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Independent Cohort (independent + cohort)
Selected AbstractsToll-like receptor-1, -2, and -6 polymorphisms influence disease extension in inflammatory bowel diseasesINFLAMMATORY BOWEL DISEASES, Issue 1 2006Marie Pierik MD Abstract Background: Evidence that a deficient innate immune response toward the bacterial flora of the gut plays a role in the pathogenesis of inflammatory bowel disease (IBD) is growing. This is underscored by the finding of the association between CARD15 variants and Crohn's disease (CD) and D299G in Toll-like receptor (TLR) 4 and IBD. Our aims were to study nonsynonymous polymorphisms in other TLR genes in IBD. Methods: Thirty-five single nucleotide polymorphisms (SNP) in TLR1-10 were identified from public databases. 284 IBD parent-child trios and a second independent cohort of 285 IBD patients and 191 healthy controls were genotyped with polymerase chain reaction-restriction fragment length polymorphisms. Patients were pooled for genotype-phenotype analyses. Results: Although none of the SNPs was involved in disease susceptibility, a number of variants influenced the disease phenotype. A positive association between TLR1 R80T and pancolitis in UC (P = .045, OR [95% CI] 2.844 [1.026-7.844]) was found. The TLR2 R753G SNP was also associated with pancolitis (P = .027, OR [95% CI] 4.741 [1.197-18.773]). The relative risks for heterozygous patients to develop pancolitis were 5.8 and 3.3 for R80T and R753G, respectively. There was a negative association between TLR6 S249P and ulcerative colitis with proctitis only (P = .026, OR [95% CI] 0.223 [0.096-0.705]). In CD, we found a negative association between ileal disease involvement and TLR1 S602I (P = .03, OR [95% CI] 0.522 [0.286-0.950]). Conclusion:TLR2 and its cofactors TLR1 and TLR6 are involved in the initial immune response to bacteria by recognizing peptidoglycan. An association between nonsynonymous variants in the TLR1, - 2, and - 6 genes and extensive colonic disease in UC and CD was found. Our findings further highlight the role of an abnormal innate immune response in the pathogenesis of IBD. [source] Association of a KCNA5 gene polymorphism with systemic sclerosis,associated pulmonary arterial hypertension in the European Caucasian populationARTHRITIS & RHEUMATISM, Issue 10 2010J. Wipff Objective Pulmonary arterial hypertension (PAH) has emerged as a leading cause of death in systemic sclerosis (SSc). The genetic basis of PAH has been unraveled in recent years, with a major role played by transforming growth factor , receptors; however, some other candidate genes have also been advocated, including potassium voltage-gated channel, shaker-related subfamily, member 5 (KCNA5). We undertook this study to determine whether KCNA5 polymorphisms confer susceptibility to SSc and its vascular phenotype, including PAH. Methods Four KCNA5 single-nucleotide polymorphisms (SNPs), rs10744676, rs1860420, rs3741930, and rs2284136, were genotyped in a discovery set of 638 SSc patients and 469 controls. In addition, rs10744676 was genotyped in an independent replication sample (938 SSc patients and 564 controls) and in a cohort of 168 patients with different PAH subtypes. Results The KCNA5 rs10744676 variant was found to be associated with SSc in the discovery sample, with an odds ratio (OR) of 0.62 (95% confidence interval [95% CI] 0.48,0.79, adjusted P = 0.0003) in comparison with controls (C allele frequency 11.4% versus 17.2%). When subphenotypes were investigated, an association was found solely for PAH associated with SSc (OR 0.31 [95% CI 0.13,0.71], adjusted P = 0.04). The other KCNA5 SNPs tested were not associated with any SSc subset. The above association with PAH associated with SSc was replicated in the second set. In the combined population, rs10744676 was strongly associated with PAH associated with SSc in comparison with controls (OR 0.36 [95% CI 0.21,0.63], P = 0.0002). In the independent cohort of patients with PAH, after investigating PAH subtypes, only rs10744676 showed an association with PAH associated with SSc. Conclusion Our results provide the first evidence for an association between the KCNA5 rs10744676 variant and PAH associated with SSc. [source] Identification of RGS1 as a candidate biomarker for undifferentiated spondylarthritis by genome-wide expression profiling and real-time polymerase chain reactionARTHRITIS & RHEUMATISM, Issue 11 2009Jieruo Gu Objective To compare gene expression profiles between ankylosing spondylitis (AS) and undifferentiated spondylarthritis (uSpA) patients