetic variants.

Background: Telomere dysfunction triggers cellular senescence and constitutes a driving force for cancer initiation. Genetic variants in genes involved in telomere maintenance may contribute to colorectal cancer susceptibility. Methods: In this study, we firstly captured germline mutations in 192 patients with colorectal cancer by sequencing the coding regions of 13 core components implicated in telomere biology. Five potential functional variants were then genotyped and assessed in a case–control set with 3,761 colorectal cancer cases and 3,839 healthy controls. The promising association was replicated in additional 6,765 cases and 6,906 controls. Functional experiments were used to further clarify the potential function of the significant variant and uncover the underlying mechanism in colorectal cancer development. Results: The two-stage association studies showed that a rare missense variant rs149418249 (c.C1520T and p.P507L) in the 11th exon of TPP1 (also known as ACD, gene ID 65057) was significantly associated with colorectal cancer risk with the ORs being 2.90 [95% confidence interval (CI), 1.04–8.07; P = 0.041], 2.50 (95% CI, 1.04–6.04; P = 0.042), and 2.66 (95% CI, 1.36–5.18; P = 0.004) in discovery, replication, and the combined samples, respectively. Further functional annotation indicated that the TPP1 P507L substitution interrupted TPP1–TIN2 interaction, impaired telomerase processivity, and shortened telomere length, which subsequently facilitated cell proliferation and promoted colorectal cancer development. Conclusions: A rare variant P507L in TPP1 confers increased risk of colorectal cancer through interrupting TPP1–TIN2 interaction, impairing telomerase processivity, and shrinking telomere length. Impact: These findings emphasize the important role of telomere dysfunction in colorectal cancer development, and provide new insights about the prevention of this type of cancer. Cancer Epidemiol Biomarkers Prev; 27(9); 1029–35. ©2018 AACR.

Multiple single nucleotide polymorphisms (SNPs) have been found to be highly correlated with colorectal cancer (CRC) risk. However, the variants identified thus far only explain a small part of the cases, suggesting the existence of many uncharacterised genetic determinants. In this study, using the multilevel 'omics' data provided in The Cancer Genome Atlas, we systematically performed expression quantitative trait locus (eQTL) analysis for CRC and identified nine SNPs with significant effects on mRNA expression (correlation |r| > 0.3 and FDR

The gender disparity observed in the incidence of hepatocellular carcinoma (HCC) suggests an important role of estrogens in HCC pathogenesis. In this study, we conducted a case-control study to investigate whether breast cancer risk-associated single nucleotide polymorphisms (SNPs) located at estrogens loci identified by genome-wide association studies (GWASs) also predispose to HCC in a Chinese population. Three candidate SNPs at 6q25.1 were genotyped in 2025 HCC cases and 2032 healthy controls. Differential expression analyses and expression quantitative trait loci (eQTL) analyses were conducted to further explore the potential function of significant SNPs and genes they reside in. Two of the three candidate SNPs (rs9383951 and rs9485372) were observed to be significantly associated with HCC risk. Under a dominant model, the odds ratios (OR) for rs9383951 and rs9485372 were 1.28 (95% CI: 1.10-1.49, P = 0.002) and 1.34 (95% CI: 1.17-1.53, P = 2.75 × 10-5), respectively. We also found a significant accumulative effect of these two SNPs and there was a gradual increase in OR with a greater number of hazard genotypes. Moreover, the association between rs9383951 and HCC risk was specific in males. Lower ESR1 and TAB2 expressions were investigated in hepatic tumor tissues than adjacent normal tissues. We found a significant association between rs9383951 and ESR1 expression (P = 0.047). Besides, ESR1 expression was significantly correlated with the expression of TAB2. Taken together, our study identified two genetic variants at 6q25.1 newly associated with HCC risk, suggesting ESR1 and estrogen signaling may play a role in mediating susceptibility to HCC in Chinese population.

// Ying Zhu 1, * , Kan Zhai 2, * , Juntao Ke 1 , Jiaoyuan Li 1 , Yajie Gong 1 , Yang Yang 1 , Jianbo Tian 1 , Yi Zhang 1 , Danyi Zou 1 , Xiating Peng 1 , Jing Gong 1 , Rong Zhong 1 , Kun Huang 3 , Jiang Chang 1 , Xiaoping Miao 1 1 Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 2 Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China 3 Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China * These authors contribute equally to this work Correspondence to: Jiang Chang, email: changjiang815@hust.edu.cn Xiaoping Miao, email: Miaoxp@hust.edu.cn Keywords: prognosis, pancreatic cancer, BRCA, SNP Received: February 09, 2017 Accepted: March 15, 2017 Published: March 21, 2017 ABSTRACT Pancreatic cancer is a highly lethal disease with limited prognostic marker. BRAC1 and BRCA2 are two classic tumor suppressor genes which play an important role in DNA repair. Somatic mutations and germline genetic variants on BRCA1/2 have been found associated with the tumorigenesis of pancreatic cancer. However, the correlations between BRCA1/2 polymorphism and pancreatic cancer prognosis remained unknown. In this study, we genotyped three tag missense variants on BRCA1/2 in 603 sporadic pancreatic cancer patients in a Chinese population. We found rs1799966 on BRCA1 was associated with poor prognosis of pancreatic cancer patients with hazard ratio being 1.23 (95% CI: 1.09–1.40, P = 0.0010). Further stratification analyses showed that significant correlation was particularly in locally advanced stage patients with hazard ratio being 1.36 (95% CI: 1.13–1.64, P = 0.0014), but not in patients in local stage ( P = 0.1139) or metastatic stage ( P = 0.5185). Two missense variants (rs766173 and rs144848) on BRAC2 showed no significant correlation with pancreatic cancer patients’ overall survival. In conclusion, we identified a germline missense variant on BRAC1 significantly associated with poor prognosis of pancreatic cancer patients with locally advanced stage. These results may contribute to the precision medicine of this disease.

