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Metabolome-wide association study identified the association between a circulating polyunsaturated fatty acids variant rs174548 and lung cancer.
Wang, C, Qin, N, Zhu, M, Chen, M, Xie, K, Cheng, Y, Dai, J, Liu, J, Xia, Y, Ma, H, et al
Carcinogenesis. 2017;(11):1147-1154
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Abstract
Quantitative trait loci (QTLs) are widely used as instruments to infer causal risk factors of diseases based on the idea of mendelian randomization. Plasma metabolites can serve as risk factors of cancer, and the heritability of many circulating metabolites was high. We conducted a metabolome-wide association study (MWAS) to systematically investigate the effects of genetic variants on metabolites and lung cancer based on published genome-wide association study (GWASs) and metabolic-QTL (mQTL) study. Then we confirmed the results by subsequent genetic and metabolic validations and inferred the causal relationship between identified metabolites and lung cancer through genetic variant(s). We firstly identified six polyunsaturated fatty acids (PUFAs) represented by rs174548-linked haplotype were significantly associated with lung cancer risk in a Chinese GWAS (2311 cases and 3077 controls). Rs174548 was further confirmed to be associated with lung cancer in 13 821 Europeans and 18 471 Asians (ORmeta = 0.87, Pmeta = 1.76 × 10-15) and the effect was much stronger in females (Pinteraction = 6.00 × 10-4). We next validated rs174548-plasma PUFA association in 253 Chinese subjects (β = -0.57, P = 1.68 × 10-3). Rs174548 was also found associated with FADS1 (the major fatty acid desaturase of identified PUFAs) expression in liver tissues. Taken together, we found that rs174548 was associated with both PUFAs and lung cancer. Because rs174548 was the only mQTL variant of PUFAs reported by previous GWASs and explained a large proportion of heritability, we proposed that plasma PUFAs could be causally associated with lung cancer based on the idea of mendelian randomization. These findings provide a diet-related risk factor and may have important implications for prevention on lung cancer.
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The gene polymorphisms of IL-8(-251T/A) and IP-10(-1596C/T) are associated with susceptibility and progression of type 2 diabetic retinopathy in northern Chinese population.
Dong, L, Bai, J, Jiang, X, Yang, MM, Zheng, Y, Zhang, H, Lin, D
Eye (London, England). 2017;(4):601-607
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Abstract
PurposeThe aim of the present study is to investigate the association of the polymorphism of two genes in CXC chemokine family, interleukin-8 (IL-8) and interferon-inducible protein 10 (IP-10), with both susceptibility and progression of DR in T2D population of northern China.Patients and methodsA total of 1043 eligible type 2 diabetic patients from Heilongjiang of northern China were recruited for this study. They were grouped into: with diabetic retinopathy (DR, 528 cases) and without diabetic retinopathy (DNR, 515 cases). Single nucleotide polymorphism (SNP) genotyping of IL-8(-251T/A) and IP-10(-1596C/T) was performed by polymerase chain reaction. Multivariate analysis and stepwise multiple logistic progression analysis were conducted to evaluate the association between gene SNP and DR susceptibility and progression. Pooled odds ratio (OR) with 95% confidence interval (CI) was applied to assess the strength of the association among study groups.ResultsThe occurring of IL-8(-251) AA genotype was correlated with susceptibility (OR: 2.286, 95% CI: 1.382-3.782, P=0.001) and progression of high-risk proliferative diabetic retinopathy (PDR) (OR: 0.354, 95% CI: 0.162-0.770, P=0.009). Reversely, T allele of IP-10 (-1596) C/T was correlated with a reduced risk of DR (OR: 0.341, 95% CI: 0.249-0.466, P<0.001). However, gene polymorphisms of IL-8-251T/A and IP-10-1596C/T were not associated with diabetic macular edema (DME)(P>0.05).ConclusionsAA genotype of IL-8-251T/A was closely correlated to DR and high-risk proliferative diabetic retinopathy (PDR). -1596T allele of the IP-10 is a beneficial genotype for DR.