with inflammatory low back pain. Methods Peripheral blood mononuclear cells (PBMCs) from patients with AS, patients with uSpA, and healthy subjects were screened using genome-wide microarrays, followed by validation by real-time polymerase chain reaction (PCR). Results Microarray profiling and real-time PCR assays showed only minor differences between AS patients and healthy subjects. In contrast, 20 genes were strikingly more highly expressed in uSpA patients. Regulator of G protein signaling 1 (RGS1) was identified as the most useful biomarker for distinguishing uSpA patients, and to a lesser extent AS patients, from control subjects (P = 2.3 × 10,7 and 6.7 × 10,3, respectively). These findings were verified in an independent cohort that also included patients with rheumatoid arthritis and patients with mechanical low back pain. The receiver operating characteristic area under the curve values in the first and second cohorts of uSpA patients were 0.99 and 0.93, respectively (P = 1 × 10,4). To evaluate the possible derivation of RGS1, we cultured a monocyte-derived cell line with a panel of cytokines and chemokines. RGS1 was significantly induced either by tumor necrosis factor , (TNF,) or by interleukin-17 (IL-17). Conclusion Our findings indicate that uSpA PBMCs carry strikingly more highly expressed genes compared with PBMCs from AS patients or healthy subjects, and that TNF,- and IL-17,inducible RGS1 is a potential biomarker for uSpA, and to a lesser extent for AS, with inflammatory low back pain. [source] Interferon-regulated chemokines as biomarkers of systemic lupus erythematosus disease activity: A validation studyARTHRITIS & RHEUMATISM, Issue 10 2009Jason W. Bauer Objective Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by unpredictable flares of disease activity and irreversible damage to multiple organ systems. An earlier study showed that SLE patients carrying an interferon (IFN) gene expression signature in blood have elevated serum levels of IFN-regulated chemokines. These chemokines were associated with more-severe and active disease and showed promise as SLE disease activity biomarkers. This study was designed to validate IFN-regulated chemokines as biomarkers of SLE disease activity in 267 SLE patients followed up longitudinally. Methods To validate the potential utility of serum chemokine levels as biomarkers of disease activity, we measured serum levels of CXCL10 (IFN,-inducible 10-kd protein), CCL2 (monocyte chemotactic protein 1), and CCL19 (macrophage inflammatory protein 3,) in an independent cohort of 267 SLE patients followed up longitudinally over 1 year (1,166 total clinic visits). Results Serum chemokine levels correlated with lupus activity at the current visit (P = 2 × 10,10), rising at the time of SLE flare (P = 2 × 10,3) and decreasing as disease remitted (P = 1 × 10,3); they also performed better than the currently available laboratory tests. Chemokine levels measured at a single baseline visit in patients with a Systemic Lupus Erythematosus Disease Activity Index of ,4 were predictive of lupus flare over the ensuing year (P = 1 × 10,4). Conclusion Monitoring serum chemokine levels in SLE may improve the assessment of current disease activity, the prediction of future disease flares, and the overall clinical decision-making. [source] Variants within MECP2, a key transcription regulator, are associated with increased susceptibility to lupus and differential gene expression in patients with systemic lupus erythematosusARTHRITIS & RHEUMATISM, Issue 4 2009Ryan Webb Objective Both genetic and epigenetic factors play an important role in the pathogenesis of lupus. The aim of this study was to examine methyl-CpG,binding protein 2 gene (MECP2) polymorphisms in a large cohort of patients with lupus and control subjects, and to determine the functional consequences of the lupus-associated MECP2 haplotype. Methods We genotyped 18 single-nucleotide polymorphisms within MECP2, located on chromosome Xq28, in a large cohort of patients with lupus and control subjects of European descent. We studied the functional effects of the lupus-associated MECP2 haplotype by determining gene expression profiles in B cell lines in female lupus patients with and those without the lupus-associated MECP2 risk haplotype. Results We confirmed, replicated, and extended the genetic association between lupus and genetic markers within MECP2 in a large independent cohort of lupus patients and control subjects of European descent (odds ratio 1.35, P = 6.65 × 10,11). MECP2 is a dichotomous transcription regulator that either