// Yi Zhang 1, 2 , Yan Li 2 , Shaojie Jiang 3 , Wei Chen 1, 4 , Jiao Lou 1 , Juntao Ke 1 , Jiaoyuan Li 1 , Ying Zhu 1 , Yajie Gong 1 , Yang Yang 1 , Jianbo Tian 1 , Xiating Peng 1 , Danyi Zou 1 , Jing Gong 1 , Jiang Chang 1 , Xiaoping Miao 1 , Rong Zhong 1 1 Department of Epidemiology and Biostatistics and State Key Laboratory of Environment Health (Incubation), Ministry of Education Key Laboratory of Environment & Health, Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China 2 Department of Preventive Medicine, School of Public Health, Zunyi Medical University, Zunyi, Guizhou, China 3 Department of Gastroenterology, Jing Zhou Central Hospital, Jingzhou, China 4 Zhuhai Center for Chronic Disease Control, Zhuhai, China Correspondence to: Rong Zhong, email: rongzhong91@gmail.com Xiaoping Miao, email: miaoxp@mail.hust.edu.cn Keywords: breast cancer, FOXA1, genetic variants, susceptibility, case-control study Received: August 20, 2016 Accepted: October 19, 2016 Published: November 07, 2016 ABSTRACT The DNA-binding protein FOXA1 has been shown to regulate nearly all estrogen receptor-chromatin interactions, thereby influencing target gene expression levels in breast cancer (BC) cells. Recently, the rs4442975 T-allele, which disrupts the recruitment of FOXA1 and interacts with the IGFBP5 promoter, was associated to BC susceptibility in a European population. We conducted a hospital-based case-control study that included 1227 cases and 1285 controls to explore the potential association between rs4442975 and BC risk in Chinese Han population, and the effect of this SNP on BC progression was also observed in cases. No significant associations between rs4442975 and BC risk were observed under any genetic models, with an odds ratio of 0.96 (95% confidence interval = 0.81-1.15) under the additive model. When stratified based on estrogen or progesterone receptor expression, smoking or drinking habits, or menopausal status, similar negative associations were observed for all subgroups. No significant associations were observed between rs4442975 and traditional progression factors such as tumor size, nodal status, distant metastasis, or TNM staging. These results reveal that rs4442975 may not confer a risk of BC occurrence or progression in the Chinese Han population, which indicates a distinct association related to genetic heterogeneity across ethnic populations.

Background & aims Genome-wide association studies have identified multiple genetic signals associated with the risk of persistent hepatitis B virus (HBV) infection and HBV-related hepatocellular carcinoma. However, the majority of the associated variants may only be markers of functional variants and the underlying biological mechanisms remain elusive. We hypothesized that the functional variants with modulating transcription factor (TF) binding affinity in genome-wide association studies-identified loci may influence the risk of persistent HBV infection in Chinese people. Methods A systematic bioinformatics approach was implemented to prioritize potential functional variants that may influence TF binding. A two-stage case-control study, including 1595 HBV-persistent carriers and 1590 subjects with HBV natural clearance, was conducted to examine the associations between candidate variants and susceptibility to persistent HBV infection. Biological assays were carried out to elucidate the underlying mechanism of the associated genetic variants. Results Twelve candidate variants were identified, and rs2523454 G > A increased the risk of persistent HBV infection (dominant model: ORcombined = 1.37, 95% CI = 1.19-1.58, P = 1.610 × 10-5 ). Functional assays indicated that the rs2523454 A allele significantly decreased transcriptional activity compared to the G allele by influencing TF-binding affinity. In addition, expression quantitative trait loci analyses revealed that the A allele was associated with the reduced expression of MICA (P Conclusions Our findings suggest that the germline G > A variation at rs2523454 may influence TF-DNA interaction, downregulate the expression of MICA and play an important role in the development of persistent HBV infection in the Chinese population.

Biliary atresia (BA) is a major neonatal cholestatic disease and main indication for pediatric liver transplantation in the world. Recently, GPC1 has been implicated as a risk gene for BA by genetic studies and follow-up functional experiments on zebrafish.Two common genetic variants of GPC1, rs2292832 and rs3828336, were selected systematically through 'SNPinfo', and were examined using TaqMan Genotyping Assays for association studies in a Chinese population containing 134 cases and 618 controls.Of the two single nucleotide polymorphisms (SNPs), we found a significantly decreased BA risk associated with rs2292832 (additive model: OR=0.638, 95% CI: 0.467-0.873, P=0.005), and a marginal effect for rs3828336 (heterozygous model: OR=0.564, 95% CI: 0.312-1.020, P=0.058). The haplotype analysis indicated that either Crs2292832-Crs3828336Trs3828336 or Trs2292832-Trs3828336 conferred a protective effect from BA (OR=0.569, 95% CI=0.414-0.783, P0.001; OR=0.528, 95% CI: 0.301-0.926, P=0.026). Moreover, bioinformatics analysis suggested that rs2292832 altered GPC1 expression via effect on transcription-factor-binding sites (TFBS) of upstream binding transcription factor (UBTF), as a regulatory DNA variation in Deoxyribonuclease I (DNase I) hypersensitive sites (DHSs).Common variants of GPC1 gene were genetically involved in BA risk.

