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Johnson N.,Institute of Cancer Research | Walker K.,London School of Hygiene and Tropical Medicine | Gibson L.J.,London School of Hygiene and Tropical Medicine | Orr N.,Institute of Cancer Research | And 26 more authors.
Journal of the National Cancer Institute | Year: 2012

Background: Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women. Methods: We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided. Results: rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10-9) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82). Conclusions: Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer. © The Author 2012. Published by Oxford University Press. All rights reserved.


Robinson P.C.,University of Queensland | Claushuis T.A.M.,University of Queensland | Cortes A.,University of Queensland | Martin T.M.,Oregon Health And Science University | And 28 more authors.
Arthritis and Rheumatology | Year: 2015

Conclusion These findings of both novel AAU-specific associations and associations shared with AS demonstrate overlapping but also distinct genetic susceptibility loci for AAU and AS. The associations in IL10 and IL18R1 are shared with inflammatory bowel disease, suggesting common etiologic pathways.Objective To use high-density genotyping to investigate the genetic associations of acute anterior uveitis (AAU) in patients with and those without ankylosing spondylitis (AS)Methods We genotyped samples from 1,711 patients with AAU (either primary or combined with AS), 2,339 AS patients without AAU, and 10,000 control subjects on an Illumina Immunochip Infinium microarray. We also used data for AS patients from previous genome-wide association studies to investigate the AS risk locus ANTXR2 for its putative effect in AAU. ANTXR2 expression in mouse eyes was investigated by real-time quantitative reverse transcription-polymerase chain reaction.Results A comparison between all patients with AAU and healthy control subjects showed strong association over HLA-B, corresponding to the HLA-B27 tag single-nucleotide polymorphism rs116488202. The association of 3 non-major histocompatibility complex loci, IL23R, the intergenic region 2p15, and ERAP1, reached genome-wide significance (P < 5 × 10-8). Five loci harboring the immune-related genes IL10-IL19, IL18R1-IL1R1, IL6R, the chromosome 1q32 locus harboring KIF21B, as well as the eye-related gene EYS, were also associated, reaching a suggestive level of significance (P < 5 × 10-6). Several previously confirmed AS associations demonstrated significant differences in effect size between AS patients with AAU and AS patients without AAU. ANTXR2 expression varied across eye compartments. © 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc.


Piret S.E.,University of Oxford | Gorvin C.M.,University of Oxford | Trinh A.,Monash University | Taylor J.,University of Oxford | And 6 more authors.
American Journal of Medical Genetics, Part A | Year: 2016

The aim of this study was to identify the causative mutation in a family with an unusual presentation of autosomal dominant osteopetrosis (OPT), proximal renal tubular acidosis (RTA), renal stones, epilepsy, and blindness, a combination of features not previously reported. We undertook exome sequencing of one affected and one unaffected family member, followed by targeted analysis of known candidate genes to identify the causative mutation. This identified a missense mutation (c.643G>A; p.Gly215Arg) in the gene encoding the chloride/proton antiporter 7 (gene CLCN7, protein CLC-7), which was confirmed by amplification refractory mutation system (ARMS)-PCR, and to be present in the three available patients. CLC-7 mutations are known to cause autosomal dominant OPT type 2, also called Albers–Schonberg disease, which is characterized by osteosclerosis, predominantly of the spine, pelvis and skull base, resulting in bone fragility and fractures. Albers–Schonberg disease is not reported to be associated with RTA, but autosomal recessive OPT type 3 (OPTB3) with RTA is associated with carbonic anhydrase type 2 (CA2) mutations. No mutations were detected in CA2 or any other genes known to cause proximal RTA. Neither CLCN7 nor CA2 mutations have previously been reported to be associated with renal stones or epilepsy. Thus, we identified a CLCN7 mutation in a family with autosomal dominant osteopetrosis, RTA, renal stones, epilepsy, and blindness. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.


