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1.
Br J Cancer ; 113(3): 382-9, 2015 Jul 28.
Article in English | MEDLINE | ID: mdl-26103570

ABSTRACT

BACKGROUND: The natural history of prostate cancer is highly variable and difficult to predict accurately. Better markers are needed to guide management and avoid unnecessary treatment. In this study, we validate the prognostic value of a cell cycle progression score (CCP score) independently and in a prespecified linear combination with standard clinical variables, that is, a clinical-cell-cycle-risk (CCR) score. METHODS: Paraffin sections from 761 men with clinically localized prostate cancer diagnosed by needle biopsy and managed conservatively in the United Kingdom, mostly between 2000 and 2003. The primary end point was prostate cancer death. Clinical variables consisted of centrally reviewed Gleason score, baseline PSA level, age, clinical stage, and extent of disease; these were combined into a single predefined risk assessment (CAPRA) score. Full data were available for 585 men who formed a fully independent validation cohort. RESULTS: In univariate analysis, the CCP score hazard ratio was 2.08 (95% CI (1.76, 2.46), P<10(-13)) for one unit change of the score. In multivariate analysis including CAPRA, the CCP score hazard ratio was 1.76 (95% CI (1.44, 2.14), P<10(-6)). The predefined CCR score was highly predictive, hazard ratio 2.17 (95% CI (1.83, 2.57), χ(2)=89.0, P<10(-20)) and captured virtually all available prognostic information. CONCLUSIONS: The CCP score provides significant pretreatment prognostic information that cannot be provided by clinical variables and is useful for determining which patients can be safely managed conservatively, avoiding radical treatment.


Subject(s)
Cell Cycle/genetics , Prostatic Neoplasms/mortality , Prostatic Neoplasms/pathology , Prostatic Neoplasms/surgery , Research Design , Adult , Aged , Biopsy, Needle , Cohort Studies , Disease Progression , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Grading , Neoplasm Staging , Prognosis , Prostatic Neoplasms/blood , RNA/genetics
2.
Br J Cancer ; 108(12): 2582-9, 2013 Jun 25.
Article in English | MEDLINE | ID: mdl-23695019

ABSTRACT

BACKGROUND: The natural history of prostate cancer is highly variable and difficult to predict. We report on the prognostic value of phosphatase and tensin homologue (PTEN) loss in a cohort of 675 men with conservatively managed prostate cancer diagnosed by transurethral resection of the prostate. METHODS: The PTEN status was assayed by immunohistochemistry (PTEN IHC) and fluorescent in situ hybridisation (PTEN FISH). The primary end point was death from prostate cancer. RESULTS: The PTEN IHC loss was observed in 18% cases. This was significantly associated with prostate cancer death in univariate analysis (hazard ratio (HR)=3.51; 95% CI 2.60-4.73; P=3.1 × 10(-14)). It was highly predictive of prostate cancer death in the 50% of patients with a low risk score based on Gleason score, PSA, Ki-67 and extent of disease (HR=7.4; 95% CI 2.2-24.6; P=0.012) ), but had no prognostic value in the higher risk patients. The PTEN FISH loss was only weakly associated with PTEN IHC loss (κ=0.5). Both PTEN FISH loss and amplification were univariately predictive of death from prostate cancer, but this was not maintained in the multivariate analyses. CONCLUSION: In low-risk patients, PTEN IHC loss adds prognostic value to Gleason score, PSA, Ki-67 and extent of disease.


Subject(s)
Adenocarcinoma/diagnosis , Biomarkers, Tumor/genetics , PTEN Phosphohydrolase/genetics , Prostatic Neoplasms/diagnosis , Adenocarcinoma/genetics , Adenocarcinoma/mortality , Adenocarcinoma/surgery , Adult , Aged , Biomarkers, Tumor/metabolism , Gene Expression Regulation, Neoplastic , Gene Silencing/physiology , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Ki-67 Antigen/metabolism , Male , Middle Aged , Neoplasm Grading , PTEN Phosphohydrolase/metabolism , Predictive Value of Tests , Prognosis , Prostate-Specific Antigen/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/mortality , Prostatic Neoplasms/surgery , Transurethral Resection of Prostate
3.
Br J Cancer ; 107(10): 1776-82, 2012 Nov 06.
Article in English | MEDLINE | ID: mdl-23047548

ABSTRACT

BACKGROUND: Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH). METHODS: Ovarian tumours from two independent data sets were characterised for defects in BRCA1, BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines. RESULTS: Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P=10(-11)). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P=10(-5) and 10(-29)), and identified breast and pancreatic cell lines with BRCA defects. CONCLUSION: The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers.


