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Meian He,
Chen Wu,
Jianfeng Xu,
Huan Guo,
Handong Yang,
Xiaomin Zhang,
Jielin Sun,
Dianke Yu,
Li Zhou,
Tao Peng, [......],
Weimin Fang,
Yuan Liang,
Yun Zhai,
Weihong Chen,
Xiaoping Miao,
Gangqiao Zhou,
Frank B Hu,
Dongxin Lin,
Zengnan Mo,
Tangchun Wu
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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<0.05). 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.
Gut 01/2013; · 10.11 Impact Factor
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Jielin Sun,
Sha Tao,
Yong Gao,
Tao Peng,
Aihua Tan,
Haiying Zhang,
Xiaobo Yang,
Xue Qin,
Yanling Hu,
Junjie Feng, [......],
Zhengjia Liang,
Deyi Shi,
Zhang Huang,
Xianghua Huang,
Ming Liu,
Qian Liu, Shijun Zhang,
S Lilly Zheng,
Jianfeng Xu,
Zengnan Mo
[show abstract]
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ABSTRACT: Prostate-specific antigen (PSA) is a commonly used cancer biomarker for prostate cancer, and is often included as part of routine physical examinations in China. Serum levels of PSA may be influenced by genetic factors as well as other factors. A genome-wide association study (GWAS) conducted in a European population successfully identified six genetic loci that were significantly associated with PSA level. In this study, we aimed to identify common genetic variants that are associated with serum level of PSA in a Chinese population. We also evaluated the effects of those variants by creating personalized PSA cutoff values. A two-stage GWAS of PSA level was performed among men age 20-69 years and self-reported cancer-free participants that underwent routine physical examinations at several hospitals in Guangxi Province, China. Single nucleotide polymorphisms (SNPs) significantly associated with PSA levels in the first stage of sample (N = 1,999) were confirmed in the second stage of sample (N = 1,496). Multivariate linear regression was used to assess the independent contribution of confirmed SNPs and known covariates, such as age, to the level of PSA. SNPs in three regions were significantly associated with levels of PSA in this two-stage GWAS, and had combined P values between 4.62 × 10(-17) and 6.45 × 10(-37). The three regions are located on 1q32.1 at SLC45A3, 10q11.23 at MSMB, and 19q13.33 at KLK3. The region 1q32.1 at SLC45A3 was identified as a novel locus. Genetic variants contributed significantly more to the variance of PSA level than known covariates such as age. Personalized cutoff values of serum PSA, calculated based on the inheritance of these associated SNPs, differ considerably among individuals. Identification of these genetic markers provides new insight into the molecular mechanisms of PSA. Taking individual variation into account, these genetic variants may improve the performance of PSA to predict prostate cancer.
Human Genetics 12/2012; · 5.07 Impact Factor
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Xiaobo Yang,
Jielin Sun,
Yong Gao,
Aihua Tan,
Haiying Zhang,
Yanling Hu,
Junjie Feng,
Xue Qin,
Sha Tao,
Zhuo Chen, [......],
Deyi Shi,
Zhang Huang,
Xianghua Huang,
Ming Liu,
Qian Liu, Shijun Zhang,
Jeffrey M Trent,
S Lilly Zheng,
Jianfeng Xu,
Zengnan Mo
[show abstract]
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ABSTRACT: Complement C3 and C4 play key roles in the main physiological activities of complement system, and their deficiencies or over-expression are associated with many clinical infectious or immunity diseases. A two-stage genome-wide association study (GWAS) was performed for serum levels of C3 and C4. The first stage was conducted in 1,999 healthy Chinese men, and the second stage was performed in an additional 1,496 subjects. We identified two SNPs, rs3753394 in CFH gene and rs3745567 in C3 gene, that are significantly associated with serum C3 levels at a genome-wide significance level (P = 7.33×10(-11) and P = 1.83×10(-9), respectively). For C4, one large genomic region on chromosome 6p21.3 is significantly associated with serum C4 levels. Two SNPs (rs1052693 and rs11575839) were located in the MHC class I area that include HLA-A, HLA-C, and HLA-B genes. Two SNPs (rs2075799 and rs2857009) were located 5' and 3' of C4 gene. The other four SNPs, rs2071278, rs3763317, rs9276606, and rs241428, were located in the MHC class II region that includes HLA-DRA, HLA-DRB, and HLA-DQB genes. The combined P-values for those eight SNPs ranged from 3.19×10(-22) to 5.62×10(-97). HBsAg-positive subjects have significantly lower C3 and C4 protein concentrations compared with HBsAg-negative subjects (P<0.05). Our study is the first GWAS report which shows genetic components influence the levels of complement C3 and C4. Our significant findings provide novel insights of their related autoimmune, infectious diseases, and molecular mechanisms.
