Interleukin 6 promoter polymorphisms influence the outcome of chronic hepatitis C

Host genetic variation may affect the outcome of chronic viral hepatitides, favoring viral clearance and/or modulating the inflammatory response to persistent infection. Our aims were to assess whether interleukin 6 (IL-6) promoter polymorphisms are associated with chronic hepatitis C virus (HCV) infection and to clarify the role of IL-6 haplotypes in facilitating progressive disease. The study included 424 Italian patients (233 males, median age 53 years) affected by HCV chronic infection. IL6 -1363, -597, -572, -174, and +2954 polymorphic loci were assayed by means of restriction fragment length polymorphism. Three hundred forty-four healthy Italian blood donors (245 males, median age 50 years) served as controls. Comparing patients and controls analysis of molecular variance was highly significant (p?相似文献   

The SRY-1532 site of the human Y chromosome is subject to recurrent single nucleotide mutations

Haplotype determination based on three Y-linked polymorphic sites, 92R7 (C/T), SRY-1532 (A/G), and YAP (-/+), in 127 males belonging to three caste Hindu populations of South India (Vizag Brahmins, Peruru Brahmins, and Kammas) and 13 males belonging to a migrant group (the Siddis) showed the existence of all four haplotypes (CA-, CG-, TG-, and TA-) under the YAP- background. This finding suggests that the reverse mutation (G-->A) at the SRY-1532 site, described earlier in the literature, is present in South Indian populations as well. The YAP+ mutation was seen in only five Siddi individuals. Four of these were of the CG+ haplotype structure, but a novel haplotype (CA+) was found in one male. To explain the occurrence of the six haplotypes found within these three sites, a haplotype tree is constructed that introduces a new reverse mutation at the SRY-1532 site (G-->A), occurring under the CG+ background after the migrant Siddi population arrived in India.     

A haplotype constituted of four MMP-2 promoter polymorphisms (-1575G/A, -1306C/T, -790T/G and -735C/T) is associated with coronary triple-vessel disease.

Vascular lesion development is associated with an accumulation of extracellular matrix proteins within the vessel wall. The proteins are degraded by matrix metalloproteinases (MMPs). There is also evidence indicating a participation of the MMPs in the weakening of atherosclerotic plaque that predisposes to lesion disruption. The aim of the study was to test an association among haplotypes of four single nucleotide MMP-2 promoter polymorphisms and the angiographically confirmed coronary triple-vessel disease (TVD). Incidence of haplotypes of four MMP-2 promoter polymorphisms (-1575G/A, -1306C/T, -790T/G and -735C/T) determined by PCR reactions with restriction analyses in 187 patients with coronary TVD (153 men, 34 women, age median 65 years) was compared to 196 control subjects without clinical signs of coronary heart disease (131 men and 65 women, age median 60 years). The incidence of two similar haplotypes was found to be different between patients and healthy subjects. The haplotype GCTC was more frequent in the TVD patients (P=0.01) though the haplotype GCGC was identified only in healthy subjects (P=0.001). Interestingly, the GCTC is the most frequent polymorphic haplotype composed of four promoter SNPs localized in the MMP-2 gene (53% in healthy subjects vs. 66% in patients with TVD) and the haplotype GCGC is the least frequent polymorphic one (4.4% in healthy subjects vs. 0% in patients with TVD). Two different MMP-2 promoter haplotypes differing only in -790T/G allele are significantly more or less frequent in coronary TVD compared to non-ischemic persons. Thus, the -790T/G MMP-2 genotype might be used as a genetic marker representing MMP-2 promoter variability for the TVD with odds ratio for TT and TG genotypes 2.59, 95% confidential interval 1.21-5.55, P=0.009. The analysis of promoter MMP-2 gene variability could help us to understand individual susceptibility to MMP inhibitor treatment of the coronary artery disease.     

Genetic variants of IL6 gene promoter influence on C-reactive protein levels but are not associated with susceptibility to invasive pulmonary aspergillosis in haematological patients

Several lines of evidence indicate that IL6 plays a major role in the pathogenesis of a number of infectious diseases. The purpose of this study was to determine whether IL6 promoter polymorphisms were genetic markers of susceptibility to invasive pulmonary aspergillosis (IPA). To clarify the relationship between IL6 variants and IPA susceptibility, the IL6−174(G/C) and IL6−634(G/C) promoter single nucleotide polymorphisms (SNPs) were defined and plasma concentrations of IL6 and C-reactive protein (CRP) were measured. The study included 130 patients with haematological malignancies and 145 unrelated healthy individuals. No significant genotypic and allelic differences were found between patients and healthy controls. IPA was diagnosed in 71 of 130 patients according to the consensus criteria. CRP values were significantly associated with both IL6−174(G/C) and IL6−634(G/C) polymorphisms. However, IL6 and CRP values were similar between IPA and non-IPA groups. Neither IL6−174(G/C) nor IL6−634(G/C) polymorphisms were associated with IPA infection (p = 0.414 and p = 0.184, respectively). No evidence of association was found between allelic frequencies of IL6 promoter polymorphisms and IPA infection (p = 0.864 and p = 0.104, respectively). Further, no association was detected between IL6 genotypes and clinical profiles in IPA patients. Haplotype analysis also revealed that IL6 gene was not associated with IPA susceptibility in a Spanish population (Global haplotype association p value: 0.31). These findings suggest that IL6 polymorphisms influence on CRP circulating levels but are not associated with IPA susceptibility. Because the sample size is relatively small in our series, larger investigations of IL6−174(G/C)/IL6−634(G/C) genotypes and haplotypes are needed to clarify the potential role of this gene in the pathophysiology of IPA infection.     

