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Davies J.L.,University of Oxford | Cazier J.-B.,University of Oxford | Dunlop M.G.,University of Edinburgh | Houlston R.S.,Institute of Cancer Research | And 3 more authors.

Genome-wide association study (GWAS) data on a disease are increasingly available from multiple related populations. In this scenario, meta-analyses can improve power to detect homogeneous genetic associations, but if there exist ancestry-specific effects, via interactions on genetic background or with a causal effect that co-varies with genetic background, then these will typically be obscured. To address this issue, we have developed a robust statistical method for detecting susceptibility gene-ancestry interactions in multi-cohort GWAS based on closely-related populations. We use the leading principal components of the empirical genotype matrix to cluster individuals into "ancestry groups" and then look for evidence of heterogeneous genetic associations with disease or other trait across these clusters. Robustness is improved when there are multiple cohorts, as the signal from true gene-ancestry interactions can then be distinguished from gene-collection artefacts by comparing the observed interaction effect sizes in collection groups relative to ancestry groups. When applied to colorectal cancer, we identified a missense polymorphism in iron-absorption gene CYBRD1 that associated with disease in individuals of English, but not Scottish, ancestry. The association replicated in two additional, independently-collected data sets. Our method can be used to detect associations between genetic variants and disease that have been obscured by population genetic heterogeneity. It can be readily extended to the identification of genetic interactions on other covariates such as measured environmental exposures. We envisage our methodology being of particular interest to researchers with existing GWAS data, as ancestry groups can be easily defined and thus tested for interactions. © 2012 Davies et al. Source

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

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. Source

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

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. Source

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

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. Source

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

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. Source

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