Subject(s)
Loss of Heterozygosity , Neoplasms, Glandular and Epithelial/genetics , Ovarian Neoplasms/genetics , Recombinational DNA Repair , Adult , Aged , Aged, 80 and over , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Carcinoma, Ovarian Epithelial , Cell Line, Tumor , Cohort Studies , DNA Breaks, Double-Stranded , DNA-Binding Proteins/genetics , Disease-Free Survival , Female , Humans , Middle Aged
4.
Br J Cancer ; 106(6): 1095-9, 2012 Mar 13.
Article in English | MEDLINE | ID: mdl-22361632

ABSTRACT

BACKGROUND: The natural history of prostate cancer is highly variable and it is difficult to predict. We showed previously that a cell cycle progression (CCP) score was a robust predictor of outcome in a conservatively managed cohort diagnosed by transurethral resection of the prostate. A greater need is to predict outcome in patients diagnosed by needle biopsy. METHODS: Total RNA was extracted from paraffin specimens. A CCP score was calculated from expression levels of 31 genes. Clinical variables consisted of centrally re-reviewed Gleason score, baseline prostate-specific antigen level, age, clinical stage, and extent of disease. The primary endpoint was death from prostate cancer. RESULTS: In univariate analysis (n=349), the hazard ratio (HR) for death from prostate cancer was 2.02 (95% CI (1.62, 2.53), P<10(-9)) for a one-unit increase in CCP score. The CCP score was only weakly correlated with standard prognostic factors and in a multivariate analysis, CCP score dominated (HR for one-unit increase=1.65, 95% CI (1.31, 2.09), P=3 × 10(-5)), with Gleason score (P=5 × 10(-4)) and prostate-specific antigen (PSA) (P=0.017) providing significant additional contributions. CONCLUSION: For conservatively managed patients, the CCP score is the strongest independent predictor of cancer death outcome yet described and may prove valuable in managing clinically localised prostate cancer.


Subject(s)
Adenocarcinoma/pathology , Cell Cycle , Prostatic Neoplasms/pathology , Adenocarcinoma/blood , Adenocarcinoma/mortality , Adenocarcinoma/surgery , Aged , Biopsy, Needle , Cohort Studies , Humans , Kaplan-Meier Estimate , Male , Multivariate Analysis , Neoplasm Grading , Neoplasm Staging , Proportional Hazards Models , Prostate-Specific Antigen , Prostatic Neoplasms/blood , Prostatic Neoplasms/mortality , Prostatic Neoplasms/surgery , Transurethral Resection of Prostate
5.
Genes Immun ; 8(1): 57-68, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17159887

ABSTRACT

A pragmatic approach that balances the benefit of a whole-genome association (WGA) experiment against the cost of individual genotyping is to use pooled genomic DNA samples. We aimed to determine the feasibility of this approach in a WGA scan in rheumatoid arthritis (RA) using the validated human leucocyte antigen (HLA) and PTPN22 associations as test loci. A total of 203 269 single-nucleotide polymorphisms (SNPs) on the Affymetrix 100K GeneChip and Illumina Infinium microarrays were examined. A new approach to the estimation of allele frequencies from Affymetrix hybridization intensities was developed involving weighting for quality signals from the probe quartets. SNPs were ranked by z-scores, combined from United Kingdom and New Zealand case-control cohorts. Within a 1.7 Mb HLA region, 33 of the 257 SNPs and at PTPN22, 21 of the 45 SNPs, were ranked within the top 100 associated SNPs genome wide. Within PTPN22, individual genotyping of SNP rs1343125 within MAGI3 confirmed association and provided some evidence for association independent of the PTPN22 620W variant (P=0.03). Our results emphasize the feasibility of using genomic DNA pooling for the detection of association with complex disease susceptibility alleles. The results also underscore the importance of the HLA and PTPN22 loci in RA aetiology.