To examine the association between self-reported nighttime sleep duration and nonalcoholic fatty liver disease (NAFLD) risk by comparing the incidence rates of NAFLD among healthy subjects with different sleep duration during the 5 years follow-up.8965 eligible NAFLD-free subjects with a mean age of 61.6 years (males, 43.4%) from Dongfeng-Tongji cohort study at baseline were enrolled in the study. Logistic regression analysis was used to estimate the association between sleep duration and incident NAFLD with potential confounders adjusted. Sleep duration was categorized into five groups: 6 h, 6-7 h, 7-8 h, 8-9 h, ≥9 h.During the 5-years of follow-up, a total of 2,197 participants were newly diagnosed as NAFLD. Compared with those reported 7-8 h per day of nighttime sleep, the multivariable-adjusted odds ratio (95% confidence intervals) were 1.21 (1.07-1.38) for those who sleep 8-9 h/day, and 1.31 (1.13-1.52) for those who sleep over 9 h/day. However, no significant association was found with short nightly sleep duration (7 h/day).Long nighttime sleep duration was associated with a modestly increased risk of NAFLD in a middle-aged and elderly Chinese population. Key messages Long nighttime sleep duration was associated with a modestly increased risk of NAFLD in a middle-aged and elderly Chinese population. The effect of long nighttime sleep on the risk of incident NAFLD was attenuated greatly by body mass index (BMI) in men.

Genome-wide association studies (GWASs) have established chromosome 5q31.1 as a risk locus for colorectal cancer (CRC). We previously identified a potentially regulatory single nucleotide polymorphism (SNP) rs17716310 within 5q31.1. Now, we extended our study with another independent Chinese population, functional assays and analyses of TCGA (The Cancer Genome Atlas) data. Significant associations between rs17716310 and CRC risk were found in Present Study including 1075 CRC cases and 1999 controls (additive model: OR = 1.149, 95% CI = 1.027-1.286, P = 0.016), and in Combined Study including 1766 cases and 2708 controls (additive model: OR = 1.145, 95% CI = 1.045-1.254, P = 0.004). Dual luciferase reporter gene assays indicated that the variant C allele obviously increased transcriptional activity. Using TCGA datasets, we indicated rs17716310 as a cis expression quantitative trait locus (eQTL) for the gene SMAD5, whose expression was significantly higher in CRC tissues. These findings suggested that the functional polymorphism rs17716310 A > C might be a genetic modifier for CRC, promoting the expression of SMAD5 that belonged to the transforming growth factor beta (TGF-β) signaling pathway.

Bisphenol A (BPA), a well-known endocrine disruptor, was reported to promote migration and invasion of lung cancer cells, but findings in human study is absent. A case-control study in Chinese population was conducted to evaluate the association between BPA exposure and non-small cell lung cancer (NSCLC), and explore the interaction between BPA exposure and estrogen-related genetic polymorphism on NSCLC. BPA concentrations were measured in urine samples using an UHPLC-MS method and rs2046210 in estrogen receptor α (ESR1) gene was genotyped by TaqMan genotyping system. Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association analyses. As a result, 615 NSCLC cases and 615 healthy controls were enrolled from Wuhan, central China. The mean age was 58.0 (SD: 7.9) years old for controls and 59.2 (SD: 8.8) years old for cancer cases. The creatinine-adjusted BPA levels were significantly higher in NSCLC cases than that in healthy controls (median: 0.97 vs 0.73 μg/L, P 0.001). Exposure to high levels of BPA was significantly associated with NSCLC (adjusted OR = 1.91, 95%CI: 1.39-2.62, P 0.001 for the highest quartile). We also observed a shallow concave dose-response relationship about the overall association between BPA and NSCLC. Moreover, interaction analyses showed that BPA exposure interacted multiplicatively with rs2046210, with a marginal P value (P = 0.049), to contribute to NSCLC. In conclusion, exposure to high levels BPA may be associated with NSCLC and the relationship may be modified by genetic polymorphism in ESR1.

Background Genome-wide association studies (GWAS) have identified 5p15.33 as a susceptible locus for lung cancer. However, for non-small cell lung cancer (NSCLC), low-frequency risk variants in this region have not been systematically studied. We intended to explore the associations between low-frequency variants on 5p15.33 and NSCLC using a next-generation sequencing based approach in this study. Methods We have acquisited the variation spectrum of 400 NSCLC patients on 5p15.33 by sequencing the targeted region before. Candidate variants were primarily selected by restricting the minor allele frequency (MAF 1–5%) and then by comparing their frequency in 400 NSCLC patients with 1008 East Asians from The genome Aggregation Database (gnomAD). The associations between candidate variants and NSCLC were discovered and replicated in two case-control sets: discovery stage with 960 cases and 916 controls, and replication stage with 1596 cases and 1614 controls in total. Results Five low-frequency variants were selected as our candidates and subsequent association analyses showed that 2 polymorphisms were significantly associated with risk of NSCLC, including rs33963617 (OR = 0.63, 95% CI: 0.53–0.76, P = 3.80 × 10−7) in TERT and rs77518573 (OR = 0.73, 95% CI: 0.63–0.84, P = 2.00 × 10−5) in upstream of CLPTM1L. When stratified by histologic subtype, a significant association was only investigated in adenocarcinoma for rs77518573. We also observed an obvious cumulative effect of the two significant variants. Conclusions We newly identified two NSCLC related variants on chromosome 5p15.33. Both TERT-rs33963617 and CLPTM1L-rs77518573 conferred reduced risk for NSCLC in Chinese Han population.

