PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-17 (17)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
1.  A Role for PACE4 in Osteoarthritis Pain: Evidence from Human Genetic Association and Null Mutant Phenotype 
Annals of the rheumatic diseases  2012;71(6):1042-1048.
Objectives
To assess if genetic variation in the PACE4 gene, PCSK6, influences the risk for symptomatic knee OA.
Methods
Ten PCSK6 single nucleotide polymorphisms (SNP) 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 (KO) mice and wildtype 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 SNP 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 odds ratio =1.35 (95% CI 1.17, 1.56; p-value 4.3×10−5 and no significant between-study heterogeneity). Studies in mice revealed that Pcsk6 knockout (KO) 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.
doi:10.1136/annrheumdis-2011-200300
PMCID: PMC3603144  PMID: 22440827
Knee osteoarthritis; pain; PACE4; genetic association; SNP
2.  Gene-environment interaction between body mass index and transforming growth factor beta 1 (TGFβ1) gene in knee and hip osteoarthritis 
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.
doi:10.1186/ar4214
PMCID: PMC4060375  PMID: 23597094
3.  Should folic acid fortification be mandatory? No 
BMJ : British Medical Journal  2007;334(7606):1253.
The UK's Food Standards Agency recently recommended mandatory folic acid fortification of some foods. Nicholas Wald and Godfrey Oakley argue that it's a safe effective way of preventing spina bifida and anencephaly—but Richard Hubner and colleagues say that more research into the harms is needed
doi:10.1136/bmj.39232.496227.47
PMCID: PMC1892487  PMID: 17569932
4.  Do estimates of cost-utility based on the EQ-5D differ from those based on the mapping of utility scores? 
Background
Mapping has been used to convert scores from condition-specific measures into utility scores, and to produce estimates of cost-effectiveness. We sought to compare the QALY gains, and incremental cost per QALY estimates, predicted on the basis of mapping to those based on actual EQ-5D scores.
Methods
In order to compare 4 different interventions 389 individuals were asked to complete both the EQ-5D and the Western Ontartio and McMaster Universities Osteoarthritis Index (WOMAC) at baseline, 6, 12, and 24 months post-intervention. Using baseline data various mapping models were developed, where WOMAC scores were used to predict the EQ-5D scores. The performance of these models was tested by predicting the EQ-5D post-intervention scores. The preferred model (that with the lowest mean absolute error (MAE)) was used to predict the EQ-5D scores, at all time points, for individuals who had complete WOMAC and EQ-5D data. The mean QALY gain associated with each intervention was calculated, using both actual and predicted EQ-5D scores. These QALY gains, along with previously estimated changes in cost, were also used to estimate the actual and predicted incremental cost per QALY associated with each of the four interventions.
Results
The EQ-5D and the WOMAC were completed at baseline by 348 individuals, and at all time points by 259 individuals. The MAE in the preferred model was 0.129, and the mean QALY gains for each of the four interventions was predicted to be 0.006, 0.058, 0.058, and 0.136 respectively, compared to the actual mean QALY gains of 0.087, 0.081, 0.120, and 0.149. The most effective intervention was estimated to be associated with an incremental cost per QALY of £6,068, according to our preferred model, compared to £13,154 when actual data was used.
Conclusion
We found that actual QALY gains, and incremental cost per QALY estimates, differed from those predicted on the basis of mapping. This suggests that though mapping may be of value in predicting the cost-effectiveness of interventions which have not been evaluated using a utility measure, future studies should be encouraged to include a method of actual utility measurement.
Trial registration
Current Controlled Trials ISRCTN93206785
doi:10.1186/1477-7525-6-51
PMCID: PMC2490675  PMID: 18625052
5.  Mobile phone use and risk of glioma in adults: case-control study 
BMJ : British Medical Journal  2006;332(7546):883-887.
Objective To investigate the risk of glioma in adults in relation to mobile phone use.
Design Population based case-control study with collection of personal interview data.
Setting Five areas of the United Kingdom.
Participants 966 people aged 18 to 69 years diagnosed with a glioma from 1 December 2000 to 29 February 2004 and 1716 controls randomly selected from general practitioner lists.
Main outcome measures Odds ratios for risk of glioma in relation to mobile phone use.