Subject(s)
Arthritis, Rheumatoid/genetics , Genetic Predisposition to Disease , Genome, Human , Genomics/methods , Case-Control Studies , Cohort Studies , DNA/genetics , Female , HLA Antigens/genetics , Humans , Male , Oligonucleotide Array Sequence Analysis , Polymorphism, Single Nucleotide , Protein Tyrosine Phosphatase, Non-Receptor Type 22 , Protein Tyrosine Phosphatases/genetics
6.
Arthritis Rheum ; 48(5): 1200-6, 2003 May.
Article in English | MEDLINE | ID: mdl-12746892

ABSTRACT

OBJECTIVE: Susceptibility to rheumatoid arthritis (RA) is likely to involve several genes of weak effect, and consequently, individual studies may have insufficient power to detect linkage. Four major RA genome-wide linkage studies have been carried out, but apart from the well-established HLA susceptibility locus, none of the reported significant regions of linkage has been replicated. We applied a genome-search meta-analysis to 4 RA genome searches to assess linkage across studies, using published results. METHODS: For each study, 120 genomic bins of approximately 30 cM were defined and ranked according to the maximum evidence for linkage within each bin. Ranks were summed across studies and each bin was assessed empirically by the magnitude of summed rank, using a permutation test. A high summed rank indicated a region in which evidence for linkage was consistent across several studies. RESULTS: In addition to the HLA locus (P < 0.00002), the strongest evidence for an RA susceptibility locus was found on chromosome 16 (P = 0.004). This locus was not identified as statistically significant in any of the 4 individual RA genome searches. In total, 12 regions achieved a significant (P < 0.05) summed rank, compared with the 6 bins expected by random chance. Four of these regions (on chromosomes 6p, 16cen, 6q, and 12p) reached a significance value of P < 0.01, suggesting that a subset of these regions contains RA susceptibility loci. CONCLUSION: Using a meta-analysis approach, we have identified existing and novel putative RA susceptibility loci. These results can provide a basis for further positional and functional candidate-gene studies, and may prove useful in other complex rheumatic diseases.


Subject(s)
Arthritis, Rheumatoid/genetics , Chromosomes, Human, Pair 16 , Genetic Linkage , Genetic Predisposition to Disease , Genome, Human , HLA Antigens/genetics , Humans
7.
Genes Immun ; 4(4): 289-97, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12761566

ABSTRACT

Asthma is a common, heterogeneous, complex disease accompanied by raised total and specific immunoglobulin-E (IgE) antibody levels. Despite numerous previous reports of linkage and association of asthma, atopy and serum IgE levels to genes within the 5q21-33 region, definitive, replicable results are still not available. We used the classical twin design to (i) estimate the relative contributions of genes and environment to variation in total IgE levels, (ii) assess genetic linkage, and (iii) examine allelic association of 11 microsatellite markers spanning the 5q21-33 region to total IgE. Variation in total IgE level was shown to be highly heritable (65%). Although evidence for linkage of the 11 microsatellites to IgE was not observed, the omnibus test of association, not confounded by population substructure, showed positive association of D5S393 and D5S673 to IgE. Genes in the vicinity of D5S673 include hepatitis A virus receptor (HAVCR-1) and IL-12B. Recently, the mouse orthologue of HAVCR-1, the T-cell membrane family of proteins, have been shown to be in strong association with expression of airway hyperactivity in a mouse model of human asthma and atopy. IL-12B subserves many proinflammatory functions and also induces B cells proliferation.


Subject(s)
Chromosomes, Human, Pair 5/genetics , Genetic Variation , Immunoglobulin E/blood , Immunoglobulin E/genetics , Quantitative Trait Loci , Adolescent , Adult , Aged , Aged, 80 and over , Chi-Square Distribution , Confidence Intervals , Female , Genetic Linkage/genetics , Humans , Middle Aged
8.
Rheumatology (Oxford) ; 42(2): 304-7, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12595627

ABSTRACT

INTRODUCTION: It has been proposed that genetic susceptibility loci for rheumatoid arthritis (RA) may be shared with other autoimmune/inflammatory diseases. Recently, common variation in the CARD15 (NOD2) gene on chromosome 16q12 has been associated with Crohn's disease (CD) in several independent populations. CARD15 is an excellent functional and positional candidate gene for RA. METHODS: Genomic DNA was obtained from 392 RA cases and 471 ethnically matched healthy controls. All samples were genotyped for two polymorphisms in CARD15, 1007fs and R702W, using 5' nuclease reporter assays. Allele frequencies were compared between cases and controls using the chi(2) test. Estimated haplotype frequencies across the two mutations were determined using the EH program. RESULTS: The allele frequency of the 1007fs variant in RA cases was 1.8% compared with 1.6% in normal controls (not significant). The frequency of the R702W variant was 4.0% in both cases and controls. Haplotypes carrying either of the two mutations accounted for 5.6% of possible haplotypes. A haplotype carrying both mutations was rare, with estimated frequency <0.01%. This study provided high power to detect an association of similar magnitude to that in Crohn's disease. These data therefore exclude the possibility that the contribution of these mutations to RA is comparable to that seen in CD. CONCLUSION: Within defined statistical parameters, we excluded a role for the CARD15 1007fs and R702W variants in RA susceptibility. These data do not preclude a role for other polymorphisms in the CARD15 gene in RA susceptibility. Results from other autoimmune and inflammatory diseases will reveal whether the CARD15 gene is in fact a common autoimmune susceptibility locus.


