Publications by authors named "Kenneth R Muir"

62 Publications

Alcohol Intake and Alcohol-SNP Interactions Associated with Prostate Cancer Aggressiveness.

J Clin Med 2021 Feb 2;10(3). Epub 2021 Feb 2.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Excessive alcohol intake is a well-known modifiable risk factor for many cancers. It is still unclear whether genetic variants or single nucleotide polymorphisms (SNPs) can modify alcohol intake's impact on prostate cancer (PCa) aggressiveness. The objective is to test the alcohol-SNP interactions of the 7501 SNPs in the four pathways (angiogenesis, mitochondria, miRNA, and androgen metabolism-related pathways) associated with PCa aggressiveness. We evaluated the impacts of three excessive alcohol intake behaviors in 3306 PCa patients with European ancestry from the PCa Consortium. We tested the alcohol-SNP interactions using logistic models with the discovery-validation study design. All three excessive alcohol intake behaviors were not significantly associated with PCa aggressiveness. However, the interactions of excessive alcohol intake and three SNPs (rs13107662 [, = 6.2 × 10], rs9907521 [ = 7.1 × 10], and rs11925452 [ = 8.2 × 10]) were significantly associated with PCa aggressiveness. These alcohol-SNP interactions revealed contrasting effects of excessive alcohol intake on PCa aggressiveness according to the genotypes in the identified SNPs. We identified PCa patients with the rs13107662 () AA genotype, the rs11925452 () AA genotype, and the rs9907521 ( AG genotype were more vulnerable to excessive alcohol intake for developing aggressive PCa. Our findings support that the impact of excessive alcohol intake on PCa aggressiveness was varied by the selected genetic profiles.
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http://dx.doi.org/10.3390/jcm10030553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867322PMC
February 2021

Relationship of self-reported body size and shape with risk for prostate cancer: A UK case-control study.

PLoS One 2020 17;15(9):e0238928. Epub 2020 Sep 17.

Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.

Introduction: Previous evidence has suggested a relationship between male self-reported body size and the risk of developing prostate cancer. In this UK-wide case-control study, we have explored the possible association of prostate cancer risk with male self-reported body size. We also investigated body shape as a surrogate marker for fat deposition around the body. As obesity and excessive adiposity have been linked with increased risk for developing a number of different cancers, further investigation of self-reported body size and shape and their potential relationship with prostate cancer was considered to be appropriate.

Objective: The study objective was to investigate whether underlying associations exist between prostate cancer risk and male self-reported body size and shape.

Methods: Data were collected from a large case-control study of men (1928 cases and 2043 controls) using self-administered questionnaires. Data from self-reported pictograms of perceived body size relating to three decades of life (20's, 30's and 40's) were recorded and analysed, including the pattern of change. The associations of self-identified body shape with prostate cancer risk were also explored.

Results: Self-reported body size for men in their 20's, 30's and 40's did not appear to be associated with prostate cancer risk. More than half of the subjects reported an increase in self-reported body size throughout these three decades of life. Furthermore, no association was observed between self-reported body size changes and prostate cancer risk. Using 'symmetrical' body shape as a reference group, subjects with an 'apple' shape showed a significant 27% reduction in risk (Odds ratio = 0.73, 95% C.I. 0.57-0.92).

Conclusions: Change in self-reported body size throughout early to mid-adulthood in males is not a significant risk factor for the development of prostate cancer. Body shape indicative of body fat distribution suggested that an 'apple' body shape was protective and inversely associated with prostate cancer risk when compared with 'symmetrical' shape. Further studies which investigate prostate cancer risk and possible relationships with genetic factors known to influence body shape may shed further light on any underlying associations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238928PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498010PMC
October 2020

Association of Nongenetic Factors With Breast Cancer Risk in Genetically Predisposed Groups of Women in the UK Biobank Cohort.

JAMA Netw Open 2020 04 1;3(4):e203760. Epub 2020 Apr 1.

Division of Population Health, Health Services Research and Primary Care, Faculty of Biology, Medicine and Health, Centre for Epidemiology, University of Manchester, Manchester, United Kingdom.

Importance: The association between noninherited factors, including lifestyle factors, and the risk of breast cancer (BC) in women and the association between BC and genetic makeup are only partly characterized. A study using data on current genetic stratification may help in the characterization.

Objective: To examine the association between healthier lifestyle habits and BC risk in genetically predisposed groups.

Design, Setting, And Participants: Data from UK Biobank, a prospective cohort comprising 2728 patients with BC and 88 489 women without BC, were analyzed. The data set used for the analysis was closed on March 31, 2019. The analysis was restricted to postmenopausal white women. Classification of healthy lifestyle was based on Cancer Research UK guidance (healthy weight, regular exercise, no use of hormone replacement therapy for more than 5 years, no oral contraceptive use, and alcohol intake <3 times/wk). Three groups were established: favorable (≥4 healthy factors), intermediate (2-3 healthy factors), and unfavorable (≤1 healthy factor). The genetic contribution was estimated using the polygenic risk scores of 305 preselected single-nucleotide variations. Polygenic risk scores were categorized into 3 tertiles (low, intermediate, and high).

Main Outcomes And Measures: Cox proportional hazards regression was used to assess the hazard ratios (HRs) of the lifestyles and polygenic risk scores associated with a malignant neoplasm of the breast.

Results: Mean (SD) age of the 2728 women with BC was 60.1 (5.5) years, and mean age of the 88 489 women serving as controls was 59.4 (4.9) years. The median follow-up time for the cohort was 10 years (maximum 13 years) (interquartile range, 9.44-10.82 years). Women with BC had a higher body mass index (relative risk [RR], 1.14; 95% CI, 1.05-1.23), performed less exercise (RR, 1.12; 95% CI, 1.01-1.25), used hormonal replacement therapy for longer than 5 years (RR, 1.23; 95% CI, 1.13-1.34), used more oral contraceptives (RR, 1.02; 95% CI, 0.93-1.12), and had greater alcohol intake (RR, 1.11; 95% CI, 1.03-1.19) compared with the controls. Overall, 20 657 women (23.3%) followed a favorable lifestyle, 60 195 women (68.0%) followed an intermediate lifestyle, and 7637 women (8.6%) followed an unfavorable lifestyle. The RR of the highest genetic risk group was 2.55 (95% CI, 2.28-2.84), and the RR of the most unfavorable lifestyle category was 1.44 (95% CI, 1.25-1.65). The association of lifestyle and BC within genetic subgroups showed lower HRs among women following a favorable lifestyle compared with intermediate and unfavorable lifestyles among all of the genetic groups: women with an unfavorable lifestyle had a higher risk of BC in the low genetic group (HR, 1.63; 95% CI, 1.13-2.34), intermediate genetic group (HR, 1.94; 95% CI, 1.46-2.58), and high genetic group (HR, 1.39; 95% CI, 1.11-1.74) compared with the reference group of favorable lifestyle. Intermediate lifestyle was also associated with a higher risk of BC among the low genetic group (HR, 1.40; 95% CI, 1.09-1.80) and the intermediate genetic group (HR, 1.37; 95% CI, 1.12-1.68).