Results The overall odds ratio for regular phone use was 0.94 (95% confidence interval 0.78 to 1.13). There was no relation for risk of glioma and time since first use, lifetime years of use, and cumulative number of calls and hours of use. A significant excess risk for reported phone use ipsilateral to the tumour (1.24, 1.02 to 1.52) was paralleled by a significant reduction in risk (0.75, 0.61 to 0.93) for contralateral use.
Conclusions Use of a mobile phone, either in the short or medium term, is not associated with an increased risk of glioma. This is consistent with most but not all published studies. The complementary positive and negative risks associated with ipsilateral and contralateral use of the phone in relation to the side of the tumour might be due to recall bias.
doi:10.1136/bmj.38720.687975.55
PMCID: PMC1440611  PMID: 16428250
6.  The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis 
Annals of the Rheumatic Diseases  2011;70(9):1556-1561.
Objective
To assess if a coding variant in the gene encoding transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is associated with genetic risk of painful knee osteoarthritis (OA).
Methods
The Ile585Val TRPV1 variant encoded by rs8065080 was genotyped in 3270 cases of symptomatic knee OA, 1098 cases of asymptomatic knee OA and 3852 controls from seven cohorts from the UK, the USA and Australia. The genetic association between the low-pain genotype Ile–Ile and risk of symptomatic and asymptomatic knee OA was assessed.
Results
The TRPV1 585 Ile–Ile genotype, reported to be associated with lower thermal pain sensitivity, was associated with a lower risk of symptomatic knee OA in a comparison of symptomatic cases with healthy controls, with an odds ratio (OR) of 0.75 (95% CI 0.64 to 0.88; p=0.00039 by meta-analysis) after adjustment for age, sex and body mass index. No difference was seen between asymptomatic OA cases and controls (OR=1.02, 95% CI 0.82 to 1.27 p=0.86) but the Ile–Ile genotype was associated with lower risk of symptomatic versus asymptomatic knee OA adjusting for covariates and radiographic severity (OR=0.73, 95% CI 0.57 to 0.94 p=0.0136). TRPV1 expression in articular cartilage was increased by inflammatory cytokines (tumour necrosis factor α and interleukin 1). However, there were no differences in TRPV1 expression in healthy and arthritic synovial tissue.
Conclusions
A genotype involved in lower peripheral pain sensitivity is significantly associated with a decreased risk of painful knee OA. This indicates a role for the pro-nociceptive gene TRPV1 in genetic susceptibility to symptomatic knee OA, which may also be influenced by a role for this molecule in cartilage function.
doi:10.1136/ard.2010.148122
PMCID: PMC3147243  PMID: 21616913
7.  Genetic contribution to radiographic severity in osteoarthritis of the knee 
Annals of the Rheumatic Diseases  2012;71(9):1537-1540.
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.
doi:10.1136/annrheumdis-2012-201382
PMCID: PMC3414227  PMID: 22615457
8.  The genetic contribution to severe post-traumatic osteoarthritis 
Annals of the Rheumatic Diseases  2013;72(10):1687-1690.
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.
doi:10.1136/annrheumdis-2012-202562
PMCID: PMC3786638  PMID: 23355107
Osteoarthritis; Gene Polymorphism; Epidemiology
9.  A Novel Approach to Exploring Potential Interactions among Single-Nucleotide Polymorphisms of Inflammation Genes in Gliomagenesis: An Exploratory Case-Only Study 
Background
Despite extensive research on the topic, glioma etiology remains largely unknown. Exploration of potential interactions between single-nucleotide polymorphisms (SNPs) of immune genes is a promising new area of glioma research. The case-only study design is a powerful and efficient design for exploring possible multiplicative interactions between factors that are independent of one another. The purpose of our study was to use this exploratory design to identify potential pair wise SNP-SNP interactions from genes involved in several different immune-related pathways for investigation in future studies.
Methods
The study population consisted of two case groups: 1224 histological-confirmed, non-Hispanic white glioma cases from the U.S. and a validation population of 634 glioma cases from the U.K. Polytomous logistic regression, in which one SNP was coded as the outcome and the other SNP was included as the exposure, was utilized to calculate the odds ratios of the likelihood of cases simultaneously having the variant alleles of two different SNPs. Potential interactions were examined only between SNPs located in different genes or chromosomes.