Subject(s)
Arthritis, Rheumatoid/genetics , Carrier Proteins/genetics , Genetic Predisposition to Disease , Intracellular Signaling Peptides and Proteins , Polymorphism, Genetic , Chromosomes, Human, Pair 16 , Crohn Disease/genetics , Gene Frequency , Genotype , Haplotypes , Humans , Nod2 Signaling Adaptor Protein
9.
Am J Hum Genet ; 70(5): 1172-82, 2002 May.
Article in English | MEDLINE | ID: mdl-11951176

ABSTRACT

Lymphocyte subpopulation levels are used for prognosis and monitoring of a variety of human diseases, especially those with an infectious etiology. As a primary step to defining the major gene variation underlying these phenotypes, we conducted the first whole-genome screen for quantitative variation in lymphocyte count, CD4 T cell, CD8 T cell, B cell, and natural killer cell numbers, as well as CD4:CD8 ratio. The screen was performed in 15 of the CEPH families that form the main human genome genetic project mapping resource. Quantitative-trait loci (QTLs) that account for significant proportions of the phenotypic variance of lymphocyte subpopulations were detected on chromosomes 1, 2, 3, 4, 8, 9, 11, 12, and 18. The most significant QTL found was for CD4 levels on chromosome 8 (empirical P=.00005). Two regions of chromosome 4 showed significant linkage to CD4:CD8 ratio (empirical P=.00007 and P=.003). A QTL for the highly correlated measures of CD4 and CD19 levels colocalized at 18q21 (both P=.003). Similarly, a shared region of chromosome 1 was linked to CD8 and CD19 levels (P=.0001 and P=.002, respectively). Several of the identified chromosome regions are likely to harbor polymorphic candidate genes responsible for these important human phenotypes. Their discovery has important implications for understanding the generation of the immune repertoire and understanding immune-system homeostasis. More generally, these data show the power of an integrated human gene-mapping approach for heritable molecular phenotypes, using large pedigrees that have been extensively genotyped.


Subject(s)
B-Lymphocytes/metabolism , Chromosomes, Human/genetics , Lymphocyte Subsets/metabolism , Quantitative Trait, Heritable , T-Lymphocytes/metabolism , Alleles , Antigens, CD/analysis , B-Lymphocytes/cytology , Chromosome Mapping , Female , Flow Cytometry , Genes, bcl-2/genetics , Humans , Killer Cells, Natural/cytology , Killer Cells, Natural/metabolism , Linkage Disequilibrium , Lymphocyte Count , Lymphocyte Subsets/cytology , Male , Phenotype , T-Lymphocytes/cytology , Utah
10.
Genes Immun ; 2(7): 381-7, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11704804

ABSTRACT

The adaptive immune system in mammals acts in a coordinated manner to eliminate environmentally derived pathogens. Humans, mice and rats show within species variation in the levels and ratios of their peripheral CD4+ and CD8+ T cells and to a significant degree this variation is under the control of polymorphic genes. Whether genes act separately to specify CD4+ and CD8+ subpopulation levels or whether CD8+ variation is controlled through gene and environmental action on CD4+ cells or vice versa, is not known. We use a quantitative modelling approach in identical and non-identical female human twins to delineate the lines of control which act upon and between CD4+ and CD8+ subsets. The major findings of the study are: (1) genetic variation controls CD8+ T cell levels through two major routes-the first is via an effect on CD4+ T cells which accounts for the observed co-variation between CD4+ and CD8+ T cells, the second is through direct action on CD8+ T cell levels. (2) No evidence of a gene effect from CD8+ T cells on CD4+ cells is observed. Our findings have implications for the evolution of the complex defence system of which CD4+ and CD8+ T cells are a crucial part and encourage further work towards locating common pleiotropic quantitative trait loci responsible for variation in numbers of T cells.


