Future Functional Studies (future + functional_studies)

Distribution by Scientific Domains

Selected Abstracts

Replication of the tumor necrosis factor receptor,associated factor 1/complement component 5 region as a susceptibility locus for rheumatoid arthritis in a European family-based study

F. A. S. Kurreeman
Objective We recently showed, using a candidate gene approach in a case,control association study, that a 65-kb block encompassing tumor necrosis factor receptor,associated factor 1 (TRAF1) and C5 is strongly associated with rheumatoid arthritis (RA). Compared with case,control association studies, family-based studies have the added advantage of controlling potential differences in population structure and are not likely to be hampered by variation in population allele frequencies, as is seen for many genetic polymorphisms, including the TRAF1/C5 locus. The aim of this study was to confirm this association in populations of European origin by using a family-based approach. Methods A total of 1,356 western European white individuals from 452 "trio" families were genotyped for the rs10818488 polymorphism, using the TaqMan allelic discrimination assay. Results We observed evidence for association, demonstrating departure from Mendel's law, with an overtransmission of the rs10818488 A allele (A = 55%; P = 0.036). By taking into consideration parental phenotypes, we also observed an increased A allele frequency in affected versus unaffected parents (A = 64%; combined P = 0.015). Individuals carrying the A allele had a 1.2-fold increased risk of developing RA (allelic odds ratio 1.24, 95% confidence interval 1.04,1.50). Conclusion Using a family-based study that is robust against population stratification, we provide evidence for the association of the TRAF1/C5 rs10818488 A allele and RA in populations of European descent, further substantiating our previous findings. Future functional studies should yield insight into the biologic relevance of this locus to the pathways involved in RA. [source]

Carriage of a tumor necrosis factor polymorphism amplifies the cytotoxic T-lymphocyte antigen 4 attributed risk of primary biliary cirrhosis: Evidence for a gene,gene interaction,

HEPATOLOGY, Issue 1 2010
Brian D. Juran
Common genetic variants significantly influence complex diseases such as primary biliary cirrhosis (PBC). We recently reported an association between PBC and a single nucleotide polymorphism (rs231725) of the immunoreceptor gene cytotoxic T-lymphocyte antigen 4 (CTLA4). We hypothesized that PBC risk attributed to this polymorphism might be increased by propensity to an overly robust inflammatory response. Thus, we examined its potential interaction with the commonly studied ,308AG promoter polymorphism (rs1800629) of the tumor necrosis factor (TNF) gene for which the variant TNF2A allele causes increased TNF production. The polymorphisms were genotyped in 866 PBC patients and 761 controls from independent US and Canadian registries; the effects of individual single nucleotide polymorphisms (SNPs) and their interaction on PBC risk was assessed by logistic regression. The reported association of PBC with the CTLA4 "A/A" genotype was replicated in the Canadian cohort and significant for PBC risk in the combined data (odds ratio [OR], 1.68; P = 0.0005). TNF2A allele frequency was elevated in PBC patients, but only reached borderline significance using the combined data (OR, 1.21; P = 0.042). Analysis showed that TNF2A carriage was significantly increased in CTLA4 "A/A" PBC patients compared with CTLA4 "A/A" controls (39.7% versus 16.5%, P = 0.0004); no apparent increase of TNF2A carriage was noted in CTLA4 "A/G" or "G/G" individuals. Finally, interaction under a logistic model was highly significant, as TNF2A carriage in combination with the CTLA4 "A/A" genotype was present in 6.5% of PBC patients, compared with 1.7% of controls (OR, 3.98; P < 0.0001). Conclusion: TNF2A amplifies the CTLA4 rs231725 "A/A" genotype risk for PBC. Although the mechanisms remain unclear, the premise that deficiency in T-cell regulation resulting in an increased risk of PBC is amplified by overexpression of an important proinflammatory cytokine provides a basis for future functional studies. HEPATOLOGY 2010 [source]

The solution structure of ZNF593 from Homo sapiens reveals a zinc finger in a predominately unstructured protein

Paulette L. Hayes
Abstract Here, we report the solution structure of ZNF593, a protein identified in a functional study as a negative modulator of the DNA-binding activity of the Oct-2 transcription factor. ZNF593 contains a classic C2H2 zinc finger domain flanked by about 40 disordered residues on each terminus. Although the protein contains a high degree of intrinsic disorder, the structure of the zinc finger domain was resolved by NMR spectroscopy without a need for N- or C-terminal truncations. The tertiary structure of the zinc finger domain is composed of a ,-hairpin that positions the cysteine side chains for zinc coordination, followed by an atypical kinked ,-helix containing the two histidine side chain ligands. The structural topology of ZNF593 is similar to a fragment of the double-stranded RNA-binding protein Zfa and the C-terminal zinc finger of MBP-1, a human enhancer binding protein. The structure presented here will provide a guide for future functional studies of how ZNF593 negatively modulates the DNA-binding activity of Oct-2, a POU domain-containing transcription factor. Our work illustrates the unique capacity of NMR spectroscopy for structural analysis of folded domains in a predominantly disordered protein. [source]

A tissue-engineered suburethral sling in an animal model of stress urinary incontinence

Tracy W. Cannon
OBJECTIVE To create and evaluate the functional effects of a tissue-engineered sling in an animal model of stress urinary incontinence (SUI). MATERIALS AND METHODS Twenty female Sprague-Dawley rats were divided into four equal groups: a control group (C) had no intervention before the leak-point pressure (LPP) was measured; a denervated group (D) had bilateral proximal sciatic nerve transection (PSNT) and periurethral dissection with no sling placed; group S had concomitant bilateral PSNT and a suburethral sling of small intestinal submucosa (SIS) placed; and group (M) had concomitant bilateral PSNT with implantation of a tissue-engineered sling. The suburethral sling was placed via a transabdominal approach with the sling sutured to the pubic bone. Tissue-engineered slings were prepared with muscle-derived cells obtained via the pre-plate technique and subsequently seeded for 2 weeks on a SIS scaffold. Suburethral slings were implanted 2 weeks before LPP testing, using the vertical-tilt method. RESULTS Surgically placing a suburethral sling is feasible in the female rat, with few complications. LPPs from both sling groups (S and M) were not significantly different from untreated controls (C). The S, M and C groups all had significantly higher LPPs than group D. Importantly, no rat from either sling group (S and M) had signs of urinary retention. CONCLUSIONS Placing tissue-engineered slings in an animal model of SUI resulted in LPP values that were not significantly different from those in untreated control or SIS (S) groups. These data show that incorporating muscle stem cells into SIS slings does not adversely alter the advantageous mechanical properties of the SIS sling in a model of SUI, and provide the basis for future functional studies of tissue-engineered sling materials with long-term retention. [source]