Catherine Potter

Newcastle University, Newcastle-on-Tyne, England, United Kingdom

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Publications (27)230.94 Total impact

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    ABSTRACT: This study examines the relationship between common genetic variation within DNA methyltransferase genes and inter-individual variation in DNA methylation. Eleven polymorphisms spanning DNMT1 and DNMT3B were genotyped. Global and gene specific (IGF2, IGFBP3, ZNT5) DNA methylation was quantified by LUMA and bisulfite Pyrosequencing assays, respectively, in neonatal cord blood and in maternal peripheral blood. Associations between maternal genotype and maternal methylation (n (≈) 333), neonatal genotype and neonatal methylation (n (≈) 454), and maternal genotype and neonatal methylation (n (≈) 137) were assessed. The findings of this study provide some support to the hypothesis that genetic variation in DNA methylating enzymes influence DNA methylation at global and gene-specific levels; however observations were not robust to correction for multiple testing. More comprehensive analysis of the influence of genetic variation on global and site specific DNA methylation is warranted.
    PLoS ONE 01/2013; 8(10):e76506. · 3.73 Impact Factor
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    ABSTRACT: Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P = 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95% confidence interval (95% CI): 4-36 g] lower birth weight (P = 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95% CI: -4 to 14 g; P = 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight.
    Human Molecular Genetics 09/2012; · 7.69 Impact Factor
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    ABSTRACT: There is considerable interest in defining the relationship between epigenetic variation and the risk of common complex diseases. Strategies which assist in the prioritisation of target loci that have the potential to be epigenetically regulated might provide a useful approach in identifying concrete examples of epigenotype-phenotype associations. Focusing on the postulated role of epigenetic factors in the aetiopathogenesis of obesity this report outlines an approach utilising gene expression data and a suite of bioinformatic tools to prioritise a list of target candidate genes for more detailed experimental scrutiny. Gene expression microarrays were performed using peripheral blood RNA from children aged 11-13years selected from the Newcastle Preterm Birth Growth Study which were grouped by body mass index (BMI). Genes showing ≥2.0 fold differential expression between low and high BMI groups were selected for in silico analysis. Several bioinformatic tools were used for each following step; 1) a literature search was carried out to identify whether the differentially expressed genes were associated with adiposity phenotypes. Of those obesity-candidate genes, putative epigenetically regulated promoters were identified by 2) defining the promoter regions, 3) then by selecting promoters with a CpG island (CGI), 4) and then by identifying any transcription factor binding modules covering CpG sites within the CGI. This bioinformatic processing culminated in the identification of a short list of target obesity-candidate genes putatively regulated by DNA methylation which can be taken forward for experimental analysis. The proposed workflow provides a flexible, versatile and low cost methodology for target gene prioritisation that is applicable to multiple species and disease contexts.
    Gene 03/2012; 499(1):99-107. · 2.20 Impact Factor
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    ABSTRACT: At present, there is no reliable tool for predicting disease outcome in patients with rheumatoid arthritis (RA). We previously demonstrated an association between specific baseline biomarkers/clinical measures including matrix metalloproteinase-3 (MMP-3) and 2-year radiographic progression in patients with RA. This study further evaluates the predictive capability of these baseline variables with outcome extended over 8-years. Fifty-eight of the original cohort (n = 118) had radiographic progression from baseline to mean 8.2-years determined using the van der Heijde modified Sharp method. The contribution of each predictor variable towards radiographic progression was assessed with univariate and multivariate analyses. Traditional factors (including erythrocyte sedimentation rate, C-reactive protein, anti-cyclic citrullinated peptide (anti-CCP), and rheumatoid factor) and biomarkers of tissue destruction (including MMP-3, C-telopeptide of type II collagen, cartilage oligomeric matrix protein, and tissue inhibitor of metalloproteinase 1) measured at baseline were associated with radiographic progression at endpoint. Multivariate logistic regression identified anti-CCP seropositivity [OR 9.29, 95%CI: 2.29-37.64], baseline elevated MMP-3 [OR 8.25, 95%CI: 2.54-26.78] and baseline radiographic damage [OR 5.83, 95%CI: 1.88-18.10] as the strongest independent predictors of radiographic progression. A model incorporating these variables had a predictive accuracy of 0.87, assessed using the area under the receiver operating characteristic curve. In our cohort with onset of RA symptoms < 2-years, multivariate analysis identified anti-CCP status and baseline MMP-3 as the strongest independent predictors of radiographic disease outcome at 8.2-years. This finding suggests determination of baseline MMP-3, in conjunction with traditional serologic markers, may provide additional prognostic information for patients with RA. Furthermore, these findings highlight the importance of continued research into a broad range of biomarkers as potential predictors of joint damage.