Subject(s)
CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Cell Differentiation/genetics , Twins/genetics , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Chi-Square Distribution , Female , Flow Cytometry , Humans , Lymphocyte Count , Models, Genetic , Multivariate Analysis , Polymorphism, Genetic/genetics , Twins, Dizygotic/genetics , Twins, Monozygotic/genetics , White People/genetics
11.
Thromb Haemost ; 85(2): 198-203, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11246532

ABSTRACT

OBJECTIVES: To explore the possible involvement of the proinflammatory and prothrombotic cytokine TNFalpha in APS by determining the plasma levels in patients and to test for association of TNFA promoter polymorphisms and HLA class II genotypes with both plasma TNFalpha and disease. PATIENTS AND METHOD: We studied 83 Caucasoid patients with APS and two groups of healthy controls. TNFalpha levels were determined in plasma from 35 patients' and 21 controls using a highly sensitive sandwich ELISA. The full patient group was genotyped together with 95 ethnically matched healthy controls. -308 and -238 TNFA promoter polymorphisms were assessed by ARMS-PCR. HLA-DQB1, DQA1 and DRB1 genotypes were determined by PCR using sequence specific primers. RESULTS: TNFalpha levels were significantly higher in patients with APS than healthy controls (median 2.95 pg/ml [range 0.51-10.75] vs. 0.95 pg/ml [0.51-1.6], respectively; p = 0.0001). Frequencies of TNFA-308*2 genotype did not differ between patients and controls. In contrast, TNFA-238*A positive genotype was more frequent in APS patients with arterial thrombosis and pregnancy loss than in controls (OR 3.7 [95% CI 1.37-10.1], p = 0.007 and OR 3.95 [95% CI 1.3-11.7], p = 0.01; respectively). DQB1*0303-DRB1*0701 haplotype was associated with TNFA-238*A in the control group (OR 96.0 [95% CI 9.6-959], p <0.0001) as well as in APS patient's group (OR 54.2 [95% CI 9.6-306.5], p <0.0001). CONCLUSIONS: Raised plasma TNFalpha levels were found in patients with APS. As a prothrombotic and proinflammatory cytokine, TNFalpha may be involved in the development of clinical features of APS. The lack of correlation between the TNFA-238 polymorphism and plasma levels associated with disease suggests that the TNF genetic marker may only indirectly relate to protein levels by virtue of allelic association with a functional marker which may reside in the HLA class II region.


Subject(s)
Antiphospholipid Syndrome/etiology , Promoter Regions, Genetic/genetics , Tumor Necrosis Factor-alpha/metabolism , Adolescent , Adult , Aged , Antiphospholipid Syndrome/blood , Antiphospholipid Syndrome/genetics , Case-Control Studies , Cohort Studies , Female , Gene Frequency , Genes, MHC Class II , Genotype , Humans , Linkage Disequilibrium , Male , Middle Aged , Odds Ratio , Polymorphism, Genetic , Pregnancy , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/physiology , White People/genetics
12.
Rheumatology (Oxford) ; 40(1): 31-6, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11157139

ABSTRACT

OBJECTIVES: We investigated the association between HLA class II haplotypes and antiphospholipid syndrome (APS). METHODS: HLA DRB1, DQB1 and DQA1 genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with APS. The genotype frequencies were compared between subgroups of patients and 177 healthy controls. RESULTS: DQB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701 haplotypes showed significantly positive correlations with APS [P=0.0087 and P=0.0012, respectively]. The association of the former was enhanced in primary APS patients with anti-beta 2-glycoprotein I antibodies (anti-beta 2GPI) [odds ratio 6.2, 95% confidence interval (2.2-17.6), P=0.0014, corrected P=0.042]. CONCLUSIONS: These alleles and haplotypes might affect anti-ss2GPI production and APS development in different and heterogeneous fashion.