PLoS Genetics 09/2012; 8(9):e1002916. · 8.69 Impact Factor
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[show abstract]
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ABSTRACT: Glutathione S-transferases (GSTs) genetic variants have been explored extensively as a predictive factor for cancer etiology. This meta-analysis aimed to examine the associations GSTM1, GSTT1, and GSTP1 genetic polymorphisms with thyroid cancer risk. PubMed, EMBASE, Cochrane Library, and HuGNet database were searched up to November 2011 using the appropriate terms. Twelve studies regarding GSTM1 null polymorphism (1569 cases and 2907 controls), 11 studies concerning GSTT1 null polymorphism (1515 cases and 2863 controls), and 8 studies on GSTP1 Ile105Val (965 cases and 1604 controls) were included in the meta-analysis. The random effects odds ratio was 1.07 (95% CI: 0.88-1.31; I(2)=54.1%, P for heterogeneity=0.013) for the GSTM1 null vs. present genotype and 1.08 (95% CI: 0.75-1.57; I(2)=81.4%, P for heterogeneity<0.001) for the GSTT1 null vs. present genotype, and 1.02 (95% CI: 0.70-1.49; I(2)=74.6%, P for heterogeneity<0.001) for the GSTP1 Val/Val+Val/Ile vs. Ile/Ile genotype. Similarly, no significant associations were demonstrated for subgroup analyses performed by ethnicity and histological type. In conclusion, these three polymorphisms are unlikely to be major determinants of susceptibility to thyroid cancer. Reasons for potential heterogeneity of effects, which could include true biologic heterogeneity, publication bias, or chance, deserve further investigation. The relationship between these three genes and thyroid carcinoma must be evaluated further with gene-gene and gene-environment interactions.
Cancer epidemiology. 07/2012;
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Xiaoling Lin,
Daru Lu,
Yong Gao,
Sha Tao,
Xiaobo Yang,
Junjie Feng,
Aihua Tan,
Haiying Zhang,
Yanling Hu,
Xue Qin,
Seong-Tae Kim,
Tao Peng,
Li Li,
Linjian Mo, Shijun Zhang,
Jeffrey M Trent,
Zengnan Mo,
S Lilly Zheng,
Jianfeng Xu,
Jielin Sun
[show abstract]
[hide abstract]
ABSTRACT: Vitamin B12 (VitB12 or cobalamin) is an essential cofactor in several metabolic pathways. Clinically, VitB12 deficiency is associated with pernicious anemia, neurodegenerative disorder, cardiovascular disease and gastrointestinal disease. Although previous genome-wide association studies (GWAS) identified several genes, including FUT2, CUBN, TCN1 and MUT, that may influence VitB12 levels in European populations, common genetic determinants of VitB12 remain largely unknown, especially in Asian populations. Here we performed a GWAS in 1999 healthy Chinese men and replicated the top findings in an independent Chinese sample with 1496 subjects. We identified four novel genomic loci that were significantly associated with serum level of VitB12 at a genome-wide significance level of 5.00 × 10(-8). These four loci were MS4A3 (11q12.1; rs2298585; P= 2.64 × 10(-15)), CLYBL (13q32; rs41281112; P= 9.23 × 10(-10)), FUT6 (19p13.3; rs3760776; P= 3.68 × 10(-13)) and 5q32 region (rs10515552; P= 3.94 × 10(-8)). In addition, we also confirmed the association with the serum level of VitB12 for the previously reported FUT2 gene and identified one novel non-synonymous single-nucleotide polymorphism in FUT2 gene in this Chinese population (19q13.33; rs1047781; P= 3.62 × 10(-36)). The new loci identified offer new insights into the biochemical pathways involved in determining the serum level of VitB12 and provide opportunities to better delineate the role of VitB12 in health and disease.