    Arthritis research & therapy 02/2012; 14(1):R30. · 4.27 Impact Factor
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    ABSTRACT: Patterns of DNA methylation change with age and these changes are believed to be associated with the development of common complex diseases. The hypothesis that Long Interspersed Nucleotide Element 1 (LINE-1) DNA methylation (an index of global DNA methylation) is associated with biomarkers of metabolic health was investigated in this study. Global LINE-1 DNA methylation was quantified by pyrosequencing in blood-derived DNA samples from 228 individuals, aged 49-51 years, from the Newcastle Thousand Families Study (NTFS). Associations between log-transformed LINE-1 DNA methylation levels and anthropometric and blood biochemical measurements, including triglycerides, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, fasting glucose and insulin secretion and resistance were examined. Linear regression, after adjustment for sex, demonstrated positive associations between log-transformed LINE-1 DNA methylation and fasting glucose {coefficient 2.80 [95% confidence interval (CI) 0.39-5.22]}, total cholesterol [4.76 (95% CI 1.43-8.10)], triglycerides [3.83 (95% CI 1.30-6.37)] and LDL-cholesterol [5.38 (95% CI 2.12-8.64)] concentrations. A negative association was observed between log-transformed LINE-1 methylation and both HDL cholesterol concentration [-1.43 (95% CI -2.38 to -0.48)] and HDL:LDL ratio [-1.06 (95% CI -1.76 to -0.36)]. These coefficients reflect the millimoles per litre change in biochemical measurements per unit increase in log-transformed LINE-1 methylation. These novel associations between global LINE-1 DNA methylation and blood glycaemic and lipid profiles highlight a potential role for epigenetic biomarkers as predictors of metabolic disease and may be relevant to future diagnosis, prevention and treatment of this group of disorders. Further work is required to establish the role of confounding and reverse causation in the observed associations.
    International Journal of Epidemiology 02/2012; 41(1):210-7. · 6.98 Impact Factor
  • Catherine Potter, Caroline L Relton
    International Journal of Epidemiology 02/2012; 41(1):308-9. · 6.98 Impact Factor
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    ABSTRACT: Inter-individual variation in patterns of DNA methylation at birth can be explained by the influence of environmental, genetic and stochastic factors. This study investigates the genetic and non-genetic determinants of variation in DNA methylation in human infants. Given its central role in provision of methyl groups for DNA methylation, this study focuses on aspects of folate metabolism. Global (LUMA) and gene specific (IGF2, ZNT5, IGFBP3) DNA methylation were quantified in 430 infants by Pyrosequencing®. Seven polymorphisms in 6 genes (MTHFR, MTRR, FOLH1, CβS, RFC1, SHMT) involved in folate absorption and metabolism were analysed in DNA from both infants and mothers. Red blood cell folate and serum vitamin B(12) concentrations were measured as indices of vitamin status. Relationships between DNA methylation patterns and several covariates viz. sex, gestation length, maternal and infant red cell folate, maternal and infant serum vitamin B(12), maternal age, smoking and genotype were tested. Length of gestation correlated positively with IGF2 methylation (rho = 0.11, p = 0.032) and inversely with ZNT5 methylation (rho = -0.13, p = 0.017). Methylation of the IGFBP3 locus correlated inversely with infant vitamin B(12) concentration (rho = -0.16, p = 0.007), whilst global DNA methylation correlated inversely with maternal vitamin B(12) concentrations (rho = 0.18, p = 0.044). Analysis of common genetic variants in folate pathway genes highlighted several associations including infant MTRR 66G>A genotype with DNA methylation (χ(2) = 8.82, p = 0.003) and maternal MTHFR 677C>T genotype with IGF2 methylation (χ(2) = 2.77, p = 0.006). These data support the hypothesis that both environmental and genetic factors involved in one-carbon metabolism influence DNA methylation in infants. Specifically, the findings highlight the importance of vitamin B(12) status, infant MTRR genotype and maternal MTHFR genotype, all of which may influence the supply of methyl groups for DNA methylation. In addition, gestational length appears to be an important determinant of infant DNA methylation patterns.
