Functional FEN1 polymorphisms are associated with DNA damage levels and lung cancer risk

Flap endonuclease 1 (FEN1) is a key enzyme in maintaining genomic stability and protecting against carcinogenesis. This study investigated whether functional variations in FEN1 gene are associated with DNA damage and lung cancer risk. Thirty DNA samples were sequenced to identify variants and function of the variants was examined by a set of biochemical assays. DNA damage levels were detected by comet assays in a cohort of 303 coke‐oven workers and 297 controls. The association with lung cancer risk was examined in two independent case–control panels consisted of a total 1,840 lung cancer patients and 1,958 controls. We identified two single nucleotide polymorphisms (SNPs) located in the FEN1 promoter c.?69G>A (rs174538:G>A) and 3′‐untranslational region c.4150G>T (rs4246215:G>T) that were associated with reduced FEN1 expression. Among coke‐oven workers, DNA damage levels were significantly higher in the ?69GG or GA carriers compared with the ?69AA carriers. The ?69GG or 4150GG carriers had a significantly increased risk for developing lung cancer compared with the ?69AA or 4150TT carriers. These results highlight FEN1 as an important gene in human carcinogenesis and genetic polymorphisms in FEN1 confer susceptibility to lung cancer. Hum Mutat 30:1–9, 2009. © 2009 Wiley‐Liss, Inc.     

Effect of Genetic Polymorphism of ALOX15 on Aspirin-Exacerbated Respiratory Disease

Background: Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome associated with chronic inflammation in the airways coincident with chronic rhinitis, sinusitis, recurrent polyposis and asthma. Eosinophils are the key inflammatory cells in the development of AERD. AERD has been attributed to abnormalities of the arachidonic acid metabolism, but the pathogenesis of AERD is not fully understood. Our aim was to investigate the genetic contribution of the arachidonate 15-lipoxygenase gene (ALOX15) to the development of AERD. Methods: We enrolled 171 patients with AERD, 229 patients with aspirin-tolerant asthma, and 195 normal healthy controls in a Korean population. Three polymorphisms (-427G/A, -272C/A, -217G/C) in the promoter region of ALOX15 were genotyped. The functional variability of the promoter polymorphisms were analyzed by luciferase reporter activity assay. Result: No significant difference in the genotype frequency of the ALOX15 genetic polymorphism was found. Peripheral total eosinophil count was significantly higher in the patients carrying the GG genotype of the -427G/A polymorphism (p = 0.016). Similarly, the patients carrying haplotype 1 (ht1) (GCG) of -427G/A, -272C/A and -217G/C showed a significantly higher total eosinophil count compared to the other haplotypes (p = 0.008) in the AERD group. The promoter activity of the ht1 (GCG) construct was significantly higher compared to that of the ht3 (AGG) construct in A549 and U937 cells (both p < 0.001). Conclusion: These results suggest that the promoter polymorphisms of the ALOX15 gene affect ALOX15 activity leading to increased eosinophil infiltration in AERD patients.     

CTLA-4基因多态性在重症肌无力发病机理中的作用

目的探讨细胞毒性T淋巴细胞相关抗原-4(cytotoxicTlymphocyteassociatedantigen-4,CTLA-4)基因第1外显子 49位点、启动区-318、-1661、-1772位点的多态性及其导致的无效转录对重症肌无力(myastheniagravis,MG)遗传易感性的影响。方法酶联免疫吸附实验测定MG患者和健康对照血清中可溶性CTLA-4的水平;限制性片段长度多态性分析检测第1外显子 49位点、启动区-318、-1661、-1772位点的多态性;转录因子核因子(nuclearfactor1,NF-1)和CCAAT/增强子结合蛋白β(CCAAT/enhancerbindingproteinbeta,c/EBPβ)结合位点通过染色质免疫沉淀实验得以验证。结果启动区-1772、-1661位点和第1外显子 49位点的多态性与MG,特别是伴发有胸腺瘤的MG密切相关。启动子-318位点的多态性与MG无关。CTLA-4基因4个多态性位点间有一个明确的正性连锁不平衡关系。MG患者血清可溶性CTLA-4的表达水平与等位基因的突变相关联。-1772、-1661位点的多态性可改变转录因子NF-1和c/EBPβ结合位点,而ConA、PHA则能促进NF-1和c/EBPβ的这种位点特异性转录活性。结论MG患者CTLA-4A/G 49、C/T-1772和A/G-1661多态性可导致无效转录,影响MG的遗传易感性,T→C-1772的突变能影响基因的剪接,从而干扰蛋白的表达和功能。     

A cis-acting regulatory variation of the estrogen receptor α (ESR1) gene is associated with hepatitis B virus-related liver cirrhosis

The hepatic fibrogenesis and sexual dimorphism of hepatitis B virus-related liver cirrhosis (HBV-LC) are related to estrogen and its receptors. Abnormal expression of estrogen receptor α (ESR1) is implicated in the development of cirrhosis in both animal models and humans. Here, we examine whether the ESR1 polymorphisms are related to HBV-LC risk among chronic HBV carriers, and we investigate the functional significance of positively associated polymorphisms. A total of 2,404 unrelated Chinese HBV carriers were recruited to conduct the two-stage designed case-control study. Two ESR1 haplotype tagging polymorphisms, c.30T>C (rs2077647) and c.453-397T>C (rs2234693), were genotyped in 1,285 patients with HBV-LC and in 1,119 asymptomatic HBV carriers. We observed a significantly increased susceptibility to HBV-LC associated with the c.30C allele (P = 4.2 × 10(-8) ), c.453-397C allele (P = 2.0 × 10(-8) ), and [c.30C; c.453-397C] haplotype (Dominant model, P = 8.85 × 10(-10) , odds ratio = 1.50, 95% CI 1.32～1.71) compared with the T alleles and (c.30T; c.453-397T) haplotype of c.30T>C and c.453-397T>C polymorphisms, respectively. Functional analyses were conducted to verify the biological functions of the associated genetic variations and showed that the c.453-397T>C polymorphism is a novel c.453-397C allele-specific and c-myb-dependent enhancer-like cis-acting regulatory variation and could be part of the genetic variations underlying the susceptibility of individuals to HBV-LC.