9p21.3 has been identified as an unexpected hot point in multiple diseases GWAS including cancers, and we performed a two-stage case-control studies integrating functional assay strategy to find the potential functional variants modified susceptibility to pancreatic cancer (PC). An expanded Illumina HumanExome Beadchip of PC including 943 cases and 3908 controls was used to examine 39 tagSNPs in 9p21.3 and the promising single nucleotide polymorphism (SNP) was validated in stage 2 comprising 624 cases and 1048 controls. The strongest signal was rs6475609 (Odds ratio, OR = 0.81, 95% confidence interval, CI = 0.72-0.91) maps to the long non-coding RNA ANRIL. Bioinformatics analysis revealed rs1537373 lies in the linkage disequilibrium (LD) block which the rs6475609 tagged might have potential function and was also associated with a decreased risk of PC in both stages (OR = 0.82, 95% CI = 0.75-0.90 in combined analysis). Dual luciferase reporter assay and the electrophoretic mobility shift assay (EMSA) verified rs1537373 as the best candidate causative variant for influencing the activity of enhancer through differential binding to certain transcription factor. The expression quantitative trait loci (e-QTL) analysis indicated the genotypes of rs1537373 were associated with expression of CDKN2B gene (P dominant = 6.00 × 10-4 ). In conclusion, our study provided evidence that rs1537373 in ANRIL may influence transcription factor binding and regulate CDKN2B expression, thus confer the susceptibility to PC.

Genome-wide association studies (GWAS) of colorectal cancer have identified several common susceptible variants in gene regulatory regions. However, low-frequency or rare coding risk variants have not been systematically investigated in patients with colorectal cancer from Chinese populations. In this study, we performed an exome-wide association analysis with 1,062 patients with colorectal cancer and 2,184 controls from a Chinese population. Promising associations were further replicated in two replication sets: replication stage I with 2,478 cases and 3,880 controls, and replication stage II with 3,761 cases and 4,058 controls. We identified two variants significantly associated with colorectal cancer risk: a novel rare missense variant in TCF7L2 [rs138649767, OR = 2.08, 95% confidence interval (CI): 1.69–2.57, P = 5.66 × 10−12] and a previous European GWAS-identified 3′-UTR variant in ATF1 (rs11169571, OR = 1.18, 95% CI: 1.13–1.24, P = 1.65 × 10−12). We found a significant interaction between the TCF7L2 missense variant rs138649767 and a previous GWAS-identified regulatory variant rs6983267 in the MYC enhancer (Pinteraction = 0.0002). Functional analysis of this variant revealed that TCF7L2 with rs138649767-A allele harbored the ability to activate the MYC enhancer with rs6983267-G allele and enhance colorectal cancer cell proliferation. In addition, the ATF1 rs11169571 variant significantly correlated with ATF1 expression by affecting hsa-miR-1283 and hsa-miR-520d-5p binding. Further ChIP-seq and gene coexpression analyses showed that oncogenes NRAS and BRAF were activated by ATF1 in colorectal cancer. These results widen our understanding of the molecular basis of colorectal cancer risk and provide insight into pathways that might be targeted to prevent colorectal cancer. Significance: Exome-wide association analysis identifies a rare missense variant in TCF7L2 and a common regulatory variant in ATF1 as susceptibility factors of colorectal cancer. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/5164/F1.large.jpg. Cancer Res; 78(17); 5164–72. ©2018 AACR.

Background: The chromosome 5p15.33 has been reported as a susceptibility locus for lung cancer, but causal variants have not been fully investigated. We intended to explore functional polymorphisms associated with non-small cell lung cancer (NSCLC) susceptibility and their relationship with telomere length in Chinese population. Methods: We conducted a targeted sequencing at 5p15.33 with 400 patients. Comparing with genotypic frequency in 1000 Genomes Project, we selected candidate variants and validated their associations with NSCLC in 985 cases and 970 controls. The relationships between susceptibility SNPs and telomere length were evaluated in 774 healthy subjects. Luciferase assays and electrophoretic mobility shift assays were performed to reveal potential mechanisms. Findings: we identified 1478 variants through targeted sequencing and selected 17 candidate variants. Four polymorphisms exhibited prominent associations with lung cancer risk, including rs7726159 (OR = 1.34, 95% CI: 1.18-1.52, P = 7.78 × 10-6 )，rs10054203 (OR = 1.29, 95% CI: 1.13-1.46, P = 1.37 × 10-4 )，rs2736107 (OR = 1.28, 95% CI: 1.11-1.47, P = 5.14 × 10-4 ) and rs2853677 (OR = 1.23, 95% CI: 1.08-1.39, P = 0.002). The minor allele of rs7726159 and rs10053203 were associated with long telomeres (P = 0.008 and 0.036, respectively). Functional exploration characterized rs7726159 promoted TERT transcription through disrupting transcription factor binding. Interpretation: The functional polymorphism, rs7726159, confers lung cancer susceptibility by disturbing telomere biology. Our study illustrated the functional significance of this variant in lung cancer initiation, which provides a new insight into the important role of telomere dysfunction in tumor progression. Funding Statement: This work was supported by the National Natural Science Foundation of China (81572071). Declaration of Interests: The authors declare that they have no potential conflicts of interest. Ethics Approval Statement: Written informed consent was obtained from each individual, and this study was approved by the Institutional Review Board of the Tongji Medical College, HUST.