activates or represses gene expression. We identified 128 genes that are differentially expressed in lupus patients with the disease-associated MECP2 haplotype; most (,81%) were up-regulated. Genes that were up-regulated had significantly more CpG islands in their promoter regions compared with genes that were down-regulated. Gene ontology analysis using the differentially expressed genes revealed significant association with epigenetic regulatory mechanisms, suggesting that these genes are targets for MECP2 regulation in B cells. Furthermore, at least 13 of the 104 up-regulated genes are regulated by interferon. The disease-risk MECP2 haplotype was associated with increased expression of the MECP2 transcription coactivator CREB1 and decreased expression of the corepressor histone deacetylase 1. Conclusion Polymorphism in the MECP2 locus is associated with lupus and, at least in part, contributes to the interferon signature observed in lupus patients. [source] Perinatal risk factors for the neonatal abstinence syndrome in infants born to women on methadone maintenance therapyAUSTRALIAN AND NEW ZEALAND JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Issue 3 2010Anthony J.W. LIU Background:, Neonatal abstinence syndrome (NAS) occurs in more than 50% of infants exposed to intrauterine opiates. Maternal opiate dosing has been investigated with conflicting results. Aims:, The aims of this study were to correlate maternal methadone dose and other risk factors with the development of NAS requiring pharmacological treatment by using easily accessible clinical parameters. Methods:, Retrospective medical record review of data from 228 opioid dependent pregnant women who delivered 232 live-born infants. Logistic regression analysis was performed on maternal, perinatal and neonatal parameters to identify risk factors for NAS requiring treatment. A prediction model was developed and validated on a separate independent cohort of 188 infants. Results:, Of the 232 infants, 172 (74%) infants were treated for NAS. The risk of withdrawal increased by 17% per 5 mg increment of the last maternal methadone dose. The risk was lower for younger gestational ages and for those delivered by Caesarean section compared to those delivered by normal vaginal delivery. Through predictive modeling, gestational age, mode of delivery and last methadone dose were established as risk factors for withdrawal. The model was validated by other statistical measures and its diagnostic performance confirmed on the separate independent cohort. Conclusions:, Our data suggests that timing and mode of delivery as well as last maternal methadone dose are significant risk factors for the development of NAS requiring treatment. Based on these clinical parameters, risk stratification for perinatal management of pregnancies associated with opioid dependency and risk prediction for the neonate might now be possible. [source] Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemiaBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2009Amos Gaikwad Summary Recurrent, prognostically significant chromosomal abnormalities occur in approximately 75% of paediatric acute lymphoblastic leukaemia (ALL), but only infrequently in children with Down syndrome (DS) and ALL. Recently, novel somatic activating mutations in the gene Janus kinase 2 (JAK2) were reported in 18% of DS ALL. Here we report identification and clinical correlates of JAK2 mutations in an independent cohort. JAK2 activating mutations occurred in 10/53 DS ALL cases (18·9%). Mutations were overrepresented in males (P < 0·03), occurred once in association with high hyperdiploidy and were not significantly correlated with age, initial white blood count, or event-free survival. Our results confirm the significance of JAK,STAT pathway activation in DS ALL. [source] High expression of connective tissue growth factor in pre-B acute lymphoblastic leukaemiaBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2007Joanne M. Boag Summary In recent years microarrays have been used extensively to characterize gene expression in acute lymphoblastic leukaemia (ALL). Few studies, however, have analysed normal haematopoietic cell populations to identify altered gene expression in ALL. We used oligonucleotide microarrays to compare the gene expression profile of paediatric precursor-B (pre-B) ALL specimens with two control cell populations, normal CD34+ and CD19+IgM, cells, to focus on genes linked to leukemogenesis. A set of eight genes was identified with a ninefold higher average expression in ALL specimens compared with control