Conclusions And Relevance: In this cohort study of data on women in the UK Biobank, a healthier lifestyle with more exercise, healthy weight, low alcohol intake, no oral contraceptive use, and no or limited hormonal replacement therapy use appeared to be associated with a reduced level of risk for BC, even if the women were at higher genetic risk for BC.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.3760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182796PMC
April 2020

The association between weight at birth and breast cancer risk revisited using Mendelian randomisation.

Eur J Epidemiol 2019 Jun 8;34(6):591-600. Epub 2019 Feb 8.

Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Observational studies suggest that higher birth weight (BW) is associated with increased risk of breast cancer in adult life. We conducted a two-sample Mendelian randomisation (MR) study to assess whether this association is causal. Sixty independent single nucleotide polymorphisms (SNPs) known to be associated at P < 5 × 10 with BW were used to construct (1) a 41-SNP instrumental variable (IV) for univariable MR after removing SNPs with pleiotropic associations with other breast cancer risk factors and (2) a 49-SNP IV for multivariable MR after filtering SNPs for data availability. BW predicted by the 41-SNP IV was not associated with overall breast cancer risk in inverse-variance weighted (IVW) univariable MR analysis of genetic association data from 122,977 breast cancer cases and 105,974 controls (odds ratio = 0.86 per 500 g higher BW; 95% confidence interval 0.73-1.01). Sensitivity analyses using four alternative methods and three alternative IVs, including an IV with 59 of the 60 BW-associated SNPs, yielded similar results. Multivariable MR adjusting for the effects of the 49-SNP IV on birth length, adult height, adult body mass index, age at menarche, and age at menopause using IVW and MR-Egger methods provided estimates consistent with univariable analyses. Results were also similar when all analyses were repeated after restricting to estrogen receptor-positive or -negative breast cancer cases. Point estimates of the odds ratios from most analyses performed indicated an inverse relationship between genetically-predicted BW and breast cancer, but we are unable to rule out an association between the non-genetically-determined component of BW and breast cancer. Thus, genetically-predicted higher BW was not associated with an increased risk of breast cancer in adult life in our MR study.
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http://dx.doi.org/10.1007/s10654-019-00485-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497616PMC
June 2019

Review of non-clinical risk models to aid prevention of breast cancer.

Cancer Causes Control 2018 Oct 3;29(10):967-986. Epub 2018 Sep 3.

Division of Population Health, Health Services Research and Primary Care, Faculty of Biology, Medicine and Health, Centre for Epidemiology, The University of Manchester, Manchester, M139 PL, UK.

A disease risk model is a statistical method which assesses the probability that an individual will develop one or more diseases within a stated period of time. Such models take into account the presence or absence of specific epidemiological risk factors associated with the disease and thereby potentially identify individuals at higher risk. Such models are currently used clinically to identify people at higher risk, including identifying women who are at increased risk of developing breast cancer. Many genetic and non-genetic breast cancer risk models have been developed previously. We have evaluated existing non-genetic/non-clinical models for breast cancer that incorporate modifiable risk factors. This review focuses on risk models that can be used by women themselves in the community in the absence of clinical risk factors characterization. The inclusion of modifiable factors in these models means that they can be used to improve primary prevention and health education pertinent for breast cancer. Literature searches were conducted using PubMed, ScienceDirect and the Cochrane Database of Systematic Reviews. Fourteen studies were eligible for review with sample sizes ranging from 654 to 248,407 participants. All models reviewed had acceptable calibration measures, with expected/observed (E/O) ratios ranging from 0.79 to 1.17. However, discrimination measures were variable across studies with concordance statistics (C-statistics) ranging from 0.56 to 0.89. We conclude that breast cancer risk models that include modifiable risk factors have been well calibrated but have less ability to discriminate. The latter may be a consequence of the omission of some significant risk factors in the models or from applying models to studies with limited sample sizes. More importantly, external validation is missing for most of the models. Generalization across models is also problematic as some variables may not be considered applicable to some populations and each model performance is conditioned by particular population characteristics. In conclusion, it is clear that there is still a need to develop a more reliable model for estimating breast cancer risk which has a good calibration, ability to accurately discriminate high risk and with better generalizability across populations.
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http://dx.doi.org/10.1007/s10552-018-1072-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182451PMC
October 2018

Risk of breast cancer in the UK biobank female cohort and its relationship to anthropometric and reproductive factors.

PLoS One 2018 26;13(7):e0201097. Epub 2018 Jul 26.

Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.

Background: Anthropometric and reproductive factors have been reported as being established risk factors for breast cancer (BC). This study explores the contribution of anthropometric and reproductive factors in UK females developing BC in a large longitudinal cohort.

Methods: Data from the UK Biobank prospective study of 273,467 UK females were analyzed. Relative risks (RRs) and 95% confidence intervals (CIs) for each factor were adjusted for age, family history of BC and deprivation score. The analyses were stratified by the menopausal status.

Results: Over the 9 years of follow up the total number of BC cases were 14,231 with 3,378 (23.7%) incident cases with an incidence rate of 2.09 per 1000 person-years. In pre-menopausal, increase in age, height, having low BMI, low waist to hip ratio, first degree family history of BC, early menarche age, nulliparous, late age at first live birth, high reproductive interval index, and long contraceptive use duration were all significantly associated with an increased BC risk. In post-menopausal, getting older, being taller, having high BMI, first degree BC family history, nulliparous, late age at first live birth, and high reproductive interval index were all significantly associated with an increased risk of BC. The population attributable fraction (PAF) suggested that an early first live birth, lower reproductive interval index and increased number of children can contribute to BC risk reduction up to 50%.