This is the first study to estimate the association globally between violence in childhood on educational outcomes, addressing a significant gap in the current evidence base. Systematic reviews and meta-analyses were conducted to identify 67 and 43 studies respectively from 21 countries to estimate the relationship between different types of violence in childhood on educational outcomes including school dropout/graduation, school absence, academic achievement and other educational outcomes such as grade retention, learning outcomes and remedial classes. Findings show that all forms of violence in childhood have a significant impact on educational outcomes. Children who have experienced any form of violence in childhood have a 13% predicted probability that they will not graduate from school. Males who are bullied are nearly three times more likely to be absent from school and girls who have experienced sexual violence have a three-fold increased risk of being absent, AOR 2.912, 95% CI (0.904-4.92) and AOR 3.147, 95% CI (0.033-4.57) respectively. Violence in childhood also has a significant impact on children's academic achievement on standardized tests. This study shows how different forms of violence in childhood contribute to inequalities in education-for both boys and girls and that an increased investment in prevention is needed in order to meet the global Sustainable Development Goals of ending violence, raising learning outcomes and creating safe, non-violent and inclusive learning environments. More work is also needed to further define, monitor and measure the link between violence in childhood and educational outcomes in order to achieve the Sustainable Development Goals.

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 × 10

Background: A common genetic variant rs3757318, located in intron of C6orf97, was firstly identified to be associated with breast cancer (BC) risk by a genome-wide association (GWA) study. However, subsequent validation studies with different ethnicities have yielded conflicting results. Materials and Methods: We performed a meta-analysis to synthesize all available data for evaluating the precise effect of this variant on BC susceptibility. Results: A total of 8 articles containing 11 studies with 62,891 cases and 65,635 controls were included in this meta-analysis. When compared to the G allele, the rs3757318-A allele was significantly associated with BC risk with the pooled OR of 1.21 (95% CI=1.15 - 1.29, P

The TGF-β pathway plays an essential role in regulating cell proliferation and differentiation. GWASs and candidate approaches have identified a battery of genetic variants in the TGF-β pathway contributing to colorectal cancer (CRC). However, most of the significant variants are common variants and their functions remain ambiguous. To identify causal variants with low-frequency in the TGF-β pathway contributing to CRC susceptibility in Chinese population, we performed targeted sequencing of 12 key genes in TGF-β signaling in CRC patients followed by a two-stage case-control study with a total of 5109 cases and 5169 controls. Bioinformatic annotations and biochemical experiments were applied to reveal the potential functions of significant variants. Seven low-frequency genetic variants were captured through targeted sequencing. The two stage association studies showed that missense variant rs3764482 (c. 83C>T; p. S28F) in the gene SMAD7 was consistently and significantly associated with CRC risk. Compared with the wild type, the ORs for variant allele were 1.37 (95%CI: 1.10-1.70, P = 0.005), 1.55 (95%CI: 1.30-1.86, P = 1.15 × 106 ), and 1.48 (1.29-1.70, P = 2.44 × 10;8 ) in stage 1, stage 2, and the combined analyses, respectively. Functional annotations revealed that the minor allele T of rs3764482 was more effective than the major allele C in blocking the TGF-β signaling and inhibiting the phosphorylation of receptor-regulated SMADs (R-SMADs). In conclusion, low-frequency coding variant rs3764482 in SMAD7 is associated with CRC risk in Chinese population. The rs3764482 variant may block the TGF-β signaling via impeding the activation of downstream genes, leading to cancer cell proliferation, thus contributing to CRC pathogenesis.

Food safety is a global public health issue, which often arises from asymmetric information between consumers and suppliers. With the development of information technology in human life, building a food traceability information sharing platform is viewed as one of the best ways to overcome the trust crisis and resolve the problem of information asymmetry in China. However, among the myriad information available from the food supply chain, there is a lack of knowledge on consumer preference. Based on the best-worst scaling approach, this paper investigated consumer preferences for vegetable, pork, and dairy product traceability information. Specifically, this paper measured the relative importance that consumers place on the traceable information. The results indicate that consumers have varying priorities for information in different cases. "Pesticide/veterinary use," "picking/slaughtering date," and "fertilizer/feed use" are the most preferred traceable information for Chinese consumers in the case of vegetables, while "picking/slaughtering date" and "history of illness and taking protective measures" are the most preferred information in the case of pork. In the case of dairy products, consumers prefer "processing information," "environmental information of the origin," and "traceable tag certification information" most. The results of this study call for the direct involvement of the Chinese government in the food safety information sharing system as following. First, given consumers' diverse preferences, different types of traceable information should be recorded into the information sharing platform depending on food types. Second, the government could promote the step-by-step construction of such a platform based on the priority of consumers' preferences. Third, new technology should be applied to guarantee the reliability of traceable information. Finally, local preferences in terms of the way consumers receive and understand information should be taken into consideration.

