Showing papers by "Huan Guo published in 2014"

A genome wide association study of genetic loci that influence tumour biomarkers cancer antigen 19-9, carcinoembryonic antigen and α fetoprotein and their associations with cancer risk

Abstract: Objective Tumour biomarkers are used as indicators for cancer screening and as predictors for therapeutic responses and prognoses in cancer patients. We aimed to identify genetic loci that influence concentrations of cancer antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA) and α fetoprotein (AFP), and investigated the associations between the significant single nucleotide polymorphisms (SNPs) with risks of oesophageal squamous cell (OSCC), pancreatic and hepatocellular cancers. Design We carried out a genome wide association study on plasma CA19-9, CEA and AFP concentrations in 3451 healthy Han Chinese and validated the results in 10 326 individuals. Significant SNPs were further investigated in three case control studies (2031 OSCC cases and 2044 controls; 981 pancreatic cancer cases and 1991 controls; and 348 hepatocellular cancer cases and 359 controls). Results The analyses showed association peaks on three genetic loci for CA19-9 ( FUT6-FUT3 at 19p13.3, FUT2 - CA11 at 19q13.3 and B3GNT3 at 19p13.1; p=1.16×10 −13 –3.30×10 −290 ); four for CEA ( ABO at 9q34.2, FUT6 at 19p13.3, FUT2 at 19q13.3 and FAM3B at 21q22.3; p=3.33×10 −22 –5.81×10 −209 ); and two for AFP ( AFP at 4q11-q13 and HISPPD2A at 15q15.3; p=3.27×10 −18 and 1.28×10 −14 ). These explained 17.14% of the variations in CA19-9, 8.95% in CEA and 0.57% in AFP concentrations. Significant ABO variants were also associated with risk of OSCC and pancreatic cancers, and AFP variants with risk of hepatocellular cancer (p Conclusions This study identified several loci associated with CA19-9, CEA and AFP concentrations. The ABO variants were associated with risk of OSCC and pancreatic cancers and AFP variants with risk of hepatocellular cancer.

A genome-wide association study identifies common variants influencing serum uric acid concentrations in a Chinese population

Abstract: Background: Uric acid (UA) is a complex phenotype influenced by both genetic and environmental factors as well as their interactions. Current genome-wide association studies (GWASs) have identified a variety of genetic determinants of UA in Europeans; however, such studies in Asians, especially in Chinese populations remain limited. Methods: A two-stage GWAS was performed to identify single nucleotide polymorphisms (SNPs) that were associated with serum uric acid (UA) in a Chinese population of 12,281 participants (GWAS discovery stage included 1452 participants from the Dongfeng-Tongji cohort (DFTJ-cohort) and 1999 participants from the Fangchenggang Area Male Health and Examination Survey (FAMHES). The validation stage included another independent 8830 individuals from the DFTJ-cohort). Affymetrix Genome-Wide Human SNP Array 6.0 chips and Illumina Omni-Express platform were used for genotyping for DFTJ-cohort and FAMHES, respectively. Gene-environment interactions on serum UA levels were further explored in 10,282 participants from the DFTJ-cohort. Results: Briefly, we identified two previously reported UA loci of SLC2A9 (rs11722228, combined P = 8.98 × 10 -31 ) and ABCG2 (rs2231142, combined P = 3.34 × 10 -42 ). The two independent SNPs rs11722228 and rs2231142 explained 1.03% and 1.09% of the total variation of UA levels, respectively. Heterogeneity was observed across different populations. More importantly, both independent SNPs rs11722228 and rs2231142 were nominally significantly interacted with gender on serum UA levels (P for interaction = 4.0 × 10 -2 and 2.0 × 10 -2 , respectively). The minor allele (T) for rs11722228 in SLC2A9 has greater influence in elevating serum UA levels in females compared to males and the minor allele (T) of rs2231142 in ABCG2 had stronger effects on serum UA levels in males than that in females. Conclusions: Two genetic loci (SLC2A9 and ABCG2) were confirmed to be associated with serum UA concentration. These findings strongly support the evidence that SLC2A9 and ABCG2 function in UA metabolism across human populations. Furthermore, we observed these associations are modified by gender.

