Association of CD247 polymorphisms with rheumatoid arthritis: a replication study and a meta-analysis

Given the role of CD247 in the response of the T cells, its entailment in autoimmune diseases and in order to better clarify the role of this gene in RA susceptibility, we aimed to analyze CD247 gene variants previously associated with other autoimmune diseases (rs1052237, rs2056626 and rs864537) in a large independent European Caucasian population. However, no evidence of association was found for the analyzed CD247 single-nucleotide polymorphisms (SNPs) with RA and with the presence/absence of anti-cyclic citrullinated polypeptide. We performed a meta-analysis including previously published GWAS data from the rs864537 variant, revealing an overall genome-wide significant association between this CD247 SNP and RA with anti-CCP (OR = 0.90, CI 95% = 0.87-0.93, Poverall = 2.1×10−10). Our results show for first time a GWAS-level association between this CD247 polymorphism and RA risk

Dephosphorylation of YB-1 is Required for Nuclear Localisation During G2 Phase of the Cell Cycle

Elevated levels of nuclear Y-box binding protein 1 (YB-1) are linked to poor prognosis in cancer. It has been proposed that entry into the nucleus requires specific proteasomal cleavage. However, evidence for cleavage is contradictory and high YB-1 levels are prognostic regardless of cellular location. Here, using confocal microscopy and mass spectrometry, we find no evidence of specific proteolytic cleavage. Doxorubicin treatment, and the resultant G2 arrest, leads to a significant increase in the number of cells where YB-1 is not found in the cytoplasm, suggesting that its cellular localisation is variable during the cell cycle. Live cell imaging reveals that the location of YB-1 is linked to progression through the cell cycle. Primarily perinuclear during G1 and S phases, YB-1 enters the nucleus as cells transition through late G2/M and exits at the completion of mitosis. Atomistic modelling and molecular dynamics simulations show that dephosphorylation of YB-1 at serine residues 102, 165 and 176 increases the accessibility of the nuclear localisation signal (NLS). We propose that this conformational change facilitates nuclear entry during late G2/M. Thus, the phosphorylation status of YB-1 determines its cellular location

Critical Role for Cold Shock Protein YB-1 in Cytokinesis

High levels of the cold shock protein Y-box-binding protein-1, YB-1, are tightly correlated with increased cell proliferation and progression. However, the precise mechanism by which YB-1 regulates proliferation is unknown. Here, we found that YB-1 depletion in several cancer cell lines and in immortalized fibroblasts resulted in cytokinesis failure and consequent multinucleation. Rescue experiments indicated that YB-1 was required for completion of cytokinesis. Using confocal imaging we found that YB-1 was essential for orchestrating the spatio-temporal distribution of the microtubules, β-actin and the chromosome passenger complex (CPC) to define the cleavage plane. We show that phosphorylation at six serine residues was essential for cytokinesis, of which novel sites were identified using mass spectrometry. Using atomistic modelling we show how phosphorylation at multiple sites alters YB-1 conformation, allowing it to interact with protein partners. Our results establish phosphorylated YB-1 as a critical regulator of cytokinesis, defining precisely how YB-1 regulates cell division

Critical Role for Cold Shock Protein YB-1 in Cytokinesis

High levels of the cold shock protein Y-box-binding protein-1, YB-1, are tightly correlated with increased cell proliferation and progression. However, the precise mechanism by which YB-1 regulates proliferation is unknown. Here, we found that YB-1 depletion in several cancer cell lines and in immortalized fibroblasts resulted in cytokinesis failure and consequent multinucleation. Rescue experiments indicated that YB-1 was required for completion of cytokinesis. Using confocal imaging we found that YB-1 was essential for orchestrating the spatio-temporal distribution of the microtubules, β-actin and the chromosome passenger complex (CPC) to define the cleavage plane. We show that phosphorylation at six serine residues was essential for cytokinesis, of which novel sites were identified using mass spectrometry. Using atomistic modelling we show how phosphorylation at multiple sites alters YB-1 conformation, allowing it to interact with protein partners. Our results establish phosphorylated YB-1 as a critical regulator of cytokinesis, defining precisely how YB-1 regulates cell division

Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout

Introduction: The acute gout flare results from a localised self-limiting innate immune response to monosodium urate (MSU) crystals deposited in joints in hyperuricaemic individuals. Activation of the caspase recruitment domain-containing protein 8 (CARD8) NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome by MSU crystals and production of mature interleukin-1 beta (IL-1 beta) is central to acute gouty arthritis. However very little is known about genetic control of the innate immune response involved in acute gouty arthritis. Therefore our aim was to test functional single nucleotide polymorphism (SNP) variants in the toll-like receptor (TLR)-inflammasome-IL-1 beta axis for association with gout. Methods: 1,494 gout cases of European and 863 gout cases of New Zealand (NZ) Polynesian (Maori and Pacific Island) ancestry were included. Gout was diagnosed by the 1977 ARA gout classification criteria. There were 1,030 Polynesian controls and 10,942 European controls including from the publicly-available Atherosclerosis Risk in Communities (ARIC) and Framingham Heart (FHS) studies. The ten SNPs were either genotyped by Sequenom MassArray or by Affymetrix SNP array or imputed in the ARIC and FHS datasets. Allelic association was done by logistic regression adjusting by age and sex with European and Polynesian data combined by meta-analysis. Sample sets were pooled for multiplicative interaction analysis, which was also adjusted by sample set. Results: Eleven SNPs were tested in the TLR2, CD14, IL1B, CARD8, NLRP3, MYD88, P2RX7, DAPK1 and TNXIP genes. Nominally significant (P <0.05) associations with gout were detected at CARD8 rs2043211 (OR = 1.12, P = 0.007), IL1B rs1143623 (OR = 1.10, P = 0.020) and CD14 rs2569190 (OR = 1.08; P = 0.036). There was significant multiplicative interaction between CARD8 and IL1B (P = 0.005), with the IL1B risk genotype amplifying the risk effect of CARD8. Conclusion: There is evidence for association of gout with functional variants in CARD8, IL1B and CD14. The gout-associated allele of IL1B increases expression of IL-1 beta-the multiplicative interaction with CARD8 would be consistent with a synergy of greater inflammasome activity (resulting from reduced CARD8) combined with higher levels of pre-IL-1 beta expression leading to increased production of mature IL-1 beta in gout

A novel diffuse gastric cancer susceptibility variant in E-cadherin (CDH1) intron 2: A case control study in an Italian population

<p>Abstract</p> <p>Background</p> <p>Inherited genetic factors such as E-cadherin (<it>CDH1</it>) promoter variants are believed to influence the risk towards sporadic diffuse gastric cancer (DGC). Recently, a new regulatory region essential for <it>CDH1 </it>transcription has been identified in <it>CDH1 </it>intron 2.</p> <p>Methods</p> <p>We genotyped all known polymorphisms located within conserved sequences of <it>CDH1 </it>intron 2 (rs10673765, rs9932686, rs1125557, rs9282650, rs9931853) in an Italian population consisting of 134 DGC cases and 100 healthy controls (55 patient relatives and 45 unrelated, matched individuals). The influence of individual variants on DGC risk was assessed using χ²-tests and logistic regression. The relative contribution of alleles was estimated by haplotype analysis.</p> <p>Results</p> <p>We observed a significant (p < 0.0004) association of the <it>CDH1 </it>163+37235G>A variant (rs1125557) with DGC risk. Odds ratios were 4.55 (95%CI = 2.09–9.93) and 1.38 (95%CI = 0.75–2.55) for AA and GA carriers, respectively. When adjusted for age, sex, smoking status, alcohol intake and <it>H. pylori </it>infection, the risk estimates remained largely significant for AA carriers. Haplotype analysis suggested the 163+37235A-allele contributes to disease risk independently of the other variants studied.</p> <p>Conclusion</p> <p>The <it>CDH1 </it>163+37235G>A polymorphism may represent a novel susceptibility variant for sporadic DGC if confirmed in other populations. Considering the broad expression of E-cadherin in epithelia, this exploratory study encourages further evaluation of the 163+37235A-allele as a susceptibility variant in other carcinomas.</p