    PLoS ONE 01/2012; 7(3):e33290. · 3.73 Impact Factor
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    ABSTRACT: Rapid postnatal growth is associated with increased risk of childhood adiposity. The aim of this study was to establish whether this pathway is mediated by altered DNA methylation and gene expression. Two distinct cohorts, one preterm (n=121) and one term born (n=6,990), were studied. Exploratory analyses were performed using microarrays to identify differentially expressed genes in whole blood from children defined as "slow" (n=10) compared with "rapid" (n=10) postnatal (term to 12 weeks corrected age) growers. Methylation within the identified TACSTD2 gene was measured in both cohorts, and rs61779296 genotype was determined by Pyrosequencing or imputation and analyzed in relation to body composition at 9-15 years of age. In cohort 1, TACSTD2 expression was inversely correlated with methylation (P=0.016), and both measures were associated with fat mass (expression, P=0.049; methylation, P=0.037). Although associated with gene expression (cohort 1, P=0.008) and methylation (cohort 1, P=2.98×10(-11); cohort 2, P=3.43×10(-15)), rs61779296 was not associated with postnatal growth or fat mass in either cohort following multiple regression analysis. Hence, the lack of association between fat mass and a methylation proxy SNP suggests that reverse causation or confounding may explain the initial association between fat mass and gene regulation. Noncausal methylation patterns may still be useful predictors of later adiposity.
    Diabetes 12/2011; 61(2):391-400. · 7.90 Impact Factor
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    ABSTRACT: Anti-tumor necrosis factor (anti-TNF) agents are successful therapies in rheumatoid arthritis (RA); however, inadequate response occurs in 30-40% of patients treated. Knowledge of the genetic factors that influence response may facilitate personalized therapy. The purpose of this study was to identify genetic predictors of response to anti-TNF therapy in RA and to validate our findings in independent cohorts. Data from genome-wide association (GWA) studies were available from the Wellcome Trust Case Control Consortium for 566 anti-TNF-treated RA patients. Multivariate linear regression analysis of changes in the Disease Activity Score in 28 joints at 6 months was conducted at each single-nucleotide polymorphism (SNP) using an additive model. Associated markers (P < 10(-3) ) were genotyped in 2 independent replication cohorts (n = 379 and n = 341), and a combined analysis was performed. Of 171 successfully genotyped markers demonstrating association with treatment response in the GWA data, 7 were corroborated in the combined analysis. The strongest effect was at rs17301249, mapping to the EYA4 gene on chromosome 6: the minor allele conferred improved response to treatment (coefficient -0.27, P = 5.67(-05) ). The minor allele of rs1532269, mapping to the PDZD2 gene, was associated with a reduced treatment response (coefficient 0.20, P = 7.37(-04) ). The remaining associated SNPs mapped to intergenic regions on chromosomes 1, 4, 11, and 12. Using a genome-wide strategy, we have identified and validated the association of 7 genetic loci with response to anti-TNF treatment in RA. Additional confirmation of these findings in further cohorts will be required.