cells. All of these genes were significantly deregulated in an independent cohort of 101 ALL specimens. One gene, connective tissue growth factor (CTGF, also known as CCN2), had exceptionally high expression, which was confirmed in three independent leukaemia studies. Further analysis of CTGF expression in ALL revealed exclusive expression in B-lineage, not T-lineage, ALL. Within B-lineage ALL approximately 75% of specimens were consistently positive for CTGF expression, however, specimens containing the E2A-PBX1 translocation showed low or no expression. Protein studies using Western blot analysis demonstrated the presence of CTGF in ALL cell-conditioned media. These findings indicate that CTGF is secreted by pre-B ALL cells and may play a role in the pathophysiology of this disease. [source] Independent Evaluation of an Out-of-hospital Termination of Resuscitation (TOR) Clinical Decision RuleACADEMIC EMERGENCY MEDICINE, Issue 6 2008Peter B. Richman MD Abstract Objectives:, Recently, investigators described a clinical decision rule for termination of resuscitation (TOR) designed to help determine whether to terminate emergency medical services (EMS) resuscitative efforts for out-of-hospital cardiac arrests (OOHCA). The authors sought to evaluate the hypothesis that TOR would predict no survival for patients in an independent cohort of patients with OOHCA. Methods:, This was a retrospective cohort analysis conducted in the state of Arizona. Consecutive, adult, OOHCA were prospectively evaluated from October 2004 through October 2006. A statewide OOHCA database utilizing Utstein-style reporting from 30 different EMS systems was used. Data were abstracted from EMS first care reports and hospital discharge records. The TOR guidelines predict that no survival to hospital discharge will occur if 1) an OOHCA victim does not have return of spontaneous circulation (ROSC), 2) no shocks are administered, and 3) the arrest is not witnessed by EMS personnel. Data were entered into a structured database. Continuous data are presented as means (±standard deviations [SD]) and categorical data as frequency of occurrence, and 95% confidence intervals (CIs) were calculated as appropriate. The primary outcome measure was to determine if any cohort member who met TOR criteria survived to hospital discharge. Results:, There were 2,239 eligible patients; the study group included 2,180 (97.4%) patients for whom the data were complete; mean age was 64 (±11) years, and 35% were female. The majority of patients in the study group met at least one or more of the TOR criteria. A total of 2,047 (93.8%) patients suffered from cardiac arrest that was unwitnessed by EMS; 1,653 (75.8%) had an unwitnessed arrest and no ROSC. With respect to TOR, 1,160 of 2,180 (53.2%) patients met all three criteria; only one (0.09%; 95% CI = 0% to 0.5%) survived to hospital discharge. Conclusions:, The authors evaluated TOR guidelines in an independent, statewide OOHCA database. The results are consistent with the findings of the TOR investigation and suggest that this algorithm is a promising tool for TOR decision-making in the field. [source] Genetic and environmental influences on cannabis use initiation and problematic use: a meta-analysis of twin studiesADDICTION, Issue 3 2010Karin J. H. Verweij ABSTRACT Background Because cannabis use is associated with social, physical and psychological problems, it is important to know what causes some individuals to initiate cannabis use and a subset of those to become problematic users. Previous twin studies found evidence for both genetic and environmental influences on vulnerability, but due to considerable variation in the results it is difficult to draw clear conclusions regarding the relative magnitude of these influences. Methods A systematic literature search identified 28 twin studies on cannabis use initiation and 24 studies on problematic cannabis use. The proportion of total variance accounted for by genes (A), shared environment (C) and unshared environment (E) in (i) initiation of cannabis use and (ii) problematic cannabis use was calculated by averaging corresponding A, C and E estimates across studies from independent cohorts and weighting by sample size. Results For cannabis use initiation, A, C and E estimates were 48%, 25% and 27% in males and 40%, 39% and 21% in females. For problematic cannabis use A, C and E estimates were 51%, 20% and 29% for males and 59%, 15% and 26% for females. Confidence intervals of these estimates are considerably narrower than those in the source studies. Conclusions Our results indicate