Conclusions: This study utilizes the UK Biobank study to confirm associations between anthropometric and reproductive factors and the risk of breast cancer development. Result of attributable fraction of risk contributed by each risk factor suggested that lifetime risk of BC can be reduced by controlling weight, reassessing individual approaches to the timing of childbirth and options for contraception and considering early screening for women with family history in the first degree relative.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201097PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062099PMC
January 2019

Risk biomarkers enable precision in public health.

Per Med 2018 07 29;15(4):329-342. Epub 2018 Jun 29.

Center for Epidemiology, Division of Population Health, Faculty of Biology, Medicine & Health, The University of Manchester, Stopford Building, 99 Oxford Rd, Manchester, M13 9PG, UK.

Precision medicine uses biomarkers to diagnose disease. However, they can also be used to measure risk of disease. Thus, biomarkers herald a new addition to public health - Precision Public Health. We examine the implications. Risk biomarkers are identified by analyzing population cohorts. They constitute risk factors in mathematical 'Disease Risk Models'. The risk may be fixed as in a genetic biomarker or variable as in some protein biomarkers. They help monitor current risk of disease in an individual, thereby aiding efforts to reduce risk. In the UK, the NHS Health Check system is a universal system for assessing risk and for risk reduction. The system can now make use of modern biomarkers once appropriate infrastructure and governance are in place.
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http://dx.doi.org/10.2217/pme-2017-0068DOI Listing
July 2018

Development of a Cancer Risk Prediction Tool for Use in the UK Primary Care and Community Settings.

Cancer Prev Res (Phila) 2017 Jul 30;10(7):421-430. Epub 2017 May 30.

Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.

Several multivariable risk prediction models have been developed to asses an individual's risk of developing specific cancers. Such models can be used in a variety of settings for prevention, screening, and guiding investigations and treatments. Models aimed at predicting future disease risk that contains lifestyle factors may be of particular use for targeting health promotion activities at an individual level. This type of cancer risk prediction is not yet available in the UK. We have adopted the approach used by the well-established U.S.-derived "YourCancerRisk" model for use in the UK population, which allow users to quantify their individual risk of developing individual cancers relative to the population average risk. The UK version of "YourCancerRisk" computes 10-year cancer risk estimates for 11 cancers utilizing UK figures for prevalence of risk factors and cancer incidence. Because the prevalence of risk factors and the incidence rates for cancer are different between the U.S. and the UK population, this UK model provides more accurate estimates of risks for a UK population. Using an example of breast cancer and data from UK Biobank cohort, we demonstrate that the individual risk factor estimates are similar for the U.S. and UK populations. Assessment of the performance and validation of the multivariate model predictions based on a binary score confirm the model's applicability. The model can be used to estimate absolute and relative cancer risk for use in Primary Care and community settings and is being used in the community to guide lifestyle change. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-16-0288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501968PMC
July 2017

Incorporating cancer risk information into general practice: a qualitative study using focus groups with health professionals.

Br J Gen Pract 2017 Mar 13;67(656):e218-e226. Epub 2017 Feb 13.

Moulton Surgery, Moulton.

Background: It is estimated that approximately 40% of all cases of cancer are attributable to lifestyle factors. Providing people with personalised information about their future risk of cancer may help promote behaviour change.

Aim: To explore the views of health professionals on incorporating personalised cancer risk information, based on lifestyle factors, into general practice.

Design And Setting: Qualitative study using data from six focus groups with a total of 24 general practice health professionals from the NHS Nene Clinical Commissioning Group in England.

Method: The focus groups were guided by a schedule covering current provision of lifestyle advice relating to cancer and views on incorporating personalised cancer risk information. Data were audiotaped, transcribed verbatim, and then analysed using thematic analysis.

Results: Providing lifestyle advice was viewed as a core activity within general practice but the influence of lifestyle on cancer risk was rarely discussed. The word 'cancer' was seen as a potentially powerful motivator for lifestyle change but the fact that it could generate health anxiety was also recognised. Most focus group participants felt that a numerical risk estimate was more likely to influence behaviour than generic advice. All felt that general practice should provide this information, but there was a clear need for additional resources for it to be offered widely.

Conclusion: Study participants were in support of providing personalised cancer risk information in general practice. The findings highlight a number of potential benefits and challenges that will inform the future development of interventions in general practice to promote behaviour change for cancer prevention.
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http://dx.doi.org/10.3399/bjgp17X689401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325664PMC
March 2017

Improving Clinical Risk Stratification at Diagnosis in Primary Prostate Cancer: A Prognostic Modelling Study.

PLoS Med 2016 08 2;13(8):e1002063. Epub 2016 Aug 2.

National Cancer Registration Service Eastern Office, Public Health England, Cambridge, United Kingdom.

Introduction: Over 80% of the nearly 1 million men diagnosed with prostate cancer annually worldwide present with localised or locally advanced non-metastatic disease. Risk stratification is the cornerstone for clinical decision making and treatment selection for these men. The most widely applied stratification systems use presenting prostate-specific antigen (PSA) concentration, biopsy Gleason grade, and clinical stage to classify patients as low, intermediate, or high risk. There is, however, significant heterogeneity in outcomes within these standard groupings. The International Society of Urological Pathology (ISUP) has recently adopted a prognosis-based pathological classification that has yet to be included within a risk stratification system. Here we developed and tested a new stratification system based on the number of individual risk factors and incorporating the new ISUP prognostic score.