Genome-wide association studies (GWASs) have identified dozens of susceptibility loci for colorectal cancer (CRC). However, most of them lack functional genetic variants and clear biological mechanisms. MicroRNAs (miRNAs) are small noncoding RNAs involved in a variety of physiological and tumorigenic processes. Here we hypothesized that single nucleotide polymorphisms (SNPs) that affect miRNAs biogenesis and binding, could contribute to CRC risk in the Chinese population. To locate miRNA-related SNPs in established GWAS loci, we initially screened out five candidate SNPs using a systematic bioinformatics analysis. Then, we performed a two-stage case-control study consisting of 2347 cases and 3390 controls, and found a positive polymorphism rs1062044, which presented consistently significant associations with CRC in both stages, and with an odds ratio (OR) = 1.32 (95% confidence interval (95%CI) = 1.18-1.49, P = 3.43E-06) under the dominant model in the combined study. Further luciferase reporter gene assays indicated that the variant G allele obviously improved the specific binding between miR-423-5p and the gene LAMC1. These findings suggested that the functional SNP rs1062044 at 1q25.3 might be a genetic modifier for the occurrence and development of CRC.

Genome-wide association studies (GWASs) have identified multiple single nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) susceptibility. However, the elucidation of causal SNPs and the biological mechanisms behind are still limited. In this study, we initially performed systematic bioinformatics analyses on CRC GWAS-identified loci to seek for potential functional SNPs located at transcription factor binding sites (TFBSs), and then a two-stage case-control study comprised of 1353 cases and 1448 controls of Chinese populations and functional analyses were conducted. As a result, only one SNP rs6695837 out of the nine candidate SNPs survived after two-stage analyses by Bonferroni correction. In combined analyses, rs6695837 exhibited significant associations with CRC risk (TT: CC, odds ratio (OR) = 1.31, 95% confidence interval (CI) = 1.06-1.63; dominant model, OR = 1.21, 95% CI = 1.03-1.43; additive model, OR = 1.15, 95% CI = 1.03-1.28). Functional annotations by RegulomeDB and rSNPBase indicated its biological role and dual-luciferase reporter assays revealed a significant increase in luciferase expression for the reconstructed plasmid with rs6695837T allele, compared with the one with C allele (PSW480 = 0.0002, PLovo = 0.0003). Further gene expression analyses demonstrated significantly higher expression of LAMC1 gene in CRC tumor tissues than that in adjacent non-cancerous tissues (P = 0.0004). These findings strongly suggest that the functional SNP located at TFBSs, rs6695837 might contribute to CRC susceptibility, and the exact biological mechanism awaits further research.

The study aimed to assess the association between total, direct and indirect bilirubin and nonalcoholic fatty live disease (NAFLD) risk given its high prevalence and serious clinical prognosis. Among 27,009 subjects who participated in a healthy screening program from the Dongfeng-Tongji cohort study in 2008, 8189 eligible subjects (aged 35–86 years; males, 43.95%) were ultimately enrolled. The incidence rates of NAFLD in 2013 were compared with respect to baseline bilirubin levels among subjects free of NAFLD and the effect sizes were estimated by logistic regression analysis. During 5 years follow-up, we observed 1956 cases of newly developed NAFLD with the overall incidence of 23.88%. Direct bilirubin was presented to inversely associate with NAFLD risk. Compared with quartile 1 of direct bilirubin, the multivariable-adjusted ORs (95% CIs) for NAFLD of quartile 2 to 4 were 1.104 (0.867–1.187), 0.843 (0.719–0.989) and 0.768 (0.652–0.905), respectively, P for trend 0.002). Similarly, inverse effects of direct bilirubin on NAFLD incidence were also observed when stratified by sex and BMI. However, no significant associations were found between total and indirect bilirubin and NAFLD risk. Direct bilirubin reduced NAFLD risk independent of possible confounders among middle-aged and elderly Chinese population, probably based on the endogenous antioxidation of bilirubin.

For many years, the question of whether hyperglycaemia, a manifestation of prediabetes, diabetes mellitus and metabolic syndrome, is a risk factor for colorectal cancer has been intensely studied. In fact, even after the conclusion of several prospective studies, the topic is still controversial. We conducted a systematic review and meta-analysis to investigate the dose-response relationship between blood glucose concentration and the incidence of colorectal cancer. A linear (P = 0.303 for non-linearity) dose-response relationship was observed between fasting plasma glucose (FPG) and colorectal cancer risk without significant heterogeneity. The relative risk (RR) for colorectal cancer per 20 mg/dL increase in FPG was 1.015 (95% CI: 1.012–1.019, P = 0.000). In subgroup analyses, the pooled RRs for colon cancer (CC) and rectal cancer (RC) studies were 1.035 (95% CI 1.008–1.062, P = 0.011) and 1.031 (95% CI: 0.189–5.628, P = 0.972), respectively; in the analysis comparing men and women, the pooled RRs were 1.016 (95% CI: 1.012–1.020, P = 0.000) and 1.011 (95% CI: 0.995–1.027, P = 0.164), respectively. Sensitivity analyses using two methods showed similar results. In conclusion, there is a significant linear dose-response relationship between FPG and the incidence risk of colorectal cancer. For people with diabetes or prediabetes, controlling blood glucose might be useful to prevent colorectal cancer.

