Polymorphisms in the TNF-α and IL-10 gene promoters and risk of psoriasis and correlation with disease severity

Several cytokines were assumed to play an essential role in the induction and the pathogenesis of psoriasis. The aim of this work was to investigate the role of TNF-α-308 and IL-10-1082 polymorphisms and their serum levels in the pathogenesis of psoriasis and determine their relation to disease severity. 110 Psoriasis patients and 120 healthy volunteers were genotyped for TNF-α-308 and IL-10-1082 polymorphism by polymerase chain reaction. Serum level of TNF-α and IL-10 were measured by ELISA. Our study demonstrated an association of IL-10-1082 polymorphism and psoriasis and between TNF α-308 polymorphism and psoriasis disease and severity. Serum TNF α increased in patients, while serum IL-10 decreased in patients with significant correlation between serum TNF-α and psoriasis severity. These results indicated that TNF-α-308 and IL-10-1082 polymorphisms imparted significant risk towards the development of psoriasis.     

IL-10(-1082A/G)基因多态性和乳腺癌的相关性：Meta分析

目的:系统评价IL-10(interleukin-10)-1082A/G基因位点多态性和乳腺癌的相关性。方法:PUBMED和EMBASE文献数据库收集关于IL-10 rs1800896(-1082A/G)基因多态性和乳腺癌危险性的相关文献资料,提取原始数据。采用STATA软件11.0进行统计分析,以OR值和95%CI作为IL-10基因多态性和乳腺癌发病风险的相关性检测指标,并根据对照来源进行分层分析。Q检验和I2统计检测研究的异质性,并进行敏感性分析,Begg's漏斗图和Egger's检验评价发表偏倚。结果:12篇病例对照研究文献纳入本研究,包含5038例乳腺癌病例,5437例对照。GG和AA等位基因相比,OR值为1.134,95%可信区间为1.004-1.280,P0.05。GG和AA+AG相比,OR值为1.131,95%可信区间为1.018-1.257,P0.05,提示存在相关性。在分层分析中,合并以社区来源人群为对照的研究,OR值为1.144,95%可信区间为1.028-1.273,P0.05。结论:IL-10的-1082A/G的GG等位基因和A等位基因相比,可能增加乳腺癌的发生风险。     

Evaluation of interleukin 13 polymorphisms in systemic sclerosis

Systemic sclerosis (SSc) is a multisystem disease of unknown etiology. It is characterized by excessive cutaneous and visceral fibrosis, damage to small blood vessels, and production of autoantibodies. Interleukin-13 (IL-13) has been shown to be involved in abnormal fibrosis in other diseases. Therefore, we have evaluated its possible involvement in SSc. We analyzed four IL13 gene polymorphisms, rs1800925 (IL13-1055), rs20541 (Arg130Gln), rs847, and rs2243204 in 107 unrelated SSc patients (40 patients having diffuse cutaneous form and 67 patients having limited cutaneous form) and in 170 controls. All subjects were Caucasians. In the total patient population and in the diffuse cutaneous subset, we observed an association between two IL13 polymorphisms, IL13 rs1800925 (IL13-1055), and IL13 rs2243204, and disease (p=0.03–0.04). The IL13 rs2243204T allele was more common in SSc patients (p=0.01, OR=2.3 CI 1.21–4.38) and in the diffuse cutaneous form (p=0.01, OR=2.95, CI 1.35–6.49) than in control subjects. Our result supports the suggestion that polymorphisms in IL13 are associated to SSc and skin fibrosis process. However, further studies on larger and independent population and functional analyses are needed to confirm these findings.     