Results
Using this data-mining strategy, we found 396 significant SNP-SNP interactions among polymorphisms of immune-related genes that were present in both the U.S. and U.K. study populations.
Conclusion
This exploratory study was conducted for the purpose of hypothesis generation, and thus has provided several new hypotheses that can be tested using traditional case-control study designs to obtain estimates of risk.
Impact
This is the first study, to our knowledge, to take this novel approach to identifying SNP-SNP interactions relevant to glioma etiology.
doi:10.1158/1055-9965.EPI-11-0203
PMCID: PMC3904785  PMID: 21724854
10.  9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium 
Warren, Helen | Dudbridge, Frank | Fletcher, Olivia | Orr, Nick | Johnson, Nichola | Hopper, John L. | Apicella, Carmel | Southey, Melissa C. | Mahmoodi, Maryam | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | Braaf, Linda M. | Muir, Kenneth R. | Lophatananon, Artitaya | Chaiwerawattana, Arkom | Wiangnon, Surapon | Fasching, Peter A. | Beckmann, Matthias W. | Ekici, Arif B. | Schulz-Wendtland, Ruediger | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Mulot, Claire | Bojesen, Stig E | Nielsen, Sune F. | Flyger, Henrik | Nordestgaard, Børge G | Milne, Roger L. | Benítez, Javier | Arias-Pérez, José-Ignacio | Zamora, M. Pilar | Anton-Culver, Hoda | Ziogas, Argyrios | Bernstein, Leslie | Dur, Christina Clarke | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Langheinz, Anne | Meindl, Alfons | Golatta, Michael | Bartram, Claus R. | Schmutzler, Rita K. | Brauch, Hiltrud | Justenhoven, Christina | Brüning, Thomas | Chang-Claude, Jenny | Wang-Gohrke, Shan | Eilber, Ursula | Dörk, Thilo | Schürmann, Peter | Bremer, Michael | Hillemanns, Peter | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Bogdanova, Natalia | Antonenkova, Natalia | Rogov, Yuriy | Bermisheva, Marina | Prokofyeva, Darya | Zinnatullina, Guzel | Khusnutdinova, Elza | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kosma, Veli-Matti | Hartikainen, Jaana M. | Kataja, Vesa | Chenevix-Trench, Georgia | Beesley, Jonathan | Chen, Xiaoqing | Lambrechts, Diether | Smeets, Ann | Paridaens, Robert | Weltens, Caroline | Flesch-Janys, Dieter | Buck, Katharina | Behrens, Sabine | Peterlongo, Paolo | Bernard, Loris | Manoukian, Siranoush | Radice, Paolo | Couch, Fergus J. | Vachon, Celine | Wang, Xianshu | Olson, Janet | Giles, Graham | Baglietto, Laura | McLean, Cariona A. | Severi, Gianluca | John, Esther M. | Miron, Alexander | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Andrulis, Irene L. | Knight, Julia A. | Mulligan, Anna Marie | Weerasooriya, Nayana | Devilee, Peter | Tollenaar, Robert A.E.M. | Martens, John W.M. | Seynaeve, Caroline M. | Hooning, Maartje J. | Hollestelle, Antoinette | Jager, Agnes | Tilanus-Linthorst, Madeleine M.A. | Hall, Per | Czene, Kamila | Liu, Jianjun | Li, Jingmei | Cox, Angela | Cross, Simon S. | Brock, Ian W. | Reed, Malcolm W.R. | Pharoah, Paul | Blows, Fiona M. | Dunning, Alison M. | Ghoussaini, Maya | Ashworth, Alan | Swerdlow, Anthony | Jones, Michael | Schoemaker, Minouk | Easton, Douglas F. | Humphreys, Manjeet | Wang, Qin | Peto, Julian | dos-Santos-Silva, Isabel
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 (Phet) = 1.3 × 10–143], but no evidence of ethnic differences in per allele OR (Phet = 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; Phet = 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.