Methods And Findings: Diagnostic clinicopathological data from 10,139 men with non-metastatic prostate cancer were available for this study from the Public Health England National Cancer Registration Service Eastern Office. This cohort was divided into a training set (n = 6,026; 1,557 total deaths, with 462 from prostate cancer) and a testing set (n = 4,113; 1,053 total deaths, with 327 from prostate cancer). The median follow-up was 6.9 y, and the primary outcome measure was prostate-cancer-specific mortality (PCSM). An external validation cohort (n = 1,706) was also used. Patients were first categorised as low, intermediate, or high risk using the current three-stratum stratification system endorsed by the National Institute for Health and Care Excellence (NICE) guidelines. The variables used to define the groups (PSA concentration, Gleason grading, and clinical stage) were then used to sub-stratify within each risk category by testing the individual and then combined number of risk factors. In addition, we incorporated the new ISUP prognostic score as a discriminator. Using this approach, a new five-stratum risk stratification system was produced, and its prognostic power was compared against the current system, with PCSM as the outcome. The results were analysed using a Cox hazards model, the log-rank test, Kaplan-Meier curves, competing-risks regression, and concordance indices. In the training set, the new risk stratification system identified distinct subgroups with different risks of PCSM in pair-wise comparison (p < 0.0001). Specifically, the new classification identified a very low-risk group (Group 1), a subgroup of intermediate-risk cancers with a low PCSM risk (Group 2, hazard ratio [HR] 1.62 [95% CI 0.96-2.75]), and a subgroup of intermediate-risk cancers with an increased PCSM risk (Group 3, HR 3.35 [95% CI 2.04-5.49]) (p < 0.0001). High-risk cancers were also sub-classified by the new system into subgroups with lower and higher PCSM risk: Group 4 (HR 5.03 [95% CI 3.25-7.80]) and Group 5 (HR 17.28 [95% CI 11.2-26.67]) (p < 0.0001), respectively. These results were recapitulated in the testing set and remained robust after inclusion of competing risks. In comparison to the current risk stratification system, the new system demonstrated improved prognostic performance, with a concordance index of 0.75 (95% CI 0.72-0.77) versus 0.69 (95% CI 0.66-0.71) (p < 0.0001). In an external cohort, the new system achieved a concordance index of 0.79 (95% CI 0.75-0.84) for predicting PCSM versus 0.66 (95% CI 0.63-0.69) (p < 0.0001) for the current NICE risk stratification system. The main limitations of the study were that it was registry based and that follow-up was relatively short.

Conclusions: A novel and simple five-stratum risk stratification system outperforms the standard three-stratum risk stratification system in predicting the risk of PCSM at diagnosis in men with primary non-metastatic prostate cancer, even when accounting for competing risks. This model also allows delineation of new clinically relevant subgroups of men who might potentially receive more appropriate therapy for their disease. Future research will seek to validate our results in external datasets and will explore the value of including additional variables in the system in order in improve prognostic performance.
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http://dx.doi.org/10.1371/journal.pmed.1002063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970710PMC
August 2016

Generation of Functional Beta-Like Cells from Human Exocrine Pancreas.

PLoS One 2016 31;11(5):e0156204. Epub 2016 May 31.

School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom.

Transcription factor mediated lineage reprogramming of human pancreatic exocrine tissue could conceivably provide an unlimited supply of islets for transplantation in the treatment of diabetes. Exocrine tissue can be efficiently reprogrammed to islet-like cells using a cocktail of transcription factors: Pdx1, Ngn3, MafA and Pax4 in combination with growth factors. We show here that overexpression of exogenous Pax4 in combination with suppression of the endogenous transcription factor ARX considerably enhances the production of functional insulin-secreting β-like cells with concomitant suppression of α-cells. The efficiency was further increased by culture on laminin-coated plates in media containing low glucose concentrations. Immunocytochemistry revealed that reprogrammed cultures were composed of ~45% islet-like clusters comprising >80% monohormonal insulin+ cells. The resultant β-like cells expressed insulin protein levels at ~15-30% of that in adult human islets, efficiently processed proinsulin and packaged insulin into secretory granules, exhibited glucose responsive insulin secretion, and had an immediate and prolonged effect in normalising blood glucose levels upon transplantation into diabetic mice. We estimate that approximately 3 billion of these cells would have an immediate therapeutic effect following engraftment in type 1 diabetes patients and that one pancreas would provide sufficient tissue for numerous transplants.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156204PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887015PMC
July 2017

Krüppel-Like Factor 4 Overexpression Initiates a Mesenchymal-to-Epithelial Transition and Redifferentiation of Human Pancreatic Cells following Expansion in Long Term Adherent Culture.

PLoS One 2015 12;10(10):e0140352. Epub 2015 Oct 12.

School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, United Kingdom.

A replenishable source of insulin-producing cells has the potential to cure type 1 diabetes. Attempts to culture and expand pancreatic β-cells in vitro have resulted in their transition from insulin-producing epithelial cells to mesenchymal stromal cells (MSCs) with high proliferative capacity but devoid of any hormone production. The aim of this study was to determine whether the transcription factor Krüppel-like factor 4 (KLF4), could induce a mesenchymal-to-epithelial transition (MET) of the cultured cells. Islet-enriched pancreatic cells, allowed to dedifferentiate and expand in adherent cell culture, were transduced with an adenovirus containing KLF4 (Ad-Klf4). Cells were subsequently analysed for changes in cell morphology by light microscopy, and for the presence of epithelial and pancreatic markers by immunocytochemistry and quantitative RT/PCR. Infection with Ad-Klf4 resulted in morphological changes, down-regulation of mesenchymal markers, and re-expression of both epithelial and pancreatic cell markers including insulin and transcription factors specific to β-cells. This effect was further enhanced by culturing cells in suspension. However, the effects of Ad-KLf4 were transient and this was shown to be due to increased apoptosis in Klf4-expressing cells. Klf4 has been recently identified as a pioneer factor with the ability to modulate the structure of chromatin and enhance reprogramming/transdifferentiation. Our results show that Klf4 may have a role in the redifferentiation of expanded pancreatic cells in culture, but before this can be achieved the off-target effects that result in increased apoptosis would need to be overcome.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140352PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601732PMC
June 2016

Trends and outcome from radical therapy for primary non-metastatic prostate cancer in a UK population.

PLoS One 2015 5;10(3):e0119494. Epub 2015 Mar 5.

Academic Urology Group, Department of Surgery & Oncology, University of Cambridge, Cambridge, United Kingdom; Translational Prostate Cancer Group, Hutchison/MRC Research centre, University of Cambridge, Cambridge, United Kingdom.

Background: Increasing proportions of men diagnosed with prostate cancer in the UK are presenting with non-metastatic disease. We investigated how treatment trends in this demographic have changed.

Patient And Methods: Non-metastatic cancers diagnosed from 2000-2010 in the UK Anglian Cancer network stratified by age and risk group were analysed [n = 10,365]. Radiotherapy [RT] and prostatectomy [RP] cancer specific survival [CSS] were further compared [n = 4755].