海参微卫星DNA的多态性

微卫星DNA(microsatellite DNA)广泛存在于真核生物的基因组中。由于其具有突变频率快、多态性丰富、呈共显性遗传、通用性等特点,已成为近年来被广泛应用的分子遗传标记。本研究对10个海参微卫星DNA进行了克隆与测序。结果表明:90%的微卫星DNA序列存在长度多态性,这为进一步研究海参的分子标记辅助育种奠定了基础。     

Four human FANCG polymorphic variants show normal biological function in hamster CHO cells

Fanconi anemia (FA) is a rare cancer predisposition disease caused by mutations in at least 12 genes encoding proteins that cooperate to maintain genomic integrity. Variants of FA genes, including FANCG, have been identified in human population screening, but their potential reduction in protein function and role in cancer susceptibility is unclear. To test for possible dysfunction, we constructed plasmids containing four FANCG polymorphisms found in the human population and introduced them in the Fancg-deficient (fancg) KO40 line derived from AA8 hamster CHO cells. Expression of wild-type human FANCG provided fancg cells with complete phenotypic correction as assessed by resistance to the DNA crosslinking agent mitomycin C (MMC), thus providing a sensitive test for detecting the degree of complementation activity for the FANCG variants. We found that all four variants conferred levels of mitomycin C resistance as well as restoration of monoubiquitination of Fancd2, a key indicator of a functional FA protein pathway, similar to those observed in wild-type transfectants. Under the same conditions, the L71P amino acid substitution mutant, identified in an FA patient, gave no complementation. Using this novel system for determining FANCG functionality, we detect no decrement in function of the human FANCG polymorphic variants examined.     

Association of leishmaniasis with TNF alpha promoter and SLC11A1 gene polymorphisms in patients of two endemic areas in Mexico

Some Single Nucleotide Polymorphisms (SNPs) of interleukins and other modulatory molecules of the immune response play an important role in susceptibility to infectious diseases, particularly those involving intracellular parasites. In this study, we evaluated allele, genotype and haplotype associations of two SNPs of the TNF-α promoter and seven of the SLC11A1 gene in 79 patients with localized cutaneous leishmaniasis (CL) and 15 with visceral leishmaniasis (VL), compared with 127 and 89 locality paired controls, respectively, from two endemic areas of Chiapas State, Mexico. None of the TNF-α alleles and genotypes was associated either to CL or to VL. Alleles rs2276631-C (P = 0.02; OR [95%CI] = 2.11 [1.16–3.86]) and rs2279015-G (P = 0.005; OR [95%CI] = 2.42 [1.33–4.41]) of SLC11A1, were associated with susceptibility to VL, whereas genotypes rs2276631 C/C (P = 0.003; OR [95%CI] = 2.65 [1.41–5.00]) and rs2279015 G/G (P = 0.018; OR [95%CI] = 2.05 [1.15–3.64]) were significantly increased in CL and VL patients, respectively. Complete haplotypes involved in susceptibility were CGCCGDins with VL and CGCCADins with CL. CGCCA was the minimal susceptibility haplotype for CL and CCG for VL. Our data suggest that SLC11A1 gene polymorphisms might have a relevant role in the pathology of leishmaniasis, directing towards susceptibility outcome of this disease in residents of an endemic area.     

Factors regulating circulating vascular endothelial growth factor (VEGF): Association with bone mineral density (BMD) in post-menopausal osteoporosis

Vascular endothelial growth factor (VEGF) plays an important role in bone health. We investigated the factors which influence circulating VEGF and their association with bone mineral density (BMD). Two hundred and fifty two post-menopausal women aged 64.5 [9.2] years were studied. BMD was determined at the lumbar spine (LS), femoral neck (FN) and total hip (TH). Serum oestradiol and VEGF were measured. Subjects were genotyped for two polymorphic variants in the 5′ untranslated region of the VEGF gene; G(634)C and C(936)T. Positive correlations were seen between circulating VEGF and BMI (r = 0.2, p < 0.02) and oestradiol (r = 0.25, p < 0.001). Following multi-linear regression analysis, serum VEGF was associated with the G(634) polymorphism (p = 0.08) and dietary calcium intake (p = 0.02). The association with calcium intake may be mediated by PTH as suggested by the in vitro studies. Following correction for confounders, there was no association between circulating VEGF and BMD at any site. Both VEGF polymorphisms were significant predictors of LS BMD G(634)C: p = 0.017 and C(936)T: p = 0.05. Circulating VEGF may be influenced by genetic, environmental and endocrine factors. Polymorphic variants in the VEGF gene are associated with spine BMD. Further larger studies are needed.     