doi:10.1158/1055-9965.EPI-12-0526
PMCID: PMC3772723  PMID: 22859399
11.  Correction: Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC) 
Hein, Rebecca | Maranian, Melanie | Hopper, John L. | Kapuscinski, Miroslaw K. | Southey, Melissa C. | Park, Daniel J. | Schmidt, Marjanka K. | Broeks, Annegien | Hogervorst, Frans B. L. | Bueno-de-Mesquit, H. Bas | Muir, Kenneth R. | Lophatananon, Artitaya | Rattanamongkongul, Suthee | Puttawibul, Puttisak | Fasching, Peter A. | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Peto, Julian | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Marmee, Frederick | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Guénel, Pascal | Cordina-Duverger, Emilie | Menegaux, Florence | Truong, Thérèse | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Milne, Roger L. | Perez, Jose Ignacio Arias | Zamora, M. Pilar | Benítez, Javier | Anton-Culver, Hoda | Ziogas, Argyrios | Bernstein, Leslie | Clarke, Christina A. | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Rahman, Nazneen | Seal, Sheila | Turnbull, Clare | Renwick, Anthony | Meindl, Alfons | Schott, Sarah | Bartram, Claus R. | Schmutzler, Rita K. | Brauch, Hiltrud | Hamann, Ute | Ko, Yon-Dschun | Wang-Gohrke, Shan | Dörk, Thilo | Schürmann, Peter | Karstens, Johann H. | Hillemanns, Peter | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Bogdanova, Natalia V. | Zalutsky, Iosif V. | Antonenkova, Natalia N. | Bermisheva, Marina | Prokovieva, Darya | Farahtdinova, Albina | Khusnutdinova, Elza | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana | Chen, Xiaoqing | Beesley, Jonathan | Investigators, kConFab | Lambrechts, Diether | Zhao, Hui | Neven, Patrick | Wildiers, Hans | Nickels, Stefan | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Fredericksen, Zachary | Giles, Graham G. | Baglietto, Laura | McLean, Catriona A. | Severi, Gianluca | Offit, Kenneth | Robson, Mark | Gaudet, Mia M. | Vijai, Joseph | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børresen-Dale, Anne-Lise | John, Esther M. | Miron, Alexander | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Figueroa, Jonine D. | García-Closas, Montserrat | Lissowska, Jolanta | Sherman, Mark E. | Hooning, Maartje | Martens, John W. M. | Seynaeve, Caroline | Collée, Margriet | Hall, Per | Humpreys, Keith | Czene, Kamila | Liu, Jianjun | Cox, Angela | Brock, Ian W. | Cross, Simon S. | Reed, Malcolm W. R. | Ahmed, Shahana | Ghoussaini, Maya | Pharoah, Paul DP. | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Jakubowska, Anna | Jaworska, Katarzyna | Durda, Katarzyna | Złowocka, Elżbieta | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Shen, Chen-Yang | Yu, Jyh-Cherng | Hsu, Huan-Ming | Hou, Ming-Feng | Orr, Nick | Schoemaker, Minouk | Ashworth, Alan | Swerdlow, Anthony | Trentham-Dietz, Amy | Newcomb, Polly A. | Titus, Linda | Egan, Kathleen M. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Humphreys, Manjeet K. | Morrison, Jonathan | Chang-Claude, Jenny | Easton, Douglas F. | Dunning, Alison M.
PLoS ONE  2012;7(10):10.1371/annotation/e5de602c-0ffc-4e6f-a2ed-f79913c2e57c.