Women are more susceptible than men to oxidative stress and chromosome damage caused by polycyclic aromatic hydrocarbons exposure

Abstract: Exposure to environmental polycyclic aromatic hydrocarbons (PAHs) has been associated with increased risk of cancer, but evidence for gender differences in this association is limited. The aim of this study was to examine the gender differences in PAHs caused early genotoxic effects such as oxidative stress and chromosome damage, which are potential carcinogenic etiology of PAHs. A total of 478 nonsmoking workers (272 men and 206 women) from a coke oven plant were recruited. We determined 16 environmental PAHs in their workplaces, and measured concentrations of 12 urinary PAH metabolites (OH-PAHs), plasma benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydotetrol-albumin (BPDE-Alb) adducts, urinary 8-hydroxydeoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α), and micronucleus frequencies in lymphocytes in all subjects. It showed that, women working at the office, adjacent to the coke oven, and on the bottom or side of the coke oven displayed significantly higher levels of urinary 8-OHdG and 8-iso-PGF2α, and lymphocytic micronucleus frequencies compared with men working at above areas, respectively (all P < 0.05). These gender differences remain significant after adjusted for potential confounders and urinary ΣOH-PAHs or plasma BPDE-Alb adducts. A significant interaction existed between gender and BPDE-Alb adducts on increasing micronucleus frequencies (Pinteraction < 0.001). We further stratified all workers by the tertiles of urinary ΣOH-PAHs or plasma BPDE-Alb adducts, and the above gender differences were more evident in the median- and high-exposure groups (all P < 0.05). In conclusion, women were more susceptible than men to oxidative stress and chromosome damage induced by PAHs, which may add potential evidence underlying gender differences in PAH exposure-related lung cacinogenesis. Environ. Mol. Mutagen. 55:472–481, 2014. © 2014 Wiley Periodicals, Inc.

A genome-wide gene–environment interaction analysis for tobacco smoke and lung cancer susceptibility

Abstract: Tobacco smoke is the major environmental risk factor underlying lung carcinogenesis. However, approximately one-tenth smokers develop lung cancer in their lifetime indicating there is significant individual variation in susceptibility to lung cancer. And, the reasons for this are largely unknown. In particular, the genetic variants discovered in genome-wide association studies (GWAS) account for only a small fraction of the phenotypic variations for lung cancer, and gene-environment interactions are thought to explain the missing fraction of disease heritability. The ability to identify smokers at high risk of developing cancer has substantial preventive implications. Thus, we undertook a gene-smoking interaction analysis in a GWAS of lung cancer in Han Chinese population using a two-phase designed case-control study. In the discovery phase, we evaluated all pair-wise (591 370) gene-smoking interactions in 5408 subjects (2331 cases and 3077 controls) using a logistic regression model with covariate adjustment. In the replication phase, promising interactions were validated in an independent population of 3023 subjects (1534 cases and 1489 controls). We identified interactions between two single nucleotide polymorphisms and smoking. The interaction P values are 6.73 × 10(-) (6) and 3.84 × 10(-) (6) for rs1316298 and rs4589502, respectively, in the combined dataset from the two phases. An antagonistic interaction (rs1316298-smoking) and a synergetic interaction (rs4589502-smoking) were observed. The two interactions identified in our study may help explain some of the missing heritability in lung cancer susceptibility and present strong evidence for further study of these gene-smoking interactions, which are benefit to intensive screening and smoking cessation interventions.

Polycyclic aromatic hydrocarbons-associated microRNAs and their interactions with the environment: influences on oxidative DNA damage and lipid peroxidation in coke oven workers.