Results: Over the decade we observed a fall in uptake of primary androgen deprivation therapy but a rise in conservative management [CM] and radical therapy [p<0.0001]. CM in particular has become the primary management for low-risk disease by the decade end [p<0.0001]. In high-risk disease however both RP and RT uptake increased significantly but in an age dependent manner [p<0.0001]. Principally, increased RP in younger men and increased RT in men ≥ 70y. In multivariate analysis of radically treated men both high-risk disease [HR 8.0 [2.9-22.2], p<0.0001] and use of RT [HR 1.9 [1.0-3.3], p = 0.024] were significant predictors of a poorer CSM. In age-stratified analysis however, the trend to benefit of RP over RT was seen only in younger men [≤ 60 years] with high-risk disease [p = 0.07]. The numbers needed to treat by RP instead of RT to save one cancer death was 19 for this group but 67 for the overall cohort.

Conclusion: This study has identified significant shifts in non-metastatic prostate cancer management over the last decade. Low-risk disease is now primarily managed by CM while high-risk disease is increasingly treated radically. Treatment of high-risk younger men by RP is supported by evidence of better CSM but this benefit is not evident in older men.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0119494PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351083PMC
January 2016

Polymorphisms of an innate immune gene, toll-like receptor 4, and aggressive prostate cancer risk: a systematic review and meta-analysis.

PLoS One 2014 31;9(10):e110569. Epub 2014 Oct 31.

Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Research Center for Genes, Environment and Human Health, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan.

Background: Toll-like receptor 4 (TLR4) is one of the best known TLR members expressed on the surface of several leukocytes and tissue cells and has a key function in detecting pathogen and danger-associated molecular patterns. The role of TLR4 in the pathophysiology of several age-related diseases is also well recognized, such as prostate cancer (PCa). TLR4 polymorphisms have been related to PCa risk, but the relationship between TLR4 genotypes and aggressive PCa risk has not been evaluated by any systematic reviews.

Methods: We performed a systematic review and meta-analysis of candidate-gene and genome-wide association studies analyzing this relationship and included only white population. Considering appropriate criteria, only nine studies were analyzed in the meta-analysis, including 3,937 aggressive PCa and 7,382 controls.

Results: Using random effects model, no significant association was found in the ten TLR4 SNPs reported by at least four included studies under any inheritance model (rs2737191, rs1927914, rs10759932, rs1927911, rs11536879, rs2149356, rs4986790, rs11536889, rs7873784, and rs1554973). Pooled estimates from another ten TLR4 SNPs reported by three studies also showed no significant association (rs10759930, rs10116253, rs11536869, rs5030717, rs4986791, rs11536897, rs1927906, rs913930, rs1927905, and rs7045953). Meta-regression revealed that study type was not a significant source of between-study heterogeneity.

Conclusions: TLR4 polymorphisms were not significantly associated with the risk of aggressive PCa.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110569PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215920PMC
June 2015

Self-reported adult footwear and the risks of lower limb osteoarthritis: the GOAL case control study.

BMC Musculoskelet Disord 2014 Sep 20;15:308. Epub 2014 Sep 20.

Division of Rheumatology, Orthopaedics and Dermatology, University of Nottingham, Nottingham, UK.

Background: Biomechanical factors may play a role in osteoarthritis (OA) development and progression. Previous biomechanical studies have indicated that types of footwear may modulate forces across the knee joint, and high heeled womens' shoes in particular are hypothesised to be detrimental to lower limb joint health. This analysis of data from a case control study investigated persistent users of different adult footwear for risks of knee and hip OA. Our underlying hypotheses were that high heeled, narrow heeled, and hard soled shoe types were putative risk factors for lower limb OA.

Methods: Data on footwear were initially obtained from participants during the Genetics of Osteoarthritis and Lifestyle (GOAL) hospital-based, case control study using standardised interview-delivered questionnaires. An additional questionnaire was later sent to GOAL study participants to verify findings and to further investigate specific shoe use per decade of life. Persistent users of footwear types (high or narrow heel; sole thickness or hardness) were identified from early adulthood. Participants were grouped into single sex knee OA, hip OA or control groups. Adjusted odds ratios (aOR) and 95% confidence interval (CI) were calculated.

Results: Univariate analysis of persistent users of women's high heeled and narrow heeled shoes during early adulthood showed negative associations with knee OA and hip OA. After logistic regression, persistent narrow heel users were associated with less risk of OA (knee OA aOR 0.59, 95% CI 0.35 - 1.00 and hip aOR: 0.50, 95% CI 0.30 - 0.85), and other analyses were not statistically significant. Further analysis suggested that women with hip OA may have stopped wearing high and narrow heeled footwear to attenuate hip pain in early adulthood. Consistent associations between shoe soles and OA were not found.

Conclusions: In general, persistent users of high and narrow heeled shoes during early adulthood had a negative association with knee or hip OA. This does not necessarily imply a causal relationship, as changing footwear during early adulthood to modulate index joint pain may provide a possible explanation. Despite the findings of previous biomechanical studies of high heels, we did not find a positive association between women's shoes and lower limb osteoarthritis.
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http://dx.doi.org/10.1186/1471-2474-15-308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190490PMC
September 2014

The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a Mendelian randomisation study.

Ann Rheum Dis 2014 Dec 6;73(12):2082-6. Epub 2013 Aug 6.

Department of Twin Research, King's College London, St Thomas' Hospital, London, UK Academic Rheumatology, Nottingham City Hospital, Nottingham, UK.

Objective: Variation in the fat mass and obesity-associated (FTO) gene influences susceptibility to obesity. A variant in the FTO gene has been implicated in genetic risk to osteoarthritis (OA). We examined the role of the FTO polymorphism rs8044769 in risk of knee and hip OA in cases and controls incorporating body mass index (BMI) information.

Methods: 5409 knee OA patients, 4355 hip OA patients and up to 5362 healthy controls from 7 independent cohorts from the UK and Australia were genotyped for rs8044769. The association of the FTO variant with OA was investigated in case/control analyses with and without BMI adjustment and in analyses matched for BMI category. A mendelian randomisation approach was employed using the FTO variant as the instrumental variable to evaluate the role of overweight on OA.

Results: In the meta-analysis of all overweight (BMI≥25) samples versus normal-weight controls irrespective of OA status the association of rs8044769 with overweight is highly significant (OR[CIs] for allele G=1.14 [01.08 to 1.19], p=7.5×10(-7)). A significant association with knee OA is present in the analysis without BMI adjustment (OR[CIs]=1.08[1.02 to 1.14], p=0.009) but the signal fully attenuates after BMI adjustment (OR[CIs]=0.99[0.93 to 1.05], p=0.666). We observe no evidence for association in the BMI-matched meta-analyses. Using mendelian randomisation approaches we confirm the causal role of overweight on OA.