doi:10.1371/annotation/e5de602c-0ffc-4e6f-a2ed-f79913c2e57c
PMCID: PMC3525690
12.  Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC) 
Hein, Rebecca | Maranian, Melanie | Hopper, John L. | Kapuscinski, Miroslaw K. | Southey, Melissa C. | Park, Daniel J. | Schmidt, Marjanka K. | Broeks, Annegien | Hogervorst, Frans B. L. | Bueno-de-Mesquit, H. Bas | Muir, Kenneth R. | Lophatananon, Artitaya | Rattanamongkongul, Suthee | Puttawibul, Puttisak | Fasching, Peter A. | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Peto, Julian | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Marmee, Frederick | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Guénel, Pascal | Cordina-Duverger, Emilie | Menegaux, Florence | Truong, Thérèse | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Milne, Roger L. | Perez, Jose Ignacio Arias | Zamora, M. Pilar | Benítez, Javier | Anton-Culver, Hoda | Ziogas, Argyrios | Bernstein, Leslie | Clarke, Christina A. | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Rahman, Nazneen | Seal, Sheila | Turnbull, Clare | Renwick, Anthony | Meindl, Alfons | Schott, Sarah | Bartram, Claus R. | Schmutzler, Rita K. | Brauch, Hiltrud | Hamann, Ute | Ko, Yon-Dschun | Wang-Gohrke, Shan | Dörk, Thilo | Schürmann, Peter | Karstens, Johann H. | Hillemanns, Peter | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Bogdanova, Natalia V. | Zalutsky, Iosif V. | Antonenkova, Natalia N. | Bermisheva, Marina | Prokovieva, Darya | Farahtdinova, Albina | Khusnutdinova, Elza | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana | Chen, Xiaoqing | Beesley, Jonathan | Investigators, kConFab | Lambrechts, Diether | Zhao, Hui | Neven, Patrick | Wildiers, Hans | Nickels, Stefan | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Fredericksen, Zachary | Giles, Graham G. | Baglietto, Laura | McLean, Catriona A. | Severi, Gianluca | Offit, Kenneth | Robson, Mark | Gaudet, Mia M. | Vijai, Joseph | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børresen-Dale, Anne-Lise | John, Esther M. | Miron, Alexander | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Figueroa, Jonine D. | García-Closas, Montserrat | Lissowska, Jolanta | Sherman, Mark E. | Hooning, Maartje | Martens, John W. M. | Seynaeve, Caroline | Collée, Margriet | Hall, Per | Humpreys, Keith | Czene, Kamila | Liu, Jianjun | Cox, Angela | Brock, Ian W. | Cross, Simon S. | Reed, Malcolm W. R. | Ahmed, Shahana | Ghoussaini, Maya | Pharoah, Paul DP. | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Jakubowska, Anna | Jaworska, Katarzyna | Durda, Katarzyna | Złowocka, Elżbieta | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Shen, Chen-Yang | Yu, Jyh-Cherng | Hsu, Huan-Ming | Hou, Ming-Feng | Orr, Nick | Schoemaker, Minouk | Ashworth, Alan | Swerdlow, Anthony | Trentham-Dietz, Amy | Newcomb, Polly A. | Titus, Linda | Egan, Kathleen M. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Humphreys, Manjeet K. | Morrison, Jonathan | Chang-Claude, Jenny | Easton, Douglas F. | Dunning, Alison M. | Chan, Kelvin Yuen Kwong
PLoS ONE  2012;7(8):e42380.
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, pheterogeneity = 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.
doi:10.1371/journal.pone.0042380
PMCID: PMC3413660  PMID: 22879957
13.  Large Scale Replication Study of the Association between HLA Class II/BTNL2 Variants and Osteoarthritis of the Knee in European-Descent Populations 
PLoS ONE  2011;6(8):e23371.
Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs) mapping to the Human Leukocyte Antigen (HLA) region and deriving from a genome wide association scan (GWAS) of knee OA in Japanese populations. The frequencies for rs10947262 were compared in 36,408 controls and 5,749 knee OA cases from European-descent populations. rs7775228 was tested in 32,823 controls and 1,837 knee OA cases of European descent. The risk (major) allele at rs10947262 in Caucasian samples was not significantly associated with an odds ratio (OR)  = 1.07 (95%CI 0.94 -1.21; p = 0.28). For rs7775228 the meta-analysis resulted in OR = 0.94 (95%CI 0.81-1.09; p = 0.42) for the allele associated with risk in the Japanese GWAS. In Japanese individuals these two SNPs are in strong linkage disequilibrium (LD) (r2 = 0.86) with the HLA class II haplotype DRB1*1502 DQA1*0103 DQB1*0601 (frequency 8%). In Caucasian and Chinese samples, using imputed data, these SNPs appear not to be in LD with that haplotype (r2<0.07). The rs10947262 and rs7775228 variants are not associated with risk of knee OA in European descent populations and they do not appear tag the same HLA class II haplotype as they do in Japanese individuals.
doi:10.1371/journal.pone.0023371
PMCID: PMC3154440  PMID: 21853121
14.  Lifestyle interventions for knee pain in overweight and obese adults aged ≥45: economic evaluation of randomised controlled trial 
Objective To estimate the cost effectiveness of four different lifestyle interventions for knee pain.
Design Cost utility analysis of randomised controlled trial.
Setting Five general practices in the United Kingdom.
Participants 389 adults aged ≥45 with self reported knee pain and body mass index (BMI) ≥28.