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Cyclooxygenase-2 Gly587Arg variant is associated with differential enzymatic activity and risk of esophageal squamous-cell carcinoma.
Zhao, D, Zhang, X, Guo, Y, Tan, W, Lin, D
Molecular carcinogenesis. 2009;(10):934-41
Abstract
Functional SNPs in the COX-2 promoter region have been associated with susceptibility to esophageal squamous-cell carcinoma (ESCC). In this study, we investigated SNPs in the COX-2 coding region and their impact on risk of ESCC. The coding region of COX-2 in DNAs from 30 Han Chinese individuals was sequenced to identify SNPs. Different coding region variants identified were cloned and expressed in MCE-7 cells for the measurement of COX-2 enzymatic activity. Genotypes were determined by PCR-RFLP in 1026 patients with ESCC and 1270 controls and odds ratios (ORs) and 95% confidence intervals (CI) were computed by logistic regression model. A SNP at exon 10 (1759G>A, rs3218625) was identified, which causes (587)Gly to (587)Arg amino acid substitution. Enzymatic assays using different recombinant COX-2 variants showed that COX-2-(587)Arg had significantly higher activity towards arachidonic acid than COX-2-(587)Gly (13.8 +/- 3.2 U/mg vs. 11.2 +/- 2.4 U/mg; P = 0.012). Case-control analysis showed that 10.2% of ESCC patients carried the 1759A allele whereas only 5.4% of controls had this allele (P < 0.0001). No homozygous 1759AA genotype was presented in controls albeit two patients carrying this genotype. Multivariate logistic regression analysis revealed that subjects with at least one 1759A allele had increased risk for the development of ESCC (OR, 1.91; 95% CI, 1.39-2.62) compared with those with the 1759GG genotype. These results extend our previous findings and indicate that inherited variant in arachidonic acid-metabolizing enzyme, which results in heightened enzymatic activity, may confer susceptibility to ESCC.
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A functional polymorphism in the SULT1A1 gene (G638A) is associated with risk of lung cancer in relation to tobacco smoking.
Liang, G, Miao, X, Zhou, Y, Tan, W, Lin, D
Carcinogenesis. 2004;(5):773-8
Abstract
Sulfotransferase 1A1, an important member of sulfotransferase superfamily, is involved in the biotransformation of many compounds including tobacco carcinogens. A single nucleotide polymorphism (G638A) in the sulfotransferase 1A1 (SULT1A1) gene causes Arg213His amino acid change and consequently results in significantly reduced enzyme activity and thermostability. We thus hypothesized that the variant SULT1A1 allele may protect against the risk of lung cancer related to tobacco smoking. To examine this hypothesis, we analyzed 805 patients with lung cancer and 809 controls for this polymorphism in a hospital-based, case-control study. We observed that, compared with the GG genotype, the variant SULT1A1 genotype (638GA or AA) was associated with a significantly increased risk for overall lung cancer [odds ratio (OR) 1.85; 95% confidence interval (CI) 1.44-2.37]. Stratification analysis showed that the increased risk of lung cancer related to the variant SULT1A1 genotypes was more pronounced in younger subjects and limited to smokers but not non-smokers [OR 2.28 (95% CI 1.66-3.13) versus OR 1.35 (95% CI 0.91-1.99); P for homogeneity = 0.000]. Furthermore, the risk of lung cancer for the variant genotypes was increased consistently with cumulative smoking dose, with the ORs being 1.66 (95% CI, 0.75-3.68), 2.28 (95% CI, 1.47-3.54) and 3.35 (95% CI, 1.71-6.57) for those who smoked <15 pack-years, 15-36 pack-years and >36 pack-years, respectively (P for trend = 0.000). When analysis was stratified by histological subtypes of lung cancer, consistent results were observed for all three major types of the cancer, i.e. squamous cell carcinoma, adenocarcinoma and other types. Our results, which are against the original hypothesis, demonstrate that the variant SULT1A1 638A allele is associated with susceptibility to lung cancer in relation to tobacco smoking.