Baraliakos X.,Rheumazentrum Ruhrgebiet | Borah B.,Novartis | Braun J.,Rheumazentrum Ruhrgebiet | Baeten D.,University of Amsterdam | And 12 more authors.
Annals of the Rheumatic Diseases | Year: 2016

Introduction: A 28-week study suggested efficacy of the anti-interleukin-17A monoclonal antibody secukinumab in active ankylosing spondylitis (AS). MRIassessed inflammation was reduced at weeks 6, 28. Objective To analyse the longer-term effects of secukinumab on MRI inflammatory and noninflammatory spinal lesions in relation to its clinical efficacy in subjects with active AS. Methods: Spinal MRI results (baseline, week 94) for 13 subjects with AS initially treated with secukinumab 2×10 mg/kg intravenously (n=10) or placebo (n=3) and receiving a secukinumab maintenance dose of 3 mg/kg IV every 4 weeks up to week 94 were evaluated by the Berlin score; inflammatory/non-inflammatory (fatty) changes were assessed at vertebral edges (VEs). Results were compared with clinical outcomes. Results: Most of the 13 subjects assessed at week 94 had sustained clinical responses: 8 (62%) achieved Assessment of SpondyloArthritis international Society 20% (ASAS20), including 6 (46%) achieving ASAS40 responses, corresponding to 75% and 83% reductions in the Berlin score, respectively. In the 10 subjects treated with secukinumab throughout the study period, 79/91 (87%) inflammatory VEs at baseline resolved by week 94; new fatty lesions occurred in 39/796 (4.9%) of VEs; 87/124 (70%) VEs with fatty lesions at baseline remained unchanged; 30% were no longer visible. Conclusions: In this pilot study, secukinumab treatment up to 2 years yielded sustained clinical improvement accompanied by regression of spinal inflammation. The impact of secukinumab on the development of fatty changes and bone formation in AS will be assessed in larger trials.


PubMed | University of Amsterdam, Schoen Klinik Hamburg, Charite Campus Benjamin Franklin, Center for Inflammatory Joint Diseases and 7 more.
Type: Journal Article | Journal: Annals of the rheumatic diseases | Year: 2016

A 28-week study suggested efficacy of the anti-interleukin-17A monoclonal antibody secukinumab in active ankylosing spondylitis (AS). MRI-assessed inflammation was reduced at weeks 6, 28.To analyse the longer-term effects of secukinumab on MRI inflammatory and non-inflammatory spinal lesions in relation to its clinical efficacy in subjects with active AS.Spinal MRI results (baseline, week 94) for 13 subjects with AS initially treated with secukinumab 210mg/kg intravenously (n=10) or placebo (n=3) and receiving a secukinumab maintenance dose of 3mg/kg IV every 4weeks up to week 94 were evaluated by the Berlin score; inflammatory/non-inflammatory (fatty) changes were assessed at vertebral edges (VEs). Results were compared with clinical outcomes.Most of the 13 subjects assessed at week 94 had sustained clinical responses: 8 (62%) achieved Assessment of SpondyloArthritis international Society 20% (ASAS20), including 6 (46%) achieving ASAS40 responses, corresponding to 75% and 83% reductions in the Berlin score, respectively. In the 10 subjects treated with secukinumab throughout the study period, 79/91 (87%) inflammatory VEs at baseline resolved by week 94; new fatty lesions occurred in 39/796 (4.9%) of VEs; 87/124 (70%) VEs with fatty lesions at baseline remained unchanged; 30% were no longer visible.In this pilot study, secukinumab treatment up to 2years yielded sustained clinical improvement accompanied by regression of spinal inflammation. The impact of secukinumab on the development of fatty changes and bone formation in AS will be assessed in larger trials.This study is registered with ClinicalTrials.gov, number NCT00809159.