Association of plasma lipids and apolipoproteins with the insulin response element in the apoC-III promoter region in familial combined hyperlipidemia.

The apoAI-CIII-AIV gene cluster, located on chromosome 11, contributes to the phenotype of familial combined hyperlipidemia (FCH), but this contribution is genetically complex. Combinations of haplotypes, based on three restriction enzyme polymorphisms: XmnI and MspI sites, 5' of the start site of the apoA-I gene and SstI polymorphism in the 3' untranslated region of exon 4 of the apoC-III gene, were analyzed to characterize their effect on the expression of severe hyperlipidemia. An epistatic interaction was demonstrated: the S2 allele on one haplotype was synergistic in its hyperlipidemic effect to the X2M2 allele on the other haplotype (Dallinga-Thie, G. M. et al. J. Clin. Invest. 1997. 99: 953-961). In the present study two additional polymorphic sites in the insulin response element (IRE) of the apoC-III gene promoter, T-455C: FokI restriction site, C-482T: MspI restriction site, were studied in 34 FCH pedigrees including 34 probands, 220 hyperlipidemic relatives, 300 normolipidemic relatives, and 236 spouses. In contrast to the earlier data for the other polymorphisms in this gene cluster (XmnI, MspI/AI, and SstI), there were no differences in frequency distributions of the T-455C and the C-482T variants between probands, hyperlipidemic and normolipidemic relatives and spouses. No significant associations between plasma lipid traits and DNA variants in the IRE were observed. Analysis of combinations of haplotypes based on the five polymorphisms in the gene cluster provided further evidence for a dominant role of the SstI polymorphism as a major susceptibility locus in FCH. The inclusion of the IRE markers did not improve genetic informativeness, nor our understanding of the observed synergistic relationship associated with the high risk combination of haplotypes in FCH families.     

AGT基因单倍型与原发性高血压

选取血管紧张素原（angiotensinogen, AGT）基因启动子区 -217, -152, -20, -6, 内含子1 的+31, 第二外显子T174M（3889）和 T235M（4072）共7个位点,对497例的样本（高血压患者298例,血压正常对照199例） 用PCR-RFLP、和最大期望值（expectation maximization,EM）算法为基础的最大似然法(maximum likelihood estimate,MLE)检测和估算,本群体AGT基因A-6G,C+31T,T235M三位点两两存在完全连锁不平衡(D^,=1);G-217A和G-152A位点,G-152A和3889T位点平衡传递。存在7种单倍型,单倍型H2(-217: A, -152: G, -20: A, -6: G, +31: T, 174: T, 235: M) 在正常血压个体中的频率高于高血压组。研究结果提示AGT基因中H2单倍型可能与控制血压的保护性因素连锁不平衡。此外,本研究结果支持基因剂量效应可能存在于单倍型中,而不与单个位点直接关联。     

Cxc chemokine receptor expression on human endothelial cells.

CXC chemokines play a important role in the process of leukocyte recruitment and activation at sites of inflammation. However, recent evidence suggests that these molecules can also regulate endothelial cell functions such as migration, angiogenesis and proliferation. In this study we have investigated CXC chemokine receptor expression in both primary cultures of human umbilical vein endothelial cells (HUVEC) and the spontaneously transformed HUVEC cell line, ECV304. We found that both cell types express mRNA for chemokine receptors CXCR1, CXCR2 and CXCR4, but not CXCR3. Flow cytometric analysis revealed low levels of CXCR1 but higher levels of CXCR4 cell surface expression. HUVECs responded to SDF-1alpha with a rapid and robust calcium flux, however no calcium flux was seen with either IL-8 or Gro-alpha. HUVECs and ECV304 cells did not proliferate in response to CXC chemokines, although ECV304 cells did migrate towards SDF-1alpha and IL-8. These data demonstrate that HUVECs and the endothelial cell line, ECV304 express functional CXC chemokine receptors.     

Variability in E-selectin expression, mRNA levels and sE-selectin release between endothelial cell lines and primary endothelial cells

Endothelial cell lines express markers and are assumed to exhibit other endothelial cell responses. We investigated E-selectin expression from human umbilical vein endothelial cells, the spontaneously transformed ECV304 line and the hybrid line EA.hy926 by flow cytometry and immunofluorescence, mRNA and soluble E-selectin release. In cells exposed to tumour necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta), median (range) percentage of E-selectin-positive HUVECs increased from 1.6(0.9-6. 2)% to 91.4(83.0-96.1)%, (P=0.001) using flow cytometry. In contrast, E-selectin expression by ECV304 and EA.hy926 cell lines was 100-fold lower. E-selectin mRNA was detectable after 2 h, maximal at 6 h in HUVECs and undetectable in EA.hy926 and ECV304 cell lines after exposure to TNF-alpha/IL-1beta. sE-selectin accumulation increased (P=0.004) in HUVECs only. Neutrophil adherence to ECV304 and EA.hy926 cells was poor compared to HUVECs (P=0.004). The cell lines ECV304 and EA.hy926 do not exhibit normal endothelium expression of E-selectin, and may not be appropriate for studies of adhesion.