that vulnerability to both cannabis use initiation and problematic use was influenced significantly by A, C and E. There was a trend for a greater C and lesser A component for cannabis use initiation compared to problematic use for females. [source] Contribution of the novel inflammatory bowel disease gene IL23R to disease susceptibility and phenotypeINFLAMMATORY BOWEL DISEASES, Issue 9 2007J.R. Fraser Cummings MRCP(UK) Abstract Background: A North American genome-wide single nucleotide polymorphism (SNP) association study identified IL23R as a novel inflammatory bowel disease (IBD) susceptibility gene. Association was reported with multiple risk variants in the centromeric portion of IL23R in 3 large independent cohorts. The aims of this study were to replicate the association of IL23R with Crohn's disease (CD), examine subphenotype relationships, and look for evidence of epistasis with the known CD susceptibility gene CARD15 and susceptibility haplotype IBD5 in a large collection of CD patients. We further investigated the relationship between IL23R and ulcerative colitis (UC). Methods: In all, 604 CD and 647 UC patients who had been rigorously phenotyped and who had been recruited from a single UK center were used in this study. Controls were either spouses of patients (141) or were recruited from well-person clinics (993). Eight SNPs were genotyped using MassArray (Sequenom). All 8 SNPs genotyped were significantly associated with CD. Results: The association with the nonsynonymous SNP rs11209026 was confirmed (P = 6.65 × 10,6, odds ratio [OR], 0.43, 95% confidence interval [CI]: 0.29-0.64). The most significant SNP in our study was rs7517847 (P = 4.9 × 10,9, OR 0.65, 0.56,0.75), which is statistically independent of rs11209026. Preliminary evidence suggests an epistatic interaction with the IBD5 risk haplotype. The effects of mutations in this IL23R appear weaker in UC (P = 0.008, OR 0.63, 0.45,0.89 and 0.005 OR, 0.81, 0.71,0.94, respectively). No subphenotype associations were identified. Conclusions: We confirmed the findings that IL23R is a susceptibility gene for IBD with suggestive epistasis with the IBD5 locus in the CD population. (Inflamm Bowel Dis 2007) [source] Telomere DNA content and allelic imbalance demonstrate field cancerization in histologically normal tissue adjacent to breast tumorsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2006Christopher M. Heaphy Abstract Cancer arises from an accumulation of mutations that promote the selection of cells with progressively malignant phenotypes. Previous studies have shown that genomic instability, a hallmark of cancer cells, is a driving force in this process. In the present study, two markers of genomic instability, telomere DNA content and allelic imbalance, were examined in two independent cohorts of mammary carcinomas. Altered telomeres and unbalanced allelic loci were present in both tumors and surrounding histologically normal tissues at distances at least 1 cm from the visible tumor margins. Although the extent of these genetic changes decreases as a function of the distance from the visible tumor margin, unbalanced loci are conserved between the surrounding tissues and the tumors, implying cellular clonal evolution. Our results are in agreement with the concepts of "field cancerization" and "cancer field effect," concepts that were previously introduced to describe areas within tissues consisting of histologically normal, yet genetically aberrant, cells that represent fertile grounds for tumorigenesis. The finding that genomic instability occurs in fields of histologically normal tissues surrounding the tumor is of clinical importance, as it has implications for the definition of appropriate tumor margins and the assessment of recurrence risk factors in the context of breast-sparing surgery. © 2006 Wiley-Liss, Inc. [source] Caenorhabditis elegans PI3K mutants reveal novel genes underlying exceptional stress resistance and lifespanAGING CELL, Issue 6 2009Srinivas Ayyadevara Summary Two age-1 nonsense mutants, truncating the class-I phosphatidylinositol 3-kinase catalytic subunit (PI3KCS) before its kinase domain, confer extraordinary longevity and stress-resistance to Caenorhabditis elegans. These traits, unique to second-generation homozygotes, are blunted at the first generation and are largely reversed by additional mutations to DAF-16/FOXO, a transcription factor downstream of AGE-1 in insulin-like signaling. The strong age-1 alleles (mg44, m333) were compared with the weaker hx546 allele on expression microarrays, testing four independent cohorts