Piret S.E.,University of Oxford | Gorvin C.M.,University of Oxford | Pagnamenta A.T.,Oxford Genetics | Pagnamenta A.T.,Oxford Comprehensive Biomedical Research Center | And 13 more authors.
Journal of Bone and Mineral Research | Year: 2016

Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia, inappropriately low serum parathyroid hormone concentrations and hypercalciuria. ADH is genetically heterogeneous with ADH type 1 (ADH1), the predominant form, being caused by germline gain-of-function mutations of the G-protein coupled calcium-sensing receptor (CaSR), and ADH2 caused by germline gain-of-function mutations of G-protein subunit α-11 (Gα11). To date Gα11 mutations causing ADH2 have been reported in only five probands. We investigated a multigenerational nonconsanguineous family, from Iran, with ADH and keratoconus which are not known to be associated, for causative mutations by whole-exome sequencing in two individuals with hypoparathyroidism, of whom one also had keratoconus, followed by cosegregation analysis of variants. This identified a novel heterozygous germline Val340Met Gα11 mutation in both individuals, and this was also present in the other two relatives with hypocalcemia that were tested. Three-dimensional modeling revealed the Val340Met mutation to likely alter the conformation of the C-terminal α5 helix, which may affect G-protein coupled receptor binding and G-protein activation. In vitro functional expression of wild-type (Val340) and mutant (Met340) Gα11 proteins in HEK293 cells stably expressing the CaSR, demonstrated that the intracellular calcium responses following stimulation with extracellular calcium, of the mutant Met340 Gα11 led to a leftward shift of the concentration-response curve with a significantly (p < 0.0001) reduced mean half-maximal concentration (EC50) value of 2.44 mM (95% CI, 2.31 to 2.77 mM) when compared to the wild-type EC50 of 3.14 mM (95% CI, 3.03 to 3.26 mM), consistent with a gain-of-function mutation. A novel His403Gln variant in transforming growth factor, beta-induced (TGFBI), that may be causing keratoconus was also identified, indicating likely digenic inheritance of keratoconus and ADH2 in this family. In conclusion, our identification of a novel germline gain-of-function Gα11 mutation, Val340Met, causing ADH2 demonstrates the importance of the Gα11 C-terminal region for G-protein function and CaSR signal transduction. © 2016 American Society for Bone and Mineral Research.


Karaderi T.,National Health Research Institute | Pointon J.J.,National Health Research Institute | Pointon J.J.,Oxford Comprehensive Biomedical Research Center | Wordsworth T.W.H.,National Health Research Institute | And 8 more authors.
Clinical and Experimental Rheumatology | Year: 2012

Objectives: To replicate the possible genetic association between ankylosing spondylitis (AS) and TNFRSF1A. Methods: TNFRSF1A was re-sequenced in 48 individuals with AS to identify novel polymorphisms. Nine single nucleotide polymorphisms (SNPs) in TNFRSF1A and 5 SNPs in the neighbouring gene SCNN1A were genotyped in 1604 UK Caucasian individuals with AS and 1019 matched controls. An extended study was implemented using additional genotype data on 8 of these SNPs from 1400 historical controls from the 1958 British Birth Cohort. A meta-analysis of previously published results was also undertaken. Results: One novel variant in intron 6 was identified but no new coding variants. No definite associations were seen in the initial study but in the extended study there were weak associations with rs4149576 (p=0.04) and rs4149577 (p=0.007). In the metaanalysis consistent, somewhat stronger associations were seen with rs4149577 (p=0.002) and rs4149578 (p=0.006). Conclusions: These studies confirm the weak genetic associations between AS and TNFRSF1A. In view of the previously reported associations of TNFRSF1A with AS, in Caucasians and Chinese, and the biological plausibility of this candidate gene, replication of this finding in well powered studies is clearly indicated. © Clinical and Experimental Rheumatology 2011.