Conclusions: Our data highlight the contribution of genetic risk to overweight in defining risk to OA but the association is exclusively mediated by the effect on BMI. This is consistent with what is known of the biology of the FTO gene and supports the causative role of high BMI in OA.
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http://dx.doi.org/10.1136/annrheumdis-2013-203772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251538PMC
December 2014

Suppression of epithelial-to-mesenchymal transitioning enhances ex vivo reprogramming of human exocrine pancreatic tissue toward functional insulin-producing β-like cells.

Diabetes 2013 Aug 22;62(8):2821-33. Epub 2013 Apr 22.

School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, UK.

Because of the lack of tissue available for islet transplantation, new sources of β-cells have been sought for the treatment of type 1 diabetes. The aim of this study was to determine whether the human exocrine-enriched fraction from the islet isolation procedure could be reprogrammed to provide additional islet tissue for transplantation. The exocrine-enriched cells rapidly dedifferentiated in culture and grew as a mesenchymal monolayer. Genetic lineage tracing confirmed that these mesenchymal cells arose, in part, through a process of epithelial-to-mesenchymal transitioning (EMT). A protocol was developed whereby transduction of these mesenchymal cells with adenoviruses containing Pdx1, Ngn3, MafA, and Pax4 generated a population of cells that were enriched in glucagon-secreting α-like cells. Transdifferentiation or reprogramming toward insulin-secreting β-cells was enhanced, however, when using unpassaged cells in combination with inhibition of EMT by inclusion of Rho-associated kinase (ROCK) and transforming growth factor-β1 inhibitors. Resultant cells were able to secrete insulin in response to glucose and on transplantation were able to normalize blood glucose levels in streptozotocin diabetic NOD/SCID mice. In conclusion, reprogramming of human exocrine-enriched tissue can be best achieved using fresh material under conditions whereby EMT is inhibited, rather than allowing the culture to expand as a mesenchymal monolayer.
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http://dx.doi.org/10.2337/db12-1256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3717833PMC
August 2013

Gene-environment interaction between body mass index and transforming growth factor beta 1 (TGFβ1) gene in knee and hip osteoarthritis.

Arthritis Res Ther 2013 Apr 18;15(2):R52. Epub 2013 Apr 18.

Introduction: The objective was to investigate potential gene-environment interaction between body mass index (BMI) and each of eight TGFβ1 polymorphisms in knee and hip osteoarthritis (OA).

Methods: We conducted a case-control study of Caucasian men and women aged 45 to 86 years from Nottingham, United Kingdom (Genetics of OA and Lifestyle (GOAL) study). Cases had clinically severe symptoms and radiographic knee or hip OA; controls had no symptoms and no radiographic knee/hip OA. We used logistic regression to investigate the association of TGFβ1 polymorphisms and OA when stratifying by BMI. Knee and hip OA were analyzed separately with adjustment for potential confounders. Additive and multiplicative interactions were examined.

Results: 2,048 cases (1,042 knee OA, 1,006 hip OA) and 967 controls were studied. For hip OA, the highest risk was in overweight (BMI ≥ 25 kg/m2) individuals with the variant allele of single-nucleotide polymorphism (SNP) rs1800468 (odds ratio (OR) 2.21, 95% confidence interval (CI) 1.55, 3.15). Evaluation of gene-environment interaction indicated significant synergetic interaction (relative excess risk due to interaction (RERI) = 0.93, synergy index (SI) = 4.33) with an attributable proportion due to interaction (AP) of 42% (AP = 0.42; 95% CI 0.16, 0.68). Multiplicative interaction was also significant (OR for interaction (ORINT) = 2.27, P = 0.015). For knee OA, the highest risk was in overweight individuals with homozygous genotype 11 of SNP rs2278422 (OR = 6.95, P <0.001). In contrast, the variant allele indicated slightly lower risks (OR = 4.72, P <0.001), a significant antagonistic interaction (RERI = -2.66, SI = 0.59), AP = -0.56 (95%CI -0.94, -0.17) and a significant multiplicative interaction (ORINT = 0.47, P = 0.013).

Conclusion: TGFβ1 gene polymorphisms interact with being overweight to influence the risk of large joint OA.
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http://dx.doi.org/10.1186/ar4214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060375PMC
April 2013

The genetic contribution to severe post-traumatic osteoarthritis.

Ann Rheum Dis 2013 Oct 26;72(10):1687-90. Epub 2013 Jan 26.

Academic Rheumatology, Nottingham City Hospital, Nottingham, UK.

Objective: to compare the combined role of genetic variants loci associated with risk of knee or hip osteoarthritis (OA) in post-traumatic (PT) and non-traumatic (NT) cases of clinically severe OA leading to total joint replacement.

Methods: A total of 1590 controls, 2168 total knee replacement (TKR) cases (33.2% PT) and 1567 total hip replacement (THR) cases (8.7% PT) from 2 UK cohorts were genotyped for 12 variants previously reported to be reproducibly associated with risk of knee or hip OA. A genetic risk score was generated and the association with PT and NT TKR and THR was assessed adjusting for covariates.

Results: For THR, each additional genetic risk variant conferred lower risk among PT cases (OR=1.07, 95% CI 0.96 to 1.19; p=0.24) than NT cases (OR 1.11, 95% CI 1.06 to 1.17; p=1.55×10⁻⁵). In contrast, for TKR, each risk variant conferred slightly higher risk among PT cases (OR 1.12, 95% CI 1.07 to 1.19; p=1.82×10⁻⁵) than among NT cases (OR 1.08, 95% CI 1.03 to 1.1; p=0.00063).

Conclusions: Based on the variants reported to date PT TKR cases have at least as high a genetic contribution as NT cases.
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http://dx.doi.org/10.1136/annrheumdis-2012-202562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3786638PMC
October 2013

A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease.

Hum Mol Genet 2013 Jan 12;22(2):408-15. Epub 2012 Oct 12.

Strangeways Laboratory, Centre for Cancer Genetic Epidemiology, Worts Causeway, Cambridge CB1 8RN, UK.

Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.
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http://dx.doi.org/10.1093/hmg/dds425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526158PMC
January 2013

Common genetic variants associated with disease from genome-wide association studies are mutually exclusive in prostate cancer and rheumatoid arthritis.