Interventions Dietary intervention plus quadriceps strengthening exercises, dietary intervention, quadriceps strengthening exercises, and leaflet provision. Participants received home visits over a two year period.
Main outcome measure Incremental cost per quality adjusted life year (QALY) gained over two years from a health service perspective.
Results Advice leaflet was associated with a mean change in cost of −£31, and a mean QALY gain of 0.085. Both strengthening exercises and dietary intervention were more effective (0.090 and 0.133 mean QALY gain, respectively) but were not cost effective. Dietary intervention plus strengthening exercises had a mean cost of £647 and a mean QALY gain of 0.147 and was estimated to have an incremental cost of £10 469 per QALY gain (relative to leaflet provision), and a 23.1% probability of being cost effective at a £20 000/QALY threshold.
Conclusion Dietary intervention plus strengthening exercises was estimated to be cost effective for individuals with knee pain, but with a large level of uncertainty.
Trial registration ISRCTN93206785.
doi:10.1136/bmj.b2273
PMCID: PMC2728802  PMID: 19690341
15.  Effects of dietary intervention and quadriceps strengthening exercises on pain and function in overweight people with knee pain: randomised controlled trial 
Objective To determine whether dietary intervention or knee strengthening exercise, or both, can reduce knee pain and improve knee function in overweight and obese adults in the community.
Design Pragmatic factorial randomised controlled trial.
Setting Five general practices in Nottingham.
Participants 389 men and women aged 45 and over with a body mass index (BMI) of ≥28.0 and self reported knee pain.
Interventions Participants were randomised to dietary intervention plus quadriceps strengthening exercises; dietary intervention alone; quadriceps strengthening exercises alone; advice leaflet only (control group). Dietary intervention consisted of individualised healthy eating advice that would reduce normal intake by 2.5 MJ (600 kcal) a day. Interventions were delivered at home visits over a two year period.
Main outcome measures The primary outcome was severity of knee pain scored with the Western Ontario McMaster (WOMAC) osteoarthritis index at 6, 12, and 24 months. Secondary outcomes (all at 24 months) included WOMAC knee physical function and stiffness scores and selected domains on the SF-36 and the hospital anxiety and depression index.
Results 289 (74%) participants completed the trial. There was a significant reduction in knee pain in the knee exercise groups compared with those in the non-exercise groups at 24 months (percentage risk difference 11.61, 95% confidence interval 1.81% to 21.41%). The absolute effect size (0.25) was moderate. The number needed to treat to benefit from a ≥30% improvement in knee pain at 24 months was 9 (5 to 55). In those randomised to knee exercise improvement in function was evident at 24 months (mean difference −3.64, −6.01 to −1.27). The mean difference in weight loss at 24 months in the dietary intervention group compared with no dietary intervention was 2.95 kg (1.44 to 4.46); for exercise versus no exercise the difference was 0.43 kg (−0.82 to 1.68). This difference in weight loss was not associated with improvement in knee pain or function but was associated with a reduction in depression (absolute effect size 0.19).
Conclusions A home based, self managed programme of simple knee strengthening exercises over a two year period can significantly reduce knee pain and improve knee function in overweight and obese people with knee pain. A moderate sustained weight loss is achievable with dietary intervention and is associated with reduced depression but is without apparent influence on pain or function.
Trial registration Current Controlled Trials ISRCTN 93206785.
doi:10.1136/bmj.b3170
PMCID: PMC2728801  PMID: 19690345
16.  Comparing the performance of the EQ-5D and SF-6D when measuring the benefits of alleviating knee pain 
Objective
To assess the practicality, validity and responsiveness of using each of two utility measures (the EQ-5D and SF-6D) to measure the benefits of alleviating knee pain.
Methods
Participants in a randomised controlled trial, which was designed to compare four different interventions for people with self-reported knee pain, were asked to complete the EQ-5D, SF-6D, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at both pre- and post-intervention. For both utility measures, we assessed their practicality (completion rate), construct validity (ability to discriminate between baseline WOMAC severity levels), and responsiveness (ability to discriminate between three groups: those whose total WOMAC score, i) did not improve, ii) improved by <20%, and iii) improved by ≥20%).
Results
The EQ-5D was completed by 97.7% of the 389 participants, compared to 93.3% for the SF-6D. Both the EQ-5D and SF-6D were able to discriminate between participants with different levels of WOMAC severity (p < 