The Toll-Like Receptor 4 (TLR4) Variant rs2149356 and Risk of Gout in European and Polynesian Sample Sets

Deposition of crystallized monosodium urate (MSU) in joints as a result of hyperuricemia is a central risk factor for gout. However other factors must exist that control the progression from hyperuricaemia to gout. A previous genetic association study has implicated the toll-like receptor 4 (TLR4) which activates the NLRP3 inflammasome via the nuclear factor-κB signaling pathway upon stimulation by MSU crystals. The T-allele of single nucleotide polymorphism rs2149356 in TLR4 is a risk factor associated with gout in a Chinese study. Our aim was to replicate this observation in participants of European and New Zealand Polynesian (Māori and Pacific) ancestry. A total of 2250 clinically-ascertained prevalent gout cases and 13925 controls were used. Non-clinically-ascertained incident gout cases and controls from the Health Professional Follow-up (HPFS) and Nurses Health Studies (NHS) were also used. Genotypes were derived from genome-wide genotype data or directly obtained using Taqman. Logistic regression analysis was done including age, sex, diuretic exposure and ancestry as covariates as appropriate. The T-allele increased the risk of gout in the clinically-ascertained European samples (OR = 1.12, P = 0.012) and decreased the risk of gout in Polynesians (OR = 0.80, P = 0.011). There was no evidence for association in the HPFS or NHS sample sets. In conclusion TLR4 SNP rs2143956 associates with gout risk in prevalent clinically-ascertained gout in Europeans, in a direction consistent with previously published results in Han Chinese. However, with an opposite direction of association in Polynesians and no evidence for association in a non-clinically-ascertained incident gout cohort this variant should be analysed in other international gout genetic data sets to determine if there is genuine evidence for association

To Treat or Not to Treat: legal and ethical issues in the compulsory treatment of anorexia

Treatment resistance is a characteristic feature of anorexia nervosa, and is usually regarded as a symptom of the illness. In the case of some chronic anorexics, however, rejection of therapeutic intervention may be the result of reasoned decision making. Some patients ('end-stage' anorexics) may feel their quality of life so poor and the prospects of recovery so slight that they would prefer to be allowed to die. For others ('identity' anorexics), their illness may have become so integrated into their sense of self that they reject attempts to ‘cure’ them, despite being aware of the risks this poses to their health. Under New Zealand law, there is the possibility that such patients could be considered legally competent under the Protection of Personal and Property Rights Act (PPPRA), but mentally disordered under the Mental Health (Compulsory Assessment and Treatment) Act (MHA). Whether compulsory treatment is lawful would thus depend on the piece of legislation used when assessing the need for a treatment order. A principlist analysis of the ethics of compulsion suggests that enforced treatment is justified in the case of identity anorexia (providing effective treatment is available), but not in end-stage anorexia. I conclude that current legislation needs to be amended to ensure that the PPPRA and the MHA can be applied to anorexic patients in a legally consistent and ethically appropriate manner

To Treat or Not to Treat: legal and ethical issues in the compulsory treatment of anorexia

Treatment resistance is a characteristic feature of anorexia nervosa, and is usually regarded as a symptom of the illness. In the case of some chronic anorexics, however, rejection of therapeutic intervention may be the result of reasoned decision making. Some patients ('end-stage' anorexics) may feel their quality of life so poor and the prospects of recovery so slight that they would prefer to be allowed to die. For others ('identity' anorexics), their illness may have become so integrated into their sense of self that they reject attempts to ‘cure’ them, despite being aware of the risks this poses to their health. Under New Zealand law, there is the possibility that such patients could be considered legally competent under the Protection of Personal and Property Rights Act (PPPRA), but mentally disordered under the Mental Health (Compulsory Assessment and Treatment) Act (MHA). Whether compulsory treatment is lawful would thus depend on the piece of legislation used when assessing the need for a treatment order. A principlist analysis of the ethics of compulsion suggests that enforced treatment is justified in the case of identity anorexia (providing effective treatment is available), but not in end-stage anorexia. I conclude that current legislation needs to be amended to ensure that the PPPRA and the MHA can be applied to anorexic patients in a legally consistent and ethically appropriate manner