Subject(s)
Antiphospholipid Syndrome/genetics , Histocompatibility Antigens Class II/genetics , Polymorphism, Genetic , White People/genetics , Adolescent , Adult , Aged , Female , Genetic Predisposition to Disease , Genetic Testing , HLA-DQ Antigens/genetics , HLA-DQ alpha-Chains , HLA-DQ beta-Chains , HLA-DR Antigens/genetics , HLA-DRB1 Chains , Haplotypes , Humans , Male , Middle Aged
13.
J Immunol ; 166(3): 1492-8, 2001 Feb 01.
Article in English | MEDLINE | ID: mdl-11160188

ABSTRACT

Rheumatoid arthritis (RA) is the most common, crippling human autoimmune disease. Using Western blotting and tandem mass spectroscopy, we have identified the endoplasmic reticulum chaperone BiP, a 78-kDa glucose-regulated protein, as a possible autoantigen. It preferentially stimulated increased proliferation of synovial T cells from patients with RA but not from patients with other arthritides. Mice with established collagen- or pristane-induced arthritis developed IgG Abs to BiP. Although BiP injected in CFA failed to induce arthritis in several strains of rats and mice, including HLA-DR4(+/-)- and HLA-DR1(+/+)-transgenic animals, it completely inhibited the development of arthritis when given i.v. 1 wk before the injection of type II collagen arthritis. Preimmunization with BiP suppressed the development of adjuvant arthritis in Lewis rats in a similar manner. This is the first report of a mammalian chaperone that is an autoantigen in human RA and in experimental arthritis and that can also prevent the induction of experimental arthritis. These findings may stimulate the development of new immunotherapies for the treatment of RA.


Subject(s)
Arthritis, Experimental/immunology , Arthritis, Experimental/prevention & control , Arthritis, Rheumatoid/immunology , Autoantigens/immunology , Carrier Proteins/administration & dosage , Carrier Proteins/immunology , Heat-Shock Proteins , Molecular Chaperones/administration & dosage , Molecular Chaperones/immunology , Adult , Animals , Arthritis, Experimental/etiology , Arthritis, Rheumatoid/pathology , Autoantibodies/biosynthesis , Autoantibodies/blood , Autoantigens/blood , Autoantigens/isolation & purification , Endoplasmic Reticulum/immunology , Endoplasmic Reticulum Chaperone BiP , Female , Humans , Immunization Schedule , Injections, Intradermal , Injections, Intravenous , Lymphocyte Activation , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Transgenic , Middle Aged , Rats , Rats, Inbred Lew , Rats, Wistar , Synovial Membrane/immunology , Synovial Membrane/pathology , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Tumor Cells, Cultured
14.
Clin Genet ; 58(4): 250-64, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11076050

ABSTRACT

In this review, we consider the motivation behind contemporary single nucleotide polymorphism (SNP) initiatives. Many of these initiatives are projected to involve large, population-based surveys. We therefore emphasize the utility of SNPs for genetic epidemiology studies. We start by offering an overview of genetic polymorphism and discuss the historical use of polymorphism in the identification of disease-predisposing genes via meiotic mapping. We next consider some of the unique aspects of SNPs, and their relative advantages and disadvantages in human population-based analyses. In this context, we describe and critique the following six different areas of application for SNP technologies: Gene discovery and mapping. Association-based candidate polymorphism testing. Diagnostics and risk profiling. Prediction of response to environmental stimuli, xenobiotics and diet. Homogeneity testing and epidemiological study design. Physiologic genomics. We focus on key issues within each of these areas in an effort to point out potential problems that might plague the use of SNPs (or other forms of polymorphism) within them. However, we make no claim that our list of considerations are exhaustive. Rather, we believe that they may provide a starting point for further dialog about the ultimate utility of SNP technologies. In addition, although our emphasis is placed on applications of SNPs to the understanding of human phenotypes, we acknowledge that SNP maps and technologies applied to other species (e.g. the mouse genome, pathogen genomes, plant genomes, etc.) are also of tremendous interest.


Subject(s)
Epidemiology , Genetic Techniques , Polymorphism, Genetic , Polymorphism, Single Nucleotide , Alleles , Chromosome Mapping , Female , Haplotypes , Humans , Internet , Male , Pedigree
15.
Arthritis Rheum ; 43(8): 1673-8, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10943856