Harrison P.,University of Oxford | Southam L.,University of Oxford | Chapman K.,University of Oxford | Locklin R.,University of Oxford | And 6 more authors.
Scandinavian Journal of Rheumatology | Year: 2012

Objectives: To assess whether there are cis-regulatory polymorphisms that regulate protein tyrosine phosphatase, nonreceptor type 22 (PTPN22) expression in rheumatoid arthritis (RA). Methods: RNA was extracted from positively selected CD56+, CD8+, and CD4+ mononuclear cells and the 'residual' cells from 12 RA patients heterozygous for the PTPN22 C1858T single nucleotide polymorphism (SNP) (rs2476601). Relative allelic expression was measured by single base extension (SBE) assay. Results: There was relative differential allelic expression (DAE ≥ 20%) in eight patients (p < 10-5); seven patients demonstrated DAE in more than one cell type; four patients had statistically significant differences between these cell populations (p corrected< 0.05). Conclusions: We have demonstrated significant differences in expression of PTPN22 alleles in RA patients, indicating the probable existence of cis-acting regulatory elements. © 2012 Taylor & Francis on license from Scandinavian Rheumatology Research Foundation.


Roberts H.E.,University of Oxford | Hurst J.,University of Oxford | Hurst J.,The Institute for Emerging Infections | Robinson N.,University of Oxford | And 16 more authors.
PLoS Genetics | Year: 2015

The existence of viral variants that escape from the selection pressures imposed by cytotoxic T-lymphocytes (CTLs) in HIV-1 infection is well documented, but it is unclear when they arise, with reported measures of the time to escape in individuals ranging from days to years. A study of participants enrolled in the SPARTAC (Short Pulse Anti-Retroviral Therapy at HIV Seroconversion) clinical trial allowed direct observation of the evolution of CTL escape variants in 125 adults with primary HIV-1 infection observed for up to three years. Patient HLA-type, longitudinal CD8+ T-cell responses measured by IFN-γ ELISpot and longitudinal HIV-1 gag, pol, and nef sequence data were used to study the timing and prevalence of CTL escape in the participants whilst untreated. Results showed that sequence variation within CTL epitopes at the first time point (within six months of the estimated date of seroconversion) was consistent with most mutations being transmitted in the infecting viral strain rather than with escape arising within the first few weeks of infection. Escape arose throughout the first three years of infection, but slowly and steadily. Approximately one third of patients did not drive any new escape in an HLA-restricted epitope in just under two years. Patients driving several escape mutations during these two years were rare and the median and modal numbers of new escape events in each patient were one and zero respectively. Survival analysis of time to escape found that possession of a protective HLA type significantly reduced time to first escape in a patient (p = 0.01), and epitopes escaped faster in the face of a measurable CD8+ ELISpot response (p = 0.001). However, even in an HLA matched host who mounted a measurable, specific, CD8+ response the average time before the targeted epitope evolved an escape mutation was longer than two years. © 2015 Roberts et al.


Kinnersley B.,Institute of Cancer Research | Migliorini G.,Institute of Cancer Research | Broderick P.,Institute of Cancer Research | Whiffin N.,Institute of Cancer Research | And 10 more authors.
British Journal of Cancer | Year: 2012

Background: Polymorphic variation at the 5p15.33 (TERT-CLPTM1L) locus is associated with the risk of many cancers but a relationship with colorectal cancer (CRC) risk has yet to be defined.Methods:We used data from six genome-wide association studies (GWAS) of CRC, linkage disequilibrium mapping and imputation, to examine the relationship between 73 single-nucleotide polymorphisms at 5p15.33 and CRC risk in detail.Results:rs2736100, which localises to intron 2 of TERT, provided the strongest evidence of an association with CRC (P 2.28 × 10 -4). The association was also shown in an independent series of 10 047 CRC cases and 6918 controls (P0.02). A meta-analysis of all seven studies (totalling 16 039 cases, 16 430 controls) provided increased evidence of association (P2.49 × 10 5; per allele odds ratio1.07). The association of rs2736100 on CRC risk was shown to be independent of 15 low-penetrance variants previously identified.Conclusion:The rs2736100 association demonstrates an influence of variation at 5p15.33 on CRC risk and further evidence that the 5p15.33 (TERT-CLPTM1L) locus has pleiotropic effects (reflecting generic or lineage-specific effects) on cancer risk. © 2012 Cancer Research UK All rights reserved.

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