Genetic polymorphisms in isolated Sherpa populations of Nepal

Data are reported on the incidence of variants in the ABO blood group system, four red cell enzyme polymorphisms, and the PTU taster/non-taster polymorphism in 155 Sherpas and Tamangs living in two villages in the isolated Rolwaling valley in east Nepal. The incidence of phenotype AB was unexpectedly high in one village, as has been reproted insome other high-altitude populations: possible causes are discussed. Each of the other polymorphisms has a different pattern of distribution between the populations studied; the Sherpas' allele distribution in the phosphoglucomutase (PGM) system seems to be distinct from the surrounding populations'. ABO gene frequencies suggest affinities between Sherpas in the study villages and old- and new-clan Sherpa populations, respectively, in Solu and Khumbu.     

DNA repair gene polymorphisms affect cytotoxicity in the National Cancer Institute Human Tumour Cell Line Screening Panel

Abstract

Polymorphisms in DNA repair genes have been suggested to increase the risk of cancer and other diseases, but the epidemiological studies are often not consistent, and the results confusing. We have examined the effect of polymorphisms in base and nucleotide excision–repair genes, as well as regulatory and signalling genes, on cytotoxic sensitivity of tumour cell lines used for screening anticancer drugs by the National Cancer Institute. It was found that for the TP53 P72R and ERCC2 D312N polymorphisms, the heterozygous genotype was most sensitive, while for the OGG1 S326C and NOS3 g.?786T?>?C polymorphisms the homozygous-variant genotype was most sensitive. The biggest increase in sensitization was found with the XRCC1 R399Q homozygous dominant genotype. The sensitization was found across a broad range of drugs, indicating the importance of DNA repair responses. It was also found that while the other gene polymorphisms were in Hardy–Weinberg equilibrium, the TP53 P72R heterozygous genotype was relatively depleted. For the OGG1 polymorphism, the repair of 8-oxo-guainine from DNA was measured in three panel cell lines that differed in their OGG1 genotype. The cell line with the homozygous-variant genotype had a much poorer repair than the other genotypes, as predicted. The correlation of polymorphisms with cytotoxicity may be an approach to understanding their effects which may be difficult to reveal in epidemiological studies.     

The choice of controls in a case-control study on WBC-DNA adducts and metabolic polymorphisms

The choice of the control group is a key issue in case-control studies, particularly in studies of molecular epidemiology. We discuss the potential bias introduced by different options. To exemplify the consequences of different choices, we have analysed two sets of controls in the context of a case-control study on bladder cancer: 55 were patients with urological conditions (cystitis, prostate hypertrophy), while 49 had a miscellany of medical or surgical conditions. We measured DNA adducts in white blood cells (WBC) by ³²P-postlabelling and a series of metabolic polymorphisms (GSTM1, GSTT1, GSTP1, NAT2, NQO1). While no statistically significant differences were found for metabolic polymorphisms, the two series of controls showed different concentrations of DNA adducts, suggesting that conditions related to bladder cancer or intermediate steps leading to bladder cancer, such as chronic cystitis, may be associated with higher adduct levels. An association between DNA adduct levels and infection has been noted before in experimental animals: both in lung and in the skin, an inflammatory response increased the biologically effective doses of polycyclic aromatic hydrocarbons. An alternative explanation is confounding; in fact, after adjustment for the level of consumption of fruit and vegetables (but not for smoking) the difference between the two control groups was no longer statistically significant. In conclusion, the choice of controls in studies of molecular epidemiology has subtle methodological implications, including confounding of metabolic/molecular measurements by complex exposures such as diet.