    Arthritis & Rheumatology 11/2010; 63(3):645-53. · 7.48 Impact Factor
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    ABSTRACT: To determine whether genetic variation within genes integral to the Toll-like receptor (TLR) and NFkappaB signalling systems, two cardinal regulators of inflammatory and immune responses, contributes towards the observed variation in response to tumour necrosis factor (TNF) blocking agents in patients with rheumatoid arthritis (RA). Pairwise-tagging single nucleotide polymorphisms (SNPs) spanning 24 candidate genes were selected and genotyped in a large UK cohort of patients receiving anti-TNF therapy for RA. Multivariate regression analyses were performed to test association between individual genotypes, under an additive model, and treatment response at 6 months' follow-up assessed using both the absolute change in 28-joint count Disease Activity Score (DAS28) and the European League Against Rheumatism (EULAR) response criteria. Analyses were performed across subgroups comprising etanercept-, infliximab- and infliximab/adalimumab-treated patients as well as the combined anti-TNF-treated cohort. p Values <0.05 were considered statistically significant. A total of 187 SNPs were successfully genotyped and analysed in 909 patients. Eight SNPs spanning six genes demonstrated nominal evidence of association with response (DAS28) across the anti-TNF-treated subgroups, six of which were restricted to etanercept-treated patients. Twelve SNPs spanning nine genes demonstrated nominal evidence of association with treatment response (DAS28 and/or EULAR) across the combined anti-TNF cohort. These included SNPs mapping to MyD88 (rs7744) and CHUK (rs11591741), which were associated under each model applied (etanercept-treated and combined anti-TNF cohort analysis (DAS28 and EULAR)). Several SNPs mapping to the TLR and NFkappaB signalling systems demonstrated association with anti-TNF response as a whole and, in particular, with response to etanercept. Validation of these findings in an independent cohort is now warranted.
    Annals of the rheumatic diseases 07/2010; 69(7):1315-20. · 8.11 Impact Factor
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    ABSTRACT: Anti-tumour necrosis factor (anti-TNF) therapy has proved to be highly successful in treating rheumatoid arthritis (RA), although 30-40% of patients have little or no response. The authors hypothesise that this may be genetically determined. In other complex diseases, susceptibility genes have been shown to influence treatment response. The aim of the current study was to investigate the association of markers within confirmed RA susceptibility loci with the response to anti-TNF treatment. Eighteen single nucleotide polymorphisms (SNPs) mapping to 11 genetic loci were genotyped in 1012 patients with RA receiving treatment with etanercept, infliximab or adalimumab. Multivariate linear regression analyses were performed using the absolute change in 28 joint count disease activity score (DAS28) between baseline and 6-month follow-up as the outcome variable, adjusting for confounders. p Values <0.05 were considered statistically significant and associated markers were genotyped in an additional 322 samples. Analysis was performed in the combined cohort of 1334 subjects with RA treated with anti-TNF. In the combined analysis, SNPs mapping to AFF3 and CD226 had a statistically significant association with the response to anti-TNF treatment under an additive model. The G allele at rs10865035, mapping to AFF3, was associated with an improved response to anti-TNF treatment (coefficient -0.14 (95% CI -0.25 to -0.03), p=0.015). At the CD226 SNP rs763361, the C allele conferred reduced response to treatment (coefficient 0.11 (95% CI 0.00 to 0.22), p=0.048). These results suggest that AFF3 and CD226, two confirmed RA susceptibility genes, have an additional role in influencing the response to anti-TNF treatment.
    Annals of the rheumatic diseases 06/2010; 69(6):1029-35. · 8.11 Impact Factor
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    ABSTRACT: The introduction of tumour necrosis factor antagonists (anti-TNF) has greatly improved the treatment of rheumatoid arthritis, however, a significant proportion of patients fail to respond to therapy. We hypothesized that variants spanning the type 2 TNF receptor (TNFR2) and the TNF cleavage enzyme (TACE) genes contribute towards the observed variation in patient response (defined as the absolute change in 28-joint count disease activity score). Twenty-nine single nucleotide polymorphisms (SNPs) were genotyped in a large cohort of patients (n=602) and analysed by multivariate linear regression. Three SNPs (rs520916, rs652625, rs597519) mapping upstream of TNFR2 showed borderline evidence for association (P<0.1) across the complete cohort and, more so, in the etanercept-treated subgroup. However, the evidence of association was neither replicated in an independent cohort (n=377) nor strengthened after combined analysis (n=979). We conclude that common SNPs spanning the TNFR2 and TNF cleavage enzyme (TACE) genes do not have a major effect on the response to anti-TNF therapy in rheumatoid arthritis patients.
