Home About us Contact
|
Home About us Contact | ||
|
|
||
Regulatory Polymorphism (regulatory + polymorphism)
Selected AbstractsRegulatory polymorphisms in the IL-10 gene promoter and HBV-related acute liver failure in the Chinese populationJOURNAL OF VIRAL HEPATITIS, Issue 11 2009Z. Yan Summary., Recent reports indicated that high levels of interleukin 10 (IL-10) contribute to the monocytes paralysis and poor clinical outcome in acute liver failure (ALF). Polymorphisms in the promoter region of IL-10 affect IL-10 production and confer susceptibility to inflammatory diseases. The aim of this study was to determine the possible association of the three polymorphisms (A-1082G, T-819C, A-592C) in the IL-10 gene promoter with the susceptibility to hepatitis B virus (HBV)-related ALF in a Chinese population. The IL-10 gene promoter polymorphisms were genotyped in 414 unrelated healthy blood donors, 367 asymptomatic HBV carriers and 345 HBV-related ALF patients. Functional analyses were conducted to verify the biological significances of the associated genetic variations. The allele frequencies of IL-10,592C and ,819C were significantly higher in HBV-related ALF patients than in blood donors and asymptomatic HBV carriers. Logistic regression analysis and stratification analysis with adjustment for age and sex indicated that the polymorphisms of A-592C and T-819C were associated with susceptibility to HBV-related ALF (P = 6.9 × 10,7), and the -1082A-819C-592C haplotype in the IL-10 gene promoter were associated with an increased susceptibility to ALF in HBV carriers (dominant model, P = 0.0002, odds ratio = 1.60, 95% CI 1.25,2.07). Functional analyses showed that the A-592C polymorphism is a nuclear proteins binding site, and the disease susceptible ,592C allele had a higher transcription activity compared with ,592A allele. This study emphasizes the importance of IL-10 in the pathophysiology of HBV-related ALF on the population level. [source] D90A- SOD1 mediated amyotrophic lateral sclerosis: A single founder for all cases with evidence for a Cis -acting disease modifier in the recessive haplotype,,HUMAN MUTATION, Issue 6 2002Matthew J. Parton Abstract More than 100 different heterozygous mutations in copper/zinc superoxide dismutase (SOD1) have been found in patients with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Uniquely, D90A- SOD1 has been identified in recessive, dominant and apparently sporadic pedigrees. The phenotype of homozygotes is stereotyped with an extended survival, whereas that of affected heterozygotes varies. The frequency of D90A- SOD1 is 50 times higher in Scandinavia (2.5%) than elsewhere, though ALS prevalence is not raised there. Our earlier study indicated separate founders for recessive and dominant/sporadic ALS and we proposed a disease-modifying factor linked to the recessive mutation. Here we have doubled our sample set and employed novel markers to characterise the mutation's origin and localise any modifying factor. Linkage disequilibrium analysis indicates that D90A homozygotes and heterozygotes share a rare haplotype and are all descended from a single ancient founder (alpha 0.974) c.895 generations ago. Homozygotes arose subsequently only c.63 generations ago (alpha 0.878). Recombination has reduced the region shared by recessive kindreds to 97-265 kb around SOD1, excluding all neighbouring genes. We propose that a cis -acting regulatory polymorphism has arisen close to D90A- SOD1 in the recessive founder, which decreases ALS susceptibility in heterozygotes and slows disease progression. © 2002 Wiley-Liss, Inc. [source] The interleukin-6 (IL6),174 G/C promoter genotype is associated with the presence of septic shock and the ex vivo secretion of IL6INTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 6 2007J. J. W. Tischendorf Summary Septic shock is associated with a high mortality and an excessive activation of immune cascades. Interleukin (IL)-6 has been found to be a key cytokine in the pathogenesis of severe sepsis, but the importance of a regulatory polymorphism within the IL6 promoter has been controversial in these patients. The aim of the study was therefore to systematically investigate the IL6,174 G/C promoter genotype with regard to the presence of shock in patients with sepsis, the IL6 serum levels, and the ex vivo secretion of IL6, respectively. Overall, 112 consecutive subjects with severe sepsis and septic shock according to consensus criteria were enrolled. The ex vivo secretion of IL6 after stimulation with lipopolysaccharide (LPS) in a whole blood assay and the IL6 serum concentrations were determined after admission of the patients. Among the 112 subjects with severe sepsis, 85 patients fulfilled the criteria of septic shock. In these patients, the frequency of the mutated C-allele of the IL6 promoter polymorphism was significantly (P = 0.04) higher compared to that in individuals without shock. IL6 serum concentrations were highest in patients with the GG genotype (mean 2209 pg mL,1), followed by CG genotype (mean 1113 pg mL,1), and lowest in individuals with the CC genotype (mean 256 pg mL,1). Interestingly, a significantly (P = 0.005) higher ex vivo secretion of IL6 is detected in heterozygote individuals (535 pg mL,1) and patients with the IL6 CC genotype (555 pg mL,1) compared to patients with the ,174 GG genotype (276 pg mL,1). In conclusion, the IL6,174 G/C promoter genotype is associated with shock in patients with sepsis. Functionally, the mutated C-allele is correlated with low IL6 serum concentrations, but a high ex vivo secretion after LPS stimulation. These results further indicate a complex regulation of the expression of IL6 during infection and have implications for the design of immune intervention trials. [source] The Causal Element for the Lactase Persistence/ non-persistence Polymorphism is Located in a 1 Mb Region of Linkage Disequilibrium in EuropeansANNALS OF HUMAN GENETICS, Issue 4 2003M. Poulter Summary Expression of lactase in the intestine persists into adult life