Genome-wide association studies (GWASs) have identified multiple susceptibility loci of colorectal cancer (CRC), however, causative polymorphisms have not been fully elucidated. Long non-coding RNAs (lncRNAs) are a recently discovered class of non-protein coding RNAs that involved in a wide variety of biological processes. We hypothesized that single nucleotide polymorphisms (SNPs) in lncRNA may associate with the CRC risk by influencing lncRNA functions. To evaluate the effects of SNPs on CRC susceptibility in Chinese populations, we first screened out all potentially functional SNPs in exons of lncRNAs located in CRC susceptibility loci identified by GWAS. Eight SNPs were selected and genotyped in 875 CRC cases and 855 controls and replicated in an independent case-control study consisting of 768 CRC cases and 768 controls. Analyses showed that CG and GG genotypes of the rs2147578 were significantly associated with increased risk for CRC occurrence in both case-control studies [combined analysis OR = 1.29; 95% confidence interval (CI) = 1.11-1.51, P = 0.001] compared to the rs2147578 CC genotype. Bioinformatics analyses showed that rs2147578 is located in the transcript of lnc-LAMC2-1:1 and could influence the binding of lnc-LAMC2-1:1/miR-128-3p. Further luciferase reporter assays demonstrated that the construct with the risk rs2147578G allele had relatively high expression activity compared with that of the rs2147578C allele. Expression quantitative trait loci analyses also showed that rs2147578 is correlated with the expression of a well established oncogene LAMC2 (laminin subunit gamma 2). These findings indicated that rs2147578 in lnc-LAMC2-1:1 might be a genetic modifier for the development of CRC.

Large-scale genome-wide association studies (GWAS) have established chromosome 5q31.1 as a susceptibility locus for colorectal cancer (CRC), which was still lack of causal genetic variants. We searched potentially regulatory single nucleotide polymorphisms (SNPs) in the overlap region between linkage disequilibrium (LD) block of 5q31.1 and regulatory elements predicted by histone modifications, then tested their association with CRC via a case-control study. Among three candidate common variants, we found rs17716310 conferred significantly (heterozygous model: OR = 1.273, 95% confidence interval (95%CI) = 1.016-1.595, P = 0.036) and marginally (dominant model: OR = 1.238, 95%CI = 1.000-1.532, P = 0.050) increase risk for CRC in a Chinese population including 695 cases and 709 controls. This variation was suggested to be regulatory altering the activity of enhancer that control PITX1 expression. Using epigenetic information such as chromatin immunoprecipitation-sequencing (ChIP-seq) data might help researchers to interpret the results of GWAS and locate causal variants for diseases in post-GWAS era.

The spindle assembly checkpoint (SAC) has been established as an important mechanism of driving aneuploidy, which occurs at a high frequency in the colorectal tumorigenesis. Two important components of SAC are MAD1L1 and MAD2L1, which function together in an interactive manner to initiate the checkpoint signal. We hypothesize that genetic variants in the binding domains of MAD1L1 and MAD2L1 may modulate protein structures and eventually contribute to CRC susceptibility. A case-control study including 710 CRC cases and 735 controls was performed to examine MAD1L1 Arg558His and MAD2L1 Leu84Met’s conferring susceptibility to CRC. Cytokinesis-block micronucleus cytome assays were applied to assess the effect of two functional variants on chromosomal instability (CIN). Significant associations with CRC risk were observed for MAD1L1 Arg558His (OR = 1.38,95% CI: 1.09–1.75) and MAD2L1 Leu84Met in a dominant model (OR = 1.48,95% CI: 1.09–2.01). Moreover, significant multiplicative gene-smoking interactions were found in MAD1L1 Arg558His (P = 0.019) and MAD2L184 Leu/Met (P = 0.016) to enhance CRC risk. Additionally, the frequencies of lymphocytic micro-nucleated binucleated cells for MAD1L1 Arg558His polymorphism were significantly different in the exposed group (P = 0.013), but not in the control group. The study emphasized that MAD1L1 Arg558His and MAD2L1 Leu84Met can significantly interact with smoking to enhance CRC risk and the genetic effects of MAD1L1Arg558His on CIN need to be further clarified in follow-up studies.

It is well-established that abnormal protein phosphorylation could play an essential role in tumorgenesis by disrupting a variety of physiological processes such as cell growth, signal transduction and cell motility. Moreover, increasing numbers of phosphorylation-related variants have been identified in association with cancers. ADD1 (α-adducin), a versatile protein expressed ubiquitously in eukaryotes, exerts an important influence on membrane cytoskeleton, cell proliferation and cell-cell communication. Recently, a missense variant at the codon of ADD1’s phosphorylation site, rs4963 (Ser586Cys), was reported to modify the risk of non-cardia gastric cancer. To explore the role of ADD1-rs4963 in colorectal cancer (CRC), we conducted a case-control study with a total of 1054 CRC cases and 1128 matched controls in a Chinese population. After adjustment for variables including age, gender, smoking and drinking, it was demonstrated that this variant significantly conferred susceptibility to CRC (G versus C: OR = 1.16, 95% CI = 1.03–1.31, P = 0.016; CG versus CC: OR = 1.25, 95% CI = 1.02–1.55, P = 0.036; GG versus CC: OR = 1.35, 95% CI = 1.06–1.72, P = 0.015). We further investigated the interaction of ADD1-rs4963 with smoking or drinking exposure, but found no significant result. This study is the first report of an association between ADD1 and CRC risk, promoting our knowledge of the genetics of CRC.