Human Molecular Genetics 03/2012; 21(11):2610-7. · 7.64 Impact Factor
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Youjie Zhang,
Yong Gao,
Aihua Tan,
Xiaobo Yang,
Haiying Zhang, Shijun Zhang,
Chunlei Wu,
Zheng Lu,
Mengjie Wang,
Ming Liao,
Xue Qin,
Li Li,
Yanling Hu,
Zengnan Mo
[show abstract]
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ABSTRACT: OBJECTIVE: To examine the association of endogenous sex hormones and SHBG with C-reactive protein (CRP) in Chinese men. DESIGN AND PARTICIPANTS: The study population comprised 1989 men at baseline recruitment of a population-based cohort in China. Participant information on risk factors was collected by a face-to-face interview and clinical examination. All subjects in the study were without taking any kind of medication for anti-inflammation purpose or treatment of hypogonadism and with CRP value less than 10 mg/L. Data were analyzed by using linear regression analyses. RESULTS: Higher levels of total testosterone (TT, β = -0.114, 95%CI, -0.162 to -0.065), free testosterone (β = -0.059, 95%CI, -0.106 to -0.012) and SHBG (β = -0.116, 95%CI, -0.169 to -0.063) were statistically significantly related to lower levels of CRP, after adjustment for age, waist circumference (WC), triglycerides, high-density lipoprotein cholesterol, fasting glucose, insulin, smoking status, hypertension, diabetes and family history of hypertension or diabetes. In the subgroup of men with body mass index ≥27.5 kg/m(2) or with metabolic syndrome, findings for TT and SHBG were more pronounced, whereas the associations of TT with CRP were attenuated and nonstatistically significant among subjects with WC ≥90 cm or with insulin resistance. No associations were observed between estradiol, LH, FSH and CRP. CONCLUSIONS: We have confirmed the association of androgens with reduced inflammation as measured by CRP in Chinese men. This is independent of conventional cardiovascular risk factors and was explained in part by markers of central obesity and insulin resistance, rather than metabolic syndrome. © 2012 Blackwell Publishing Ltd.
Clinical Endocrinology 02/2012; · 3.17 Impact Factor
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Ming Yang,
Yongming Wu,
Yanmei Lu,
Changyuan Liu,
Jielin Sun,
Ming Liao,
Min Qin,
Linjian Mo,
Yong Gao,
Zheng Lu, [......],
Xue Qin,
Yanling Hu, Shijun Zhang,
Jianling Li,
Min Dong,
S Lilly Zheng,
Jianfeng Xu,
Xiaobo Yang,
Aihua Tan,
Zengnan Mo
[show abstract]
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ABSTRACT: IgM provides a first line of defense during microbial infections. Serum IgM levels are detected routinely in clinical practice. And IgM is a genetically complex trait. We conducted a two-stage genome-wide association study (GWAS) to identify genetic variants affecting serum IgM levels in a Chinese population of 3495, including 1999 unrelated subjects in the first stage and 1496 independent individuals in the second stage. Our data show that a common single nucleotide polymorphism (SNP), rs11552708 located in the TNFSF13 gene was significantly associated with IgM levels (p = 5.00×10(-7) in first stage, p = 1.34×10(-3) in second stage, and p = 4.22×10(-9) when combined). Besides, smoking was identified to be associated with IgM levels in both stages (P<0.05), but there was no significant interaction between smoking and the identified SNP (P>0.05). It is suggested that TNFSF13 may be a susceptibility gene affecting serum IgM levels in Chinese male population.
PLoS ONE 01/2012; 7(10):e47990. · 4.09 Impact Factor
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Aihua Tan,
Jielin Sun,
Ning Xia,
Xue Qin,
Yanling Hu, Shijun Zhang,
Sha Tao,
Yong Gao,
Xiaobo Yang,
Haiying Zhang, [......],
Zhengjia Liang,
Deyi Shi,
Zhang Huang,
Xianghua Huang,
Ming Liu,
Qiang Ding,
Jeffrey M Trent,
S Lilly Zheng,
Zengnan Mo,
Jianfeng Xu
[show abstract]
[hide abstract]
ABSTRACT: Triglyceride (TG) is a complex phenotype influenced by both genetic and environmental factors. Recent genome-wide association studies (GWAS) have identified genes or loci affecting lipid levels; however, such studies in Chinese populations are limited. A two-stage GWAS were conducted to identify genetic variants that were associated with TG in a Chinese population of 3495 men. Gene-environment interactions on serum TG levels were further investigated for the seven single nucleotide polymorphisms (SNPs) that were studied in both stages. Two previously reported SNPs (rs651821 in APOA5, rs328 in LPL) were replicated in the second stage, and the combined P-values were 9.19 × 10(-26) and 1.41 × 10(-9) for rs651821 and rs328, respectively. More importantly, a significant interaction between aldehyde dehydrogenase 2 (ALDH2) rs671 and alcohol consumption on serum TG levels were observed (P = 3.34 × 10(-5)). Rs671 was significantly associated with serum TG levels in drinkers (P = 1.90 × 10(-10)), while no association was observed in non-drinkers (P > 0.05). For drinkers, men carrying the AA/AG genotype have significantly lower serum TG levels, compared with men carrying the GG genotype. For men with the GG genotype, the serum TG levels increased with the quantity of alcohol intake (P = 1.28 × 10(-8) for trend test). We identified a novel, significant interaction effect between alcohol consumption and the ALDH2 rs671 polymorphism on TG levels, which suggests that the effect of alcohol intake on TG occurs in a two-faceted manner. Just one drink can increase TG level in susceptible individuals who carry the GG genotype, while individuals carrying AA/AG genotypes may actually benefit from moderate drinking.
Human Molecular Genetics 12/2011; 21(7):1658-64. · 7.64 Impact Factor