Abstract: We previously identified five polycyclic aromatic hydrocarbons (PAHs)-associated microRNAs (miRNAs) and found they were associated with chromosome damage. As oxidative damage is the common contributory cause of various PAHs-related diseases, we further investigated the influences of these miRNAs and their interactions with environmental factors on oxidative DNA damage and lipid peroxidation. We measured PAHs internal exposure biomarkers [urinary monohydroxy-PAHs (OH-PAHs) and plasma benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydotetrol-albumin (BPDE-Alb) adducts], the expression levels of PAHs-associated plasma miRNAs (miR-24-3p, miR-27a-3p, miR-142-5p, miR-28-5p, and miR-150-5p), and urinary biomarkers of oxidative DNA damage [8-hydroxydeoxyguanosine (8-OH-dG)] and lipid peroxidation [8-iso-prostaglandin-F2α (8-iso-PGF2α)] in 365 healthy male coke oven workers. These miRNAs were associated with a dose-response increase in 8-OH-dG (β > 0), and with a dose-response decrease in 8-iso-PGF2α (β 0) to influence 8-OH-dG, while they interacted synergistically with BPDE-Alb adducts (βinteraction > 0) and antagonistically with smoking status (βinteraction < 0) to influence 8-iso-PGF2α. Our results suggested that miRNAs and their interactions with environmental factors might be novel mechanisms mediating the effects of PAHs exposure on oxidative DNA damage and lipid peroxidation.

A genome-wide gene–gene interaction analysis identifies an epistatic gene pair for lung cancer susceptibility in Han Chinese

Abstract: Lung cancer is the leading cause of cancer-related deaths worldwide. By now, genome-wide association studies (GWAS) have identified numerous loci associated with the risk of developing lung cancer. However, these loci account for only a small fraction of the familial lung cancer risk. We hypothesized that epistasis may contribute to the missing heritability. To test this hypothesis, we systematically evaluated the association of epistasis of genetic variants with risk of lung cancer in Han Chinese cohorts. We conducted a pairwise genetic interaction analysis of 591370 variants, using BOolean Operation-based Screening and Testing (BOOST), in an ongoing GWAS of lung cancer that includes 2331 cases and 3077 controls. Pairs of epistatic loci with P BOOST ≤ 1.00×10−6 were further evaluated by a logistic regression model (LRM) with covariate adjustment. Four promising epistatic pairs identified at the screening stage (P LRM ≤ 2.86×10− 13) were validated in two replication cohorts: the first from Beijing (1534 cases and 1489 controls) and the second from Shenyang and Guangzhou (2512 cases and 2449 controls). Using this combined analysis, we identified an interaction between rs2562796 and rs16832404 at 2p32.2 that was significantly associated with the risk of developing lung cancer (P LRM = 1.03×10−13 in total 13 392 subjects). This study is the first investigation of epistasis for lung cancer on a genome-wide scale in Han Chinese. It addresses part of the missing heritability in lung cancer risk and provides novel insight into the multifactorial etiology of lung cancer.

Polymorphisms in DNA repair genes, hair dye use, and the risk of non-Hodgkin lymphoma.

Abstract: Genetic polymorphisms in DNA repair genes and hair dye use may both have a role in the development of non-Hodgkin lymphoma (NHL). We aimed to examine the interaction between variants in DNA repair genes and hair dye use with risk of NHL in a population-based case–control study of Connecticut women. We examined 24 single nucleotide polymorphisms in 16 DNA repair genes among 518 NHL cases and 597 controls and evaluated the associations between hair dye use and risk of overall NHL and common NHL subtypes, stratified by genotype, using unconditional logistic regression. Women who used hair dye before 1980 had a significantly increased risk of NHL, particularly for the follicular lymphoma (FL) subtype, but not for diffuse large B-cell lymphoma. The following genotypes in combination with hair dye use before 1980 were associated with FL risk: BRCA2 rs144848 AC+CC [odds ratio (OR) (95 % confidence interval (CI)) 3.28(1.27–8.50)], WRN rs1346044 TT [OR(95 % CI) 2.70(1.30–5.65)], XRCC3 rs861539 CT+TT [OR(95 % CI) 2.76(1.32–5.77)], XRCC4 rs1805377 GG [OR(95 % CI) 2.07(1.10–3.90)] and rs1056503 TT [OR(95 % CI) 2.17(1.16–4.07)], ERCC1 rs3212961 CC [OR(95 % CI) 1.93(1.00–3.72)], RAD23B rs1805329 CC [OR(95 % CI) 2.28(1.12–4.64)], and MGMT rs12917 CC, rs2308321 AA, and rs2308327 AA genotypes [OR(95 % CI) 1.96(1.06–3.63), 2.02(1.09–3.75), and 2.23(1.16–4.29), respectively]. In addition, a significant interaction with risk of overall NHL was observed between WRN rs1346044 and hair dye use before 1980 (p interaction = 0.032). Our results indicated that genetic variation in DNA repair genes modifies susceptibility to NHL in relation to hair dye use, particularly for the FL subtype and in women who began using hair dye before 1980. Further studies are needed to confirm these observations.