BJU Int 2013 Jun 18;111(7):1148-55. Epub 2012 Sep 18.

Arthritis Research UK Epidemiology Unit, School of Translational Medicine, University of Manchester, Manchester, UK.

Unlabelled: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The link between inflammation and cancer has long been reported and inflammation is thought to play a role in the pathogenesis of many cancers, including prostate cancer (PrCa). Over the last 5 years, genome-wide association studies (GWAS) have reported numerous susceptibility loci that predispose individuals to many different traits. The present study aims to ascertain if there are common genetic risk profiles that might predispose individuals to both PrCa and the autoimmune inflammatory condition, rheumatoid arthritis. These results could have potential public heath impact in terms of screening and chemoprevention.

Objectives: To investigate if potential common pathways exist for the pathogenesis of autoimmune disease and prostate cancer (PrCa). To ascertain if the single nucleotide polymorphisms (SNPs) reported by genome-wide association studies (GWAS) as being associated with susceptibility to PrCa are also associated with susceptibility to the autoimmune disease rheumatoid arthritis (RA).

Materials And Methods: The original Wellcome Trust Case Control Consortium (WTCCC) UK RA GWAS study was expanded to include a total of 3221 cases and 5272 controls. In all, 37 germline autosomal SNPs at genome-wide significance associated with PrCa risk were identified from a UK/Australian PrCa GWAS. Allele frequencies were compared for these 37 SNPs between RA cases and controls using a chi-squared trend test and corrected for multiple testing (Bonferroni).

Results: In all, 33 SNPs were able to be analysed in the RA dataset. Proxies could not be located for the SNPs in 3q26, 5p15 and for two SNPs in 17q12. After applying a Bonferroni correction for the number of SNPs tested, the SNP mapping to CCHCR1 (rs130067) retained statistically significant evidence for association (P = 6 × 10(-4) ; odds ratio [OR] = 1.15, 95% CI: 1.06-1.24); this has also been associated with psoriasis. However, further analyses showed that the association of this allele was due to confounding by RA-associated HLA-DRB1 alleles.

Conclusions: There is currently no evidence that SNPs associated with PrCa at genome-wide significance are associated with the development of RA. Studies like this are important in determining if common genetic risk profiles might predispose individuals to many diseases, which could have implications for public health in terms of screening and chemoprevention.
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http://dx.doi.org/10.1111/j.1464-410X.2012.11492.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491307PMC
June 2013

Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC).

PLoS One 2012 7;7(8):e42380. Epub 2012 Aug 7.

Unit of Genetic Epidemiology, Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.

The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042380PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413660PMC
January 2013

9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: evidence from the Breast Cancer Association Consortium.

Cancer Epidemiol Biomarkers Prev 2012 Oct 2;21(10):1783-91. Epub 2012 Aug 2.

Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom.

Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).

Methods: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls).

Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10(-29)] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (P(het)) = 1.3 × 10(-143)], but no evidence of ethnic differences in per allele OR (P(het) = 0.43). rs865686 was associated with estrogen receptor-positive (ER(+)) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10(-22)) but less strongly, if at all, with ER-negative (ER(-)) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; P(het) = 1.16 × 10(-6)), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER(+) tumors.

Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER(+) breast cancer.

Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype.
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http://dx.doi.org/10.1158/1055-9965.EPI-12-0526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772723PMC
October 2012

Genetic contribution to radiographic severity in osteoarthritis of the knee.

Ann Rheum Dis 2012 Sep 21;71(9):1537-40. Epub 2012 May 21.

Correspondence to Dr Ana M Valdes, Kings College London, Twin Research Unit, St Thomas Hospital, Lambeth Palace Rd, London SE1 7EH, UK.

Objective: Knee osteoarthritis (OA) has a significant genetic component. The authors have assessed the role of three variants reported to influence risk of knee OA with p<5×10-8 in determining patellofemoral and tibiofemoral Kellgren Lawrence (K/L) grade in knee OA cases.

Methods: 3474 knee OA cases with sky-line and weight-bearing antero-posterior x-rays of the knee were selected based on the presentation of K/L grade ≥2 at either the tibiofemoral or patellofemoral compartments for one or both knees. Patients belonging to three UK cohorts, were genotyped for rs143383, rs4730250 and rs11842874 mapping to the GDF5, COG5 and MCF2L genes, respectively. The association between tibiofemoral K/L grade and patellofemoral K/L grade was assessed after adjusting for age, gender and body mass index.

Results: No significant association was found between the rs4730250 and radiographic severity. The rs11842874 mapping to MCF2L was found to be nominally significantly associated with patellofemoral K/L grade as a quantitative trait (p=0.027) but not as a binary trait. The GDF5 single nucleotide polymorphism rs143383 was associated with tibiofemoral K/L grade (β=0.05 (95% CI 0.02 to 0.08) p=0.0011).

Conclusions: Our data indicate that within individuals affected by radiographic knee OA, OAGDF5 has a modest but significant effect on radiographic severity after adjustment for the major risk factors.
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http://dx.doi.org/10.1136/annrheumdis-2012-201382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414227PMC
September 2012

11q13 is a susceptibility locus for hormone receptor positive breast cancer.

Hum Mutat 2012 Jul 30;33(7):1123-32. Epub 2012 Apr 30.

Vesalius Research Center, VIB, KU Leuven, Leuven, Belgium.

A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ≤ 3 × 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.
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http://dx.doi.org/10.1002/humu.22089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370081PMC
July 2012

A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype.

Ann Rheum Dis 2012 Jun 22;71(6):1042-8. Epub 2012 Mar 22.

Department of Biochemistry/ Internal Medicine, Rush University Medical Center, Chicago, Illinois 60612, USA.

Objectives: The aim of this study was to assess if genetic variation in the PACE4 (paired amino acid converting enzyme 4) gene Pcsk6 influences the risk for symptomatic knee osteoarthritis (OA).

Methods: Ten PCSK6 single nucleotide polymorphisms were tested for association in a discovery cohort of radiographic knee OA (n=156 asymptomatic and 600 symptomatic cases). Meta-analysis of the minor allele at rs900414 was performed in three additional independent cohorts (total n=674 asymptomatic and 2068 symptomatic). Pcsk6 knockout mice and wild-type C57BL/6 mice were compared in a battery of algesiometric assays, including hypersensitivity in response to intraplantar substance P, pain behaviours in response to intrathecal substance P and pain behaviour in the abdominal constriction test.