    Pharmacogenetics and Genomics 03/2010; 20(5):338-41. · 3.61 Impact Factor
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    ABSTRACT: The introduction of anti-tumour necrosis factor (TNF) agents has greatly improved the treatment of rheumatoid arthritis; however, a significant proportion of patients fail to respond to therapy. We hypothesized that genes within the TNF receptor superfamily member 1B signalling pathway contribute towards the observed variation in patient response. This was tested by genotyping 73 single-nucleotide polymorphisms (SNPs) from six candidate genes (DUSP1, HRB, IKBKAP, MAP3K1, MAP3K14 and TANK) in a large UK cohort of rheumatoid arthritis patients (n=642). Two SNPs [rs96844 (MAP3K1) and rs4792847 (MAP3K14)] showed evidence of association (P<0.05) to treatment response and were subsequently examined in an independent cohort of patients (n=428). Replication of association to either SNP was not achieved, but combined analysis of the complete cohort (n=1070) provided nominal evidence of association to both SNPs. We conclude that analysis of the common variation in the selected candidate genes did not provide strong evidence to implicate their involvement in varying patient response to anti-TNF treatment.
    Pharmacogenetics and Genomics 04/2009; 19(4):319-23. · 3.61 Impact Factor
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    ABSTRACT: Large-scale studies of genomic variation could assist efforts to eliminate malaria. But there are scientific, ethical and practical challenges to carrying out such studies in developing countries, where the burden of disease is greatest. The Malaria Genomic Epidemiology Network (MalariaGEN) is now working to overcome these obstacles, using a consortial approach that brings together researchers from 21 countries.
    Nature. 12/2008; 19079050(456):732-737.
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    ABSTRACT: Anti-tumour necrosis factor (TNF) agents have revolutionized the treatment of patients with rheumatoid arthritis (RA). These therapies are, however, expensive and 30% of patients fail to respond. In a large cohort of Caucasian RA patients treated with anti-TNF medications (total n = 1050, etanercept n = 455, infliximab n = 450), we investigated whether genotypes of eight single nucleotide polymorphisms in the region containing the TNF gene were associated with response to anti-TNF therapy. Linear regression analyses adjusted for baseline 28 joint disease activity score (DAS28), baseline health assessment questionnaire score, gender and concurrent disease modifying anti-rheumatic drug treatment were used to assess association of these polymorphisms with treatment response, defined by change in DAS28 after 6 months. Analyses were performed in the entire cohort, and also stratified by anti-TNF agent. Association between DAS28 response and TNF-308 (rs1800629) genotype (P = 0.001) was detected across the whole cohort. After stratification by anti-TNF agent, the rare TNF-308AA genotype was associated with a significantly poorer response compared with TNF-308GG in etanercept (P = 0.001, n = 7) but not infliximab (P = 0.8, n = 17) treated patients. Conversely, the GA genotype at TNF-238 (rs361525) was associated with a poorer response to infliximab (P = 0.028, n = 40), but not etanercept (P = 0.6, n = 33). Owing to the small numbers of patients in some of the genotype groups examined, our data must be regarded as preliminary and will require replication in further large cohorts of anti-TNF-treated patients. If confirmed, our findings suggest the potential for genotype at these markers to aid selection of anti-TNF agent in patients with RA.
    Human Molecular Genetics 09/2008; 17(22):3532-8. · 7.69 Impact Factor
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    ABSTRACT: Association of a functional promoter polymorphism mapping to the Fc receptor-like 3 (FCRL3) gene has recently been reported and replicated with rheumatoid arthritis (RA) in Japanese populations. The aim of this study was to investigate association of the FCRL3 gene with RA in UK subjects. DNA was available from 1065 patients with RA and 2073 population controls from the UK. Four single nucleotide polymorphism (SNP) markers (FCRL3-169*C/T (fclr3_3, rs7528684), fclr3_4 (rs11264799), fclr3_5 (rs945635), fclr3_6 (rs3761959)) all previously associated with RA in a Japanese population were genotyped in 761 RA samples and 484 controls. In the remaining samples, only the putative disease causal polymorphism, FCRL3-169*C/T, was tested. Genotyping was performed using either the Sequenom MassArray iPlex platform or a 5' Allelic discrimination assay (Taqman, ABI). Extensive linkage disequilibrium was present across the promoter SNPs genotyped (r2 values = 0.60-0.98). Allele frequencies did not differ between RA cases and controls either for the putative disease causal polymorphism (odds ratio FCRL3-169*C allele = 0.97 (0.87-1.07), p = 0.51) or for the other SNPs tested. Similarly, no association was detected with RA using haplotype analysis or when stratification by shared epitope carriage or by presence of rheumatoid factor was undertaken. This study was powered to detect an effect size of 1.24 or greater for the FCRL3-169*C/T functional promoter polymorphism but no evidence for association was detected, suggesting that this gene will not have a substantial effect in determining susceptibility to RA in populations of Northern European descent.