Associations between 25 Lung Cancer Risk–Related SNPs and Polycyclic Aromatic Hydrocarbon–Induced Genetic Damage in Coke Oven Workers

Abstract: Background: Genome-wide association studies (GWAS) have identified multiple single-nucleotide polymorphisms (SNP) associated with lung cancer. However, whether these SNPs are associated with genetic damage, a crucial event in cancer initiation and evolution, is still unknown. We aimed to establish associations between these SNPs and genetic damage caused by the ubiquitous carcinogens, polycyclic aromatic hydrocarbons (PAH). Methods: We cross-sectionally investigated the associations between SNPs from published GWAS for lung cancer in Asians and PAH-induced genetic damage in 1,557 coke oven workers in China. Urinary PAH metabolites, plasma benzo[a]pyrene-r-7,t-8,c-10-tetrahydrotetrol-albumin (BPDE-Alb) adducts, urinary 8-hydroxydeoxyguanosine (8-OHdG), and micronuclei (MN) frequency were determined by gas chromatography-mass spectrometry, sandwich ELISA, high-performance liquid chromatography, and cytokinesis-block micronucleus assay, respectively. Results: 13q12.12-rs753955C was suggestively associated with elevated 8-OHdG levels ( P = 0.003). Higher 8-OHdG levels were observed in individuals with rare allele homozygotes (CC) than in TT homozygotes (β, 0.297; 95% confidence interval, 0.124–0.471; P = 0.001). 9p21-rs1333040C, 10p14-rs1663689G, and 15q25.1-rs3813572G were significantly associated with lower MN frequency ( P values were 0.002, 0.001, and 0.005, respectively). 10p14-rs1663689G polymorphism downregulated the relationship of the total concentration of PAH metabolites to 8-OHdG levels ( P interaction = 0.002). TERT -rs2736100G and VTI1A -rs7086803A aggravated the relationship of BPDE-Alb adducts to MN frequency, whereas BPTF -rs7216064G attenuated that correlation (all P interaction < 0.001). Conclusions: Lung cancer risk–associated SNPs and their correlations with PAH exposure were associated with 8-OHdG levels and MN frequency. Impact: Lung cancer risk–associated SNPs might influence one's susceptibility to genetic damage caused by PAHs. Cancer Epidemiol Biomarkers Prev; 23(6); 986–96. ©2014 AACR .

Prenatal Exposure to Polycyclic Aromatic Hydrocarbons and Birth Weight in China

Abstract: Adverse birth outcomes are a leading cause of mortality in children in China, but the environmental influences of these conditions remain largely unexplained in this population. We aimed to evaluate the levels of polycyclic aromatic hydrocarbons (PAHs) in Chinese pregnant women and their newborns, and to examine the association between levels of PAHs and infant birth weight. We conducted a cross-sectional study including 81 pairs of mothers and newborns from four hospitals in four different cities in China. High Performance Liquid Chromatography was used to measure the concentration of nine PAHs in maternal and cord blood and multiple linear regression analyses were used to evaluate the associations of these PAHs with infant birth weight. Anthracene (ANT) had the highest average concentration and detection rate (geometric mean = 69.54 ng/g and 76.5%, respectively) in maternal serum samples, while fluoranthene (FLT) had the highest concentration and detection rate (geometric mean = 68.4 ng/g and 50.6%, respectively) in the cord blood. Most of the measured PAHs in maternal serum and three PAHs in cord blood were inversely but non-significantly associated with birth weight. The strongest associations were observed for higher concentrations of benzo (a) pyrene (BaP) in maternal serum (230.7 g decrease for levels > median vs. < LOD; p = 0.151) and for ANT in cord blood (153.1 g decrease for levels < median vs. < LOD; p = 0.208). Ant and FLT were the predominant PAHs in the maternal and cord blood serum. Serum concentrations of several measured PAHs were associated with a decreased birth weight, although not significantly, suggesting that further studies with larger sample sizes are needed to validate our findings.