ABSTRACT

OBJECTIVE: Rheumatoid arthritis (RA) is the most common disabling autoimmune disease, affecting approximately 1% of the population. The disease etiology is unknown, but it involves inflammation and immune dysregulation and is influenced by genetic variation at both HLA and other, as-yet-unidentified genetic loci. Corticotropin-releasing hormone (CRH; or corticotropin-releasing factor), a primary regulator of the hypothalamic-pituitary-adrenal axis and a key element in the response to stress and inflammation, is a strong candidate gene for RA. We examined the role of DNA variation across the region containing this gene in multicase families with RA. METHODS: We genotyped fluorescently labeled simple tandem repeat genetic markers from chromosome 8q13 in 295 families with multiple cases of RA. Singlepoint and multipoint nonparametric linkage analysis and association analysis using transmission disequilibrium testing (TDT) were also used. RESULTS: Single-point linkage analysis using a microsatellite within 30 kb of the CRH locus (CRH.PCR at position 8q13) showed a significant excess of allele sharing in 295 United Kingdom RA families with at least 2 affected members (MapMaker/Sibs logarithm of odds [LOD] 1.4; P = 5.5x10(-3); mean identity by descent [ibd] sharing 55.9%). To provide a more detailed linkage map, a multipoint analysis was conducted with an additional 7 dinucleotide microsatellite markers (average heterozygosity 0.75) flanking the CRH locus. Significant linkage was detected over a 22-cM region between D8S285 and D8S530, with the maximum singlepoint LOD score of 1.77 at D8S1723 (MapMaker/Sibs P = 2.2x10(-3); mean ibd sharing 59.3%). Multipoint analysis showed strongest evidence for linkage at the same marker (multipoint LOD 1.78, P = 2.1x10(-3), mean ibd sharing 55.8%). TDT analysis showed significant association at the CRH locus (P = 2.6x10(-3)). CRH has a sibling relative risk of 1.14, and contributes <10% to the sibling relative risk of RA. CONCLUSION: With the exception of HLA, this is the strongest evidence yet of a genetic locus that is both linked to and associated with RA, and provides an avenue for further genetic characterization and potentially novel therapeutic intervention.


Subject(s)
Arthritis, Rheumatoid/genetics , Corticotropin-Releasing Hormone/genetics , Adult , Alleles , Child , False Positive Reactions , Family Health , Female , Genetic Linkage , Genetic Predisposition to Disease , Humans , Lod Score , Male , Microsatellite Repeats
17.
Rheumatology (Oxford) ; 39(4): 393-8, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10817772

ABSTRACT

OBJECTIVE: To investigate the role of HLA class I in susceptibility to Felty's syndrome (FS) and large granular lymphocyte (LGL) syndrome. METHODS: Fifty caucasoid FS patients, and 55 patients with LGL syndrome, of whom 26 had arthritis and 29 did not, were studied. Complete HLA class I and HLA-DR typing including, where relevant, DRB1*04 subtyping was carried out by molecular methods. Comparison was made with 78 unselected healthy caucasoid controls and a further 29 DRB1*0401+ individuals. RESULTS: A significant association was found between HLA-A*02 and FS [odds ratio (OR) 3.9, 95% confidence interval (95% CI) 1.8-8.4, P = 0.0004]. At the B locus, there was an association between B*44 and LGL with arthritis [OR 3.5 (1.3-9.2), P = 0.01]. For HLA-Cw*0501, there was an association with FS [OR 4 (1. 7-9.2) P = 0.0008]. For both FS and LGL with arthritis, the extended haplotype HLA-A*02;B*44;Cw*0501;DRB1*0401 was significantly associated [OR 9.5 (2.6-35), P = 0.0001; OR 4.6 (1-22.4), P = 0.05, respectively]. There was no association between HLA class I or II and LGL without arthritis. All the allelic and haplotypic associations were lost on comparison with HLA-DRB1*0401+ controls. The strongest HLA association was with HLA-DRB1*0401 for FS [OR 27.9 (10.3-75.5), P = 10(-13)], and LGL with arthritis [OR 35.4 (9.6-131. 3), P = 10(-10)]. CONCLUSIONS: The major histocompatibility locus (MHC) associations with FS reported here are due to linkage disequilibrium with HLA-DRB1*0401. LGL syndrome with arthritis shows identical class II associations with FS, although there may be subtle immunogenetic differences between the two in the class I region. One of the extended haplotypes reported in a number of studies for FS and rheumatoid arthritis (summarized as HLA-A*02;Cw*0501; B*44;TNFb5;TNFa6;TNFd4;C4A*3;C4BQ*0;DRB1*0 401;DQB1*0301) is likely to be attributable to strong primary association with HLA-DRB1*0401, rather than to epistatic interaction between these loci.