of each allele. Among 276 genes with significantly differential expression, 92% showed fewer transcripts in adults carrying strong age-1 alleles rather than hx546. This proportion is significantly greater than the slight bias observed when contrasting age-1 alleles to wild-type worms. Thus, transcriptional changes peculiar to nonsense alleles primarily involve either gene silencing or failure of transcriptional activation. A subset of genes responding preferentially to age-1- nonsense alleles was reassessed by real-time polymerase chain reaction, in worms bearing strong or weak age-1 alleles; nearly all of these were significantly more responsive to the age-1(mg44) allele than to age-1(hx546). Additional mutation of daf-16 reverted the majority of altered mg44 -F2 expression levels to approximately wild-type values, although a substantial number of genes remained significantly distinct from wild-type, implying that age-1(mg44) modulates transcription through both DAF-16/FOXO-dependent and independent channels. When age-1 -inhibited genes were targeted by RNA interference (RNAi) in wild-type or age-1(hx546) adults, most conferred significant oxidative-stress protection. RNAi constructs targeting two of those genes were shown previously to extend life, and RNAi's targeting five novel genes were found here to increase lifespan. PI3K - null mutants may thus implicate novel mechanisms of life extension. [source] Expression of p16INK4a in peripheral blood T-cells is a biomarker of human agingAGING CELL, Issue 4 2009Yan Liu Summary Expression of the p16INK4a tumor suppressor sharply increases with age in most mammalian tissues, and contributes to an age-induced functional decline of certain self-renewing compartments. These observations have suggested that p16INK4a expression could be a biomarker of mammalian aging. To translate this notion to human use, we determined p16INK4a expression in cellular fractions of human whole blood, and found highest expression in peripheral blood T-lymphocytes (PBTL). We then measured INK4/ARF transcript expression in PBTL from two independent cohorts of healthy humans (170 donors total), and analyzed their relationship with donor characteristics. Expression of p16INK4a, but not other INK4/ARF transcripts, appeared to exponentially increase with donor chronologic age. Importantly, p16INK4a expression did not independently correlate with gender or body-mass index, but was significantly associated with tobacco use and physical inactivity. In addition, p16INK4a expression was associated with plasma interleukin-6 concentration, a marker of human frailty. These data suggest that p16INK4a expression in PBTL is an easily measured, peripheral blood biomarker of molecular age. [source] Assessing the role of DRD5 and DYT1 in two different case,control series with primary blepharospasmMOVEMENT DISORDERS, Issue 2 2007Jordi Clarimon PhD Abstract Primary blepharospasm is a common adult-onset focal dystonia. Polymorphisms of the genes encoding TorsinA (DYT1) and the D5 dopamine receptor (DRD5) have previously been associated with lifetime risk for focal dystonia. We describe here experiments testing common variability within these two genes in two independent cohorts of Italian and North American patients with primary blepharospasm. We have failed to identify a consistent association with disease in the two patient groups examined here; however, analysis of the Italian group reveals an association with the same risk genotype in DYT1 as previously described in an Icelandic population. We have also found global significant DYT1 haplotype differences between patients and controls in the Italian series. These data suggest that further examination is warranted of the role genetic variability at this locus plays in the risk for primary dystonia. © 2006 Movement Disorder Society [source] Influence of Cyclooxygenase-2 (COX-2) Gene Promoter Polymorphism ,765 on Graft Loss After Renal TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2009C. Courivaud A G,C polymorphism has been identified in the human cyclooxygenase-2 (COX-2) gene promoter at position ,765 with C allele leading to a decreased promoter activity with low prostaglandin E2 (PGE2) production. PGE2 has strong immunomodulatory properties that could influence graft survival. We studied the association between this polymorphism and allograft failure in two independent cohorts of renal transplant recipients (RTRs) including a total of 603 patients. The functional effect of COX-2 gene promoter polymorphism was analyzed by measuring serum levels of PGE2. Median