Results: In the discovery cohort of radiographic knee OA, an intronic single nucleotide polymorphism at rs900414 was significantly associated with symptomatic OA. Replication in three additional cohorts confirmed that the minor allele at rs900414 was consistently increased among asymptomatic compared to symptomatic radiographic knee OA cases in all four cohorts. A fixed-effects meta-analysis yielded an OR=1.35 (95% CI 1.17 to 1.56; p=4.3×10(-5) and no significant between-study heterogeneity). Studies in mice revealed that Pcsk6 knockout mice were significantly protected against pain in a battery of algesiometric assays.

Conclusions: These results suggest that a variant in PCSK6 is strongly associated with protection against pain in knee OA, offering some insight as to why, in the presence of the same structural damage, some individuals develop chronic pain and others are protected. Studies in Pcsk6 null mutant mice further implicate PACE4 in pain.
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http://dx.doi.org/10.1136/annrheumdis-2011-200300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603144PMC
June 2012

Genome-wide association analysis identifies three new breast cancer susceptibility loci.

Nat Genet 2012 Jan 22;44(3):312-8. Epub 2012 Jan 22.

Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, UK.

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
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http://dx.doi.org/10.1038/ng.1049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653403PMC
January 2012

Self-reported knee malalignment in early adult life as an independent risk for knee chondrocalcinosis.

Arthritis Care Res (Hoboken) 2011 Nov;63(11):1550-7

University of Nottingham, UK.

Objective: To determine if self-reported current and early adult life knee malalignment is associated with knee chondrocalcinosis (CC).

Methods: A case-control study embedded in the Genetics of Osteoarthritis and Lifestyle (GOAL) study was performed. A validated self-reported line-drawing instrument was mailed to 3,022 participants of GOAL, inquiring about knee malalignment (straight, valgus, varus) in their third decade (20s) and currently. Self-reported weight in 20s and present weight and height measured at the initial visit were used to calculate body mass index (BMI) in 20s and currently. Occupational risk was present if participants self-reported mechanically demanding activities in their longest held job. Cases were participants with radiographic CC at any tibiofemoral (TF) joints. Osteoarthritis was defined as a Kellgren/Lawrence score of ≥3 at TF joints or patellofemoral joints. Odds ratio (OR), adjusted OR, and 95% confidence interval (95% CI) were calculated for associations with knee CC.

Results: A total of 2,167 participants responded to the questionnaire, of which 7.5% respondents had knee CC. Knee CC was associated with self-reported varus (adjusted OR 1.77 [95% CI 1.05, 2.98]) and any knee malalignment in 20s (adjusted OR 1.64 [95% CI 1.02, 2.64]). This association was not restricted to the mechanically loaded TF compartment. There was no association between current knee malalignment and knee CC. Age (adjusted OR 1.73 [95% CI 1.36, 2.19]) and knee OA (adjusted OR 2.88 [95% CI 1.89, 4.38]) were associated with knee CC. There was no association between BMI in 20s (adjusted OR 1.14 [95% CI 0.92, 1.42]), occupational risk (adjusted OR 1.32 [95% CI 0.94, 1.85]), and knee CC.

Conclusion: Early life knee malalignment, predominantly varus, is an independent risk factor for knee CC. This association is not restricted to the mechanically loaded compartment, implying a generalized predisposition throughout the knee.
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http://dx.doi.org/10.1002/acr.20593DOI Listing
November 2011

A variant in MCF2L is associated with osteoarthritis.

Am J Hum Genet 2011 Sep 25;89(3):446-50. Epub 2011 Aug 25.

Wellcome Trust Sanger Institute, Hinxton, UK.

Osteoarthritis (OA) is a prevalent, heritable degenerative joint disease with a substantial public health impact. We used a 1000-Genomes-Project-based imputation in a genome-wide association scan for osteoarthritis (3177 OA cases and 4894 controls) to detect a previously unidentified risk locus. We discovered a small disease-associated set of variants on chromosome 13. Through large-scale replication, we establish a robust association with SNPs in MCF2L (rs11842874, combined odds ratio [95% confidence interval] 1.17 [1.11-1.23], p = 2.1 × 10(-8)) across a total of 19,041 OA cases and 24,504 controls of European descent. This risk locus represents the third established signal for OA overall. MCF2L regulates a nerve growth factor (NGF), and treatment with a humanized monoclonal antibody against NGF is associated with reduction in pain and improvement in function for knee OA patients.
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http://dx.doi.org/10.1016/j.ajhg.2011.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169824PMC
September 2011

Inverse relationship between preoperative radiographic severity and postoperative pain in patients with osteoarthritis who have undergone total joint arthroplasty.

Semin Arthritis Rheum 2012 Feb 24;41(4):568-75. Epub 2011 Aug 24.

Department of Twin Research, King's College London, St. Thomas' Hospital, London, UK.

Objectives: To determine cross-sectionally the influence of risk factors on chronic pain following total joint replacement (TJR) of the knee (TKR) or the hip (THR).

Methods: Eight hundred sixty post-TKR and 928 post-THR patients were studied. Western Ontario and McMaster Osteoarthritis Index pain scores taken on average 3.2 years postsurgery were correlated to preoperative radiographic severity measured by Kellgren-Lawrence grade (K/L) grade for the knee, Croft grade, and minimum joint space width (minJSW) for the hip and presence of comorbidities.

Results: Known risk factors were able to explain less than 20% of the variance in pain scores post-TJR. The presence of chronic widespread pain determined a higher risk of high pain in both TKR cases (odds ratio (OR) = 3.15 95%CI 1.86-5.30) and THR cases (OR = 5.02 95%CI 2.76-9.14). Other risk factors common to both TKR and THR pain postsurgery were the presence of depression, higher body mass index, younger age, and female gender. Interestingly, low radiographic grade at the index joint presurgery (defined as tibiofemoral K/L <3 for the knee and minJSW >2 mm for the hip) resulted in a significantly increased risk of high pain post-TJR (OR = 1.56; 95%CI 1.04-2.36).

Conclusions: The risk factors contributing to chronic pain post-TJR remain mostly unknown. Individuals with lower preoperative radiographic OA severity undergoing TJR are more likely to experience high pain post-TJR.
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http://dx.doi.org/10.1016/j.semarthrit.2011.07.002DOI Listing
February 2012
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