in some people and not others, and this is due to a cis -acting regulatory polymorphism. Previous data indicated that a mutation leading to lactase persistence had occurred on the background of a 60 kb 11-site LCT haplotype known as A (Hollox et al. 2001). Recent studies reported a 100% correlation of lactase persistence with the presence of the T allele at a CT SNP at ,14 kb from LCT, in individuals of Finnish origin, suggesting that this SNP may be causal of the lactase persistence polymorphism, and also reported a very tight association with a second SNP (GA ,22 kb) (Enattah et al. 2002). Here we report the existence of a one megabase stretch of linkage disequilibrium in the region of LCT and show that the ,14 kb T allele and the ,22 kb A allele both occur on the background of a very extended A haplotype. In a series of Finnish individuals we found a strong correlation (40/41 people) with lactose digestion and the presence of the T allele. The T allele was present in all 36 lactase persistent individuals from the UK (phenotyped by enzyme assay) studied, 31/36 of whom were of Northern European ancestry, but not in 11 non-persistent individuals who were mainly of non-UK ancestry. However, the CT heterozygotes did not show intermediate lactase enzyme activity, unlike those previously phenotyped by determining allelic transcript expression. Furthermore the one lactase persistent homozygote identified by having equally high expression of A and B haplotype transcripts, was heterozygous for CT at the ,14 kb site. SNP analysis across the 1 megabase region in this person showed no evidence of recombination on either chromosome between the ,14 kb SNP and LCT. The combined data shows that although the ,14 kb CT SNP is an excellent candidate for the cause of the lactase persistence polymorphism, linkage disequilibrium extends far beyond the region searched so far. In addition, the CT SNP does not, on its own, explain all the variation in expression of LCT, suggesting the possibility of genetic heterogeneity. [source] Functional analysis of the osteoarthritis susceptibility,associated GDF5 regulatory polymorphismARTHRITIS & RHEUMATISM, Issue 7 2009Rainer J. Egli Objective Single-nucleotide polymorphism (SNP) rs143383 (T to C) in the 5,-untranslated region (5,-UTR) of GDF5 has recently been reported to be associated with osteoarthritis (OA) susceptibility, with lower expression of the risk-associated T allele observed in vitro and in vivo. The in vivo studies were performed on cartilage tissue from OA patients. The present study was undertaken to expand the analysis of the effect of this SNP on GDF5 allelic expression to more joint tissue types, to investigate for cis and trans factors that interact with the SNP, and to examine novel cis -acting GDF5 regulatory polymorphisms. Methods Tissue samples were collected from OA patients undergoing joint replacement of the hip or knee. Nucleic acid was extracted, and, using rs143383 and an assay that discriminates and quantifies allelic expression, the relative amount of GDF5 expression from the T and C alleles was measured. Additional common variants in the GDF5 transcript sequence were interrogated as potential regulatory elements using allelic expression and luciferase reporter assays, and electrophoretic mobility shift assays were used to search for trans factors binding to rs143383. Results We observed a consistent allelic expression imbalance of GDF5 in all tissues tested, implying that the functional effect mediated by rs143383 on GDF5 expression is joint-wide. We identified a second polymorphism, located in the 3,-UTR of GDF5, that influenced allelic expression of the gene independent of rs143383. Finally, we observed differential binding of deformed epidermal autoregulatory factor 1 (DEAF-1) to the 2 alleles of rs143383. Conclusion These findings show that the OA susceptibility mediated by polymorphism in GDF5 is not restricted to cartilage, emphasizing the need to consider the disease as involving the whole joint. The existence of an additional cis -acting regulatory polymorphism highlights the complexity of the regulation of expression of this important OA susceptibility locus. DEAF-1 is a trans -acting factor that merits further investigation as a potential tool for modulating GDF5 expression. [source] Evidence for cis -acting regulation of ANK3 and CACNA1C gene expressionBIPOLAR DISORDERS, Issue 4 2010Emma M Quinn Quinn EM, Hill M, Anney R, Gill M, Corvin AP, Morris DW. Evidence for cis -acting regulation of ANK3 and CACNA1C gene expression. Bipolar Disord 2010: 12: 440,445. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives:, Genome-wide association studies (GWAS) have identified Ankyrin-G (ANK3) and the ,-1C subunit of the L-type voltage-gated calcium channel (CACNA1C) as susceptibility genes for bipolar disorder. Available biological information on these genes suggests a potential molecular mechanism involving ion channel dysfunction. The associated single nucleotide polymorphisms (SNPs) at ANK3 (rs10994336) and CACNA1C (rs1006737) are both intronic with no obvious impact on gene function. We investigated whether, instead of affecting protein function, these risk variants might impact on gene regulation affecting expression. Methods:, We have done this by testing for allelic expression imbalance (AEI) to identify cis -acting regulatory polymorphisms. Results:, We identified evidence of cis -acting variation at both loci in HapMap Caucasian Europeans from Utah (CEU) lymphoblastoid cell lines. There was considerable evidence of AEI at ANK3 with more than half of all heterozygous samples (21 out of 34) for marker SNP rs3750800 showing AEI and a small number of samples showing near monoallelic expression. The AEI at either gene could not be attributed to the GWAS-associated SNPs. Conclusions:, These data indicate that there is genetic variation local to both genes affecting their expression, but that this variation is not responsible for increasing risk of bipolar disorder. [source] | |||||||||||||