follow-up was 8.7 and 7.9 years for the first and second cohort, respectively. Analysis of 603 patients identified 20 CC (3.3%), 179 GC (29.7%) and 404 GG (67%) carriers. Patients with the GG genotype had significantly higher serum PGE2 concentrations than patients with the C allele. Carriers with a C allele have an independent increased risk of graft loss (hazard ratio (HR) 2.43 [95% CI 1.19,4.97], p = 0.015 for cohort 1; HR 1.72 [95% CI 0.99,3.77], p = 0.051 for cohort 2) compared to GG patients. COX-2 gene promoter polymorphism at position ,765 (G,C) is associated with a higher rate of graft loss in RTRs. Such findings may be used to influence immunosuppressive strategies and optimize patient management. [source] Polymorphisms in TBX21 and STAT4 increase the risk of systemic sclerosis: Evidence of possible gene,gene interaction and alterations in Th1/Th2 cytokinesARTHRITIS & RHEUMATISM, Issue 12 2009Pravitt Gourh Objective Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Dysregulation of the immune system, including the Th1/Th2 cytokine balance, is central to the pathogenesis of SSc. This study was undertaken to investigate the hypothesis that single-nucleotide polymorphisms (SNPs) in TBX21 and STAT4, both of which are critical transcription factors that regulate the Th1/Th2 balance, are associated with SSc susceptibility. Methods We tested SNPs in TBX21 and STAT4 for association with SSc in 2 independent cohorts, the SSc Registry cohort (880 SSc cases and 507 controls) and the University of Texas SSc cohort (522 cases and 531 controls). Additional white control genotypes were obtained from public repositories. We also investigated for gene,gene interactions. Plasma cytokines and whole blood gene expression profiles were examined to determine functional effects of these SNPs. Results Multiple SNPs in TBX21 and STAT4 were found to be associated with SSc. In a combined analysis of 902 SSc patients and 4,745 controls, TT genotyping of the TBX21 rs11650354 variant revealed a recessive pattern for disease susceptibility (Pcorr = 1.4 × 10,15, odds ratio 3.37, 95% confidence interval 2.4,4.6). In an analysis of 1,039 SSc patients and 3,322 controls, the A allele of the STAT4 variant rs11889341 was associated with increased SSc susceptibility in a dominant pattern (Pcorr = 2.4 × 10,5, odds ratio 1.29, 95% confidence interval 1.2,1.5). Furthermore, we identified gene,gene interaction among the TBX21 and STAT4 variants, such that the STAT4 genotype increased the risk of SSc only in the TBX21 CC genotype group. SSc patients carrying the TBX21 CC genotype had higher interleukin-6 (IL-6) and tumor necrosis factor , levels, and those with the TT genotype had elevated IL-2, IL-5, IL-4, and IL-13 (Th2) levels, compared with controls. Whole blood expression profiles revealed dysregulation of type I interferon pathways in the CC group and T cell pathways in the TT group of the TBX21 SNP. Conclusion The present results, from studies of 2 independent cohorts, indicate that SNPs in TBX21 and STAT4 contribute uniquely and interactively to SSc susceptibility, leading to altered cytokine balance and immune dysregulation. [source] Early breastfeeding cessation: validation of a prognostic breastfeeding scoreACTA PAEDIATRICA, Issue 5 2007Hanne Kronborg Abstract Aim: To validate a simple breastfeeding score to identify mothers who stop breastfeeding within 4 months after birth. Methods: Two independent cohorts of Danish mothers in 1999 and 2004 with 4 months of follow-up on breastfeeding duration were used. The breastfeeding score was developed from 471 mothers' responses to a questionnaire in 1999 and based on duration of schooling, previous breastfeeding experience, self-efficacy, and mother's confidence in ability to produce milk. The 2004 cohort consisting of 723 mothers was used to validate the score. Results: A breastfeeding score of 7 or higher classified 45% of the mothers in the 2004 cohort as being at risk of breastfeeding cessation. With this cut-point the sensitivity was 70% and the specificity 71%. Among primipara the cut-point gave a sensitivity of 76% and a specificity of 54% and classified 60% to be in the risk group. Among multipara the corresponding figures were 66%, 81% and 34%, respectively. The area under the ROC curve was 0.78. Conclusion: The breastfeeding score based on a simple scoring system derived from four risk factors was capable of predicting the breastfeeding duration in an independent sample. It may help health professionals to identify mothers at risk of breastfeeding cessation before 4 months. [source] | ||||||||||