The role of Body Mass Index (BMI) for Breast Cancer (BC) remains to be great interest for a long time. However, the precise effect of nonlinear dose-response for BMI and BC risk is still unclear. We conducted a dose-response meta-analysis to quantitatively assess the effect of BMI on BC risk. Twelve prospective studies with 4,699 cases identified among 426,199 participants and 25 studies of 22,809 cases identified among 1,155,110 participants in premenopausal and postmenopausal groups, respectively, were included in this meta-analysis. Significant non-linear dose-response (P < 0.001) association was identified between BMI and BC risk in postmenopausal women. Individuals with BMI of 25, 30, and 35 kg/m2 yielded relative risks (RRs) of 1.02 [95% confidence interval (CI): 0.98–1.06], 1.12 (95% CI: 1.01–1.24), and 1.26 (95% CI: 1.07–1.50), respectively, when compared to the mean level of the normal BMI range. However, inverse result though not significant was observed in premenopausal women. In conclusion, the results of this meta-analysis highlighted that obesity contributed to increased BC risk in a nonlinear dose-response manner in postmenopausal women, and it is important to realize that body weight control may be a crucial process to reduce BC susceptibility.

Epidemiological studies have investigated the potential anticancer effects of mushroom intake. This review aims to clarify the evidence on the association of dietary mushroom intake with breast cancer risk and to quantify its dose-response relationship. Relevant studies were identified by a search of PubMed, Web of Science and Google Scholar up to December 31, 2013. Observational studies with relative risks (RRs) or hazard ratios (HRs) or odd ratios (ORs) and 95% confidence intervals (CIs) of breast cancer for three or more categories of mushroom intake were eligible. The quality of included studies was assessed by using Newcastle-Ottawa Scale. A dose-response meta-analysis was performed by utilizing generalized least squares trend estimation. Eight case-control studies and two cohort studies with a total of 6890 cases were ultimately included. For dose-response analysis, there was no evidence of non-linear association between mushroom consumption and breast cancer risk (P = 0.337) and a 1 g/d increment in mushroom intake conferred an RR of 0.97 (95% CI: 0.96-0.98) for breast cancer risk, with moderate heterogeneity (I(2) = 56.3%, P = 0.015). Besides, available menopause data extracted from included studies were used to evaluate the influence of menopausal statues. The summary RRs of mushroom consumption on breast cancer were 0.96 (95% CI: 0.91-1.00) for premenopausal women and 0.94 (95% CI: 0.91-0.97) for postmenopausal women, respectively. Our findings demonstrated that mushroom intake may be inversely associated with risk of breast cancer, which need to be confirmed with large-scale prospective studies further.

BACKGROUND: To investigate the association between rs1820453 which located in the promoter region of yes-associated protein 1 (YAP1) gene and breast cancer (BC) risk. METHOD AND FINDINGS: We conducted a hospital-based case-control study including a total of 480 BC cases and 545 cancer-free controls in Chinese population. Then the expression quantitative trait locus (e-QTL) analysis was performed to explore the possible function of rs1820453 to the YAP1 gene expression. The association between rs1820453 and BC risk was significantly identified with the odds ratio (OR) was 1.27 (95 % confidence interval (CI) =1.03-1.57) under allelic model when adjusted by age and menopausal status. In addition, the correlation analysis of rs1820453 and YAP1 expression level found that this variant was significantly associated with the gene expression in Chinese population. When compared with level of mRNA expression of the AA genotype (6.011 ± 0.046), the mRNA expression level in CC genotype (5.903 ± 0.026) was statistically lower (P=0.024). CONCLUSION: The results from this study suggested that rs1820453 A>C change may affect the gene expression and contribute to the risk of developing BC in Chinese population though larger sample-size studies along with functional experiments were anticipated to warrant the results.

Genome-wide association studies (GWASs) of breast cancer (BC) have identified multiple risk variants. However, the multiple interactions among these variants are still not well established. In this study, we utilized the multi-analytic strategy combing random forest (RF), multifactor dimensionality reduction (MDR), and logistic regression approaches to investigate the high-order interactions among ten genetic variants recently identified by GWAS in 477 BC patients and 534 healthy controls. Expectedly, six variants, rs1219648, rs3757318, rs1926657, rs6556756, rs2046210, and rs4973768, were significantly associated with BC risk under independent analysis. In RF analysis, rs3757318, rs2046210, and rs4973768 were ranked as the top three important risk factors and were selected as the best set which taking interactions into consideration. Subsequently, the MDR analysis of the ten variants found that the three-factor model including rs3757318, rs2046210, and rs4973768 interpret the best interaction model with the maximized testing accuracy of 0.6183 and cross-validation consistency of 10/10. Intriguingly, cumulative effect was observed in the manner of dose-dependent with increasing numbers of risk alleles (P trend = 9.80 × 10−5), and the individuals carrying 4–6 risk alleles had a threefold higher risk of BC than carrying 0 risk alleles (OR 3.27, 95 % CI 1.96–5.48). Our findings emphasized the proof of principle that multiple interactions of genetic variants, including rs3757318, rs2046210, and rs4973768 may play important roles in the susceptibility of BC though the biological mechanisms underlying the observed associations need to be elucidated.