    Arthritis research & therapy 09/2008; 10(4):405. · 4.27 Impact Factor
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    ABSTRACT: To determine whether rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibodies, or carriage of shared epitope (SE) and PTPN22 genetic susceptibility variants predict response to therapy in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor (TNF) agents. UK-wide multicentre collaborations were established to recruit a large cohort of patients treated with anti-TNF drugs for RA. Serum RF, anti-CCP antibody and SE status were determined using commercially available kits. PTPN22 R620W genotyping was performed by Sequenom MassArray. Linear regression analyses were performed to investigate the role of these four factors in predicting response to treatment by 6 months, defined as the absolute change in 28-joint Disease Activity Score (DAS28). Of the 642 patients analysed, 46% received infliximab, 43% etanercept and 11% adalimumab. In all, 89% and 82% of patients were RF and anti-CCP positive, respectively. Patients that were RF negative had a 0.48 (95% CI 0.08 to 0.87) greater mean improvement in DAS28 compared to patients that were RF positive. A better response was also seen among patients that were anti-CCP negative. No association was demonstrated between drug response and SE or PTPN22 620W carriage. The presence of RF or anti-CCP antibodies was associated with a reduced response to anti-TNF drugs. However, these antibodies only account for a small proportion of the variance in treatment response. It is likely that genetic factors will contribute to treatment response, but these do not include the well established RA susceptibility loci, SE and PTPN22.
    Annals of the rheumatic diseases 04/2008; 68(1):69-74. · 8.11 Impact Factor
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    ABSTRACT: We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.
    Nature Genetics 12/2007; 39(11):1329-37. · 35.21 Impact Factor
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    ABSTRACT: The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes
    Nature 11/2007; 450(7171):887-892. · 38.60 Impact Factor
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    ABSTRACT: The tumour necrosis factor (TNF) receptor-associated factor (TRAF) family is important in activating multiple inflammatory and immune related processes induced by cytokines such as TNFalpha and interleukin-1. These genes therefore represent strong candidate susceptibility factors for rheumatoid arthritis (RA). A study was undertaken to investigate the association between single nucleotide polymorphisms (SNPs) spanning six TRAF genes and RA in a British population. Twenty-three haplotype tagging (ht) SNPs and 26 random SNPs spanning the six TRAF genes were initially tested for association in a cohort of 351 unrelated patients with RA and 368 controls. Any SNPs demonstrating an association were genotyped in further samples. Sequenom MassARRAY technology was preferentially used for genotyping. Both single point and haplotypic analyses were performed. Forty-four SNPs were successfully genotyped and conformed to Hardy-Weinberg expectation. A single SNP, rs7514863, mapping upstream of the TRAF5 gene and affecting a putative transcription factor binding site, demonstrated a significant association across the entire cohort of 1273 cases with RA compared with 2463 healthy controls (OR for minor T allele 1.2 (95% CI 1.06 to 1.36), p = 0.005). The association was stronger in the subgroup carrying at least one copy of the shared epitope alleles (OR 1.43 (95% CI 1.18 to 1.73), p = 0.0003). These findings provide evidence for the association of an SNP upstream of a strong candidate RA susceptibility gene, TRAF5, in a large cohort of patients and controls. Further association and functional studies are required to investigate the role of this variant, or one in linkage disequilibrium with it, in RA disease causation.
    Annals of the Rheumatic Diseases 11/2007; 66(10):1322-6. · 9.11 Impact Factor

Publication Stats

1k Citations
230.94 Total Impact Points

Institutions

  • 2010–2013
    • Newcastle University
      • • Institute of Health and Society
      • • Institute of Cellular Medicine
      Newcastle-on-Tyne, England, United Kingdom
  • 2005–2010
    • The University of Manchester
      • Centre for Integrated Genomic Medical Research (CIGMR)
      Manchester, England, United Kingdom