Subject(s)
Arthritis, Rheumatoid/complications , Felty Syndrome/genetics , Felty Syndrome/immunology , HLA-DR Antigens/genetics , Major Histocompatibility Complex/genetics , Adult , Aged , Alleles , Arthritis, Rheumatoid/genetics , Female , Genetic Predisposition to Disease , HLA-DRB1 Chains , Haplotypes , Humans , Leukemia, Lymphoid/genetics , Linkage Disequilibrium , Major Histocompatibility Complex/immunology , Male , Middle Aged , Syndrome
18.
Arthritis Rheum ; 43(4): 834-43, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10765928

ABSTRACT

OBJECTIVE: To investigate the ability of CD8+,CD57+ large granular lymphocytes (LGL) from normal individuals and from Felty's syndrome (FS) or LGL syndrome patients to suppress allogeneic neutrophil precursor development. METHODS: Six FS patients, 5 LGL syndrome patients, and 13 elderly controls were studied. CD8+,CD57+ T cells were cocultured with cord blood-derived stem cells, and percentage inhibition was calculated. Recombinant chemokines and Fas-stimulating molecules were used in separate cultures to address possible mechanisms of suppression. Proliferation after stimulation with interleukin-2 (IL-2) and anti-CD3 was assessed. RESULTS: Significant (79%) suppression of colony-forming unit-granulocyte-macrophage (CFU-GM) by the CD8+,CD57+ subset was shown by 1 FS patient. None of the CD8+,CD57+ cells from LGL syndrome patients had any effect. Six of 13 controls studied showed >40% inhibition of CFU-GM, and all but 2 showed at least some suppression. The suppressive effect was not mediated by Fas/Fas ligand interactions or by the chemokines macrophage inhibitory protein 1alpha or IL-8. LGL from both patients and controls were largely CD28- and had reduced proliferative capacity. CONCLUSION: In a subset of FS patients, expansion of CD8+,CD57+ T cells in the bone marrow may be responsible for neutropenia by suppressing neutrophil precursors. This effect is also seen with normal LGL, which are likely to have an important function in neutrophil homeostasis.


Subject(s)
Aged/physiology , CD57 Antigens/blood , CD8-Positive T-Lymphocytes , Neutrophils/cytology , T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/physiology , Cell Division , Felty Syndrome/complications , Fetal Blood/cytology , Granulocytes/cytology , Humans , Leukemia, Lymphoid/complications , Macrophages/cytology , Neutropenia/etiology , Stem Cells
19.
Z Rheumatol ; 59(1): 29-34, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10769420

ABSTRACT

UNLABELLED: The regulatory region of the corticotropin releasing hormone (CRH) is highly conserved and plays a crucial role in the response of the organism to stress. Release of CRH initiates a cascade of events leading to the release of cortisone and the regulation of inflammatory and immune events. OBJECTIVE: Since it has been postulated that the impaired corticotropin releasing hormone (CRH) response to stress in patients with rheumatoid arthritis (RA) has a genetic basis, we investigated the distribution of CRH alleles in a cohort of UK patients as well as in South African RA patients. METHODS: Restriction fragment length polymorphism of PCR amplified DNA products of the CRH promoter. We compared the allele frequencies in the RA patients with the respective healthy control population described previously. RESULTS: As in the control populations we found two biallelic polymorphic sequences (named A1 and A2 and B1 and B2, respectively) in the CRH promoter which could be assigned to compound alleles. The A2B1 compound allele was protective against development of RA in a large group of UK Caucasoid patients (p = 0.03; odds ratio 0.43, 95% confidence interval 0.21-0.88). In contrast, A1B1 was positively associated with RA in a cohort of black South African RA patients (p = 0.05; odds ratio 1.78, 95% confidence interval 1.01-3.15). CONCLUSION: Taken together, these findings support the hypothesis that CRH promoter polymorphism represents a new genetic marker for RA susceptibility and may prove useful for the prediction of RA risk in the future when further genetic and environmental risk factors are determined.


Subject(s)
Arthritis, Rheumatoid/genetics , Asian People/genetics , Black People/genetics , Corticotropin-Releasing Hormone/genetics , Polymorphism, Restriction Fragment Length , Promoter Regions, Genetic/genetics , White People/genetics , Adult , Alleles , Arthritis, Rheumatoid/ethnology , Cohort Studies , England , Female , Gene Frequency/genetics , Genetics, Population , Genotype , HLA-DR4 Antigen/genetics , Hong Kong , Humans , Male , Middle Aged , Polymerase Chain Reaction , Reference Values , South Africa
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