Different time trends by gender for the incidence of Hodgkin's lymphoma among young adults in the USA: a birth cohort phenomenon.

Abstract: Hodgkin’s lymphoma (HL) is one of the most common cancers among young adults. We investigated the time trends for HL among the 20–44 age group in the USA by gender to identify the potential factors accounting for the incidence trends. Using data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results program for 1973–2010, we conducted age–period–cohort modeling to evaluate birth cohort patterns on incidence trends of HL over time. For all races combined, the age-adjusted incidence patterns were similar to that of whites. The birth cohort patterns for whites and all races were similar, but the patterns differed according to gender. Specifically, except for the 1970–1975 birth cohort, all other birth cohorts showed an increasing birth cohort trend for females. Conversely, there was a decreasing cohort trend in males beginning in the 1960 birth cohort regardless of the assumptions of the period effect. The established risk factors for HL can seemingly not explain the gender disparities of the cohort pattern, which necessitates further analytical epidemiological studies to explore the risk factors for this disease with respect to potential differences by gender and by histological subtype.

Association between urinary polycyclic aromatic hydrocarbon metabolites and elevated serum uric acid levels in coke oven workers

Abstract: Objective To analyze the relationship between metabolites of polycyclic aromatic hydrocarbons (PAHs) and serum uric acid levels in coke oven workers and to provide new clues to the pathogenic mechanism of PAHs.Methods A total of 1302 coke oven workers were divided into four groups,namely control group and low-,intermediate-,and high-dose exposure groups.The concentrations of ambient PAHs at each workplace were determined by high-performance liquid chromatography.The detailed information on the occupational history and health of workers was collected by questionnaire survey and physical examination,and so were their blood and urine samples.Serum uric acid and creatinine levels were measured using a Hitachi 7020 automatic biochemical analyzer.Ten urinary PAH metabolites were detected by gas chromatography-mass spectrometry.Results Serum uric acid levels were the highest in the high-dose exposure group,followed by the intermediate-and low-dose exposure groups,and were the lowest in the control group.There were significant correlations between serum uric acid levels and the quartiles of 1-hydroxynathalene and 1-hydroxyphenanthrene (P＜0.05).After adjustment for PAH metabolite-related relationship,only urinary 1-hydroxyphenanthrene was significantly correlated with serum uric acid levels (P=0.001).After adjustment for confounding factors and using the 1st quartile of 1-hydroxyphenanthrene as a reference,the odds ratio for hyperuricemia in subjects with the 2nd,3rd,and 4th quartiles of 1-hydroxyphenanthrene were 1.55,1.57,and 2.35,respectively.Conclusion Urinary 1-hydroxyphenanthrene is associated with a dose-response increase in serum uric acid levels in coke oven workers,and exposure to phenanthrene in PAHs may be a risk factor for hyperuricemia. Key words: Polycyclic aromatic hydrocarbon; Coke oven worker; 1-Hydroxyphenanthrene; Serum uric acid, Hyperuricemia

Association between genetic variations in TFR2 gene and coronary heart disease in Chinese: a case-control study.

Abstract: AIMS Studies indicated that body iron stores were associated with coronary heart disease (CHD). Type 2 transferrin receptor (TFR2) participates in cellular iron overload and is related to cardiovascular disease. No studies investigated the associations between variants in TFR2 gene and CHD risk. METHODS We sought to investigate this association in a Chinese Han population and performed a case-control study recruiting 1264 CHD patients and 1264 age and sex frequency matched controls. TaqMan single nucleotide polymorphisms (SNP) allelic discrimination was used to examine genotypes of the tagging single nucleotide polymorphisms (tagSNPs) of TFR2. The plasma ferritin levels were measured by ELISA. RESULTS We did not find significant associations between variants of TFR2 gene (including tagSNPs rs2075674 and rs7385804) and the risk of CHD. After adjustment for the conventional risk factors of CHD, such as smoking and age, the results did not materially alter. Interaction analyses indicated that there were no significant interactions between conventional risk factors of CHD and these two tagSNPs on CHD risk. Among different genotypes of these two tagSNPs, no significant differences in plasma ferritin levels were found. CONCLUSION In summary, the variants of rs2075674 and rs7385804 in TFR2 gene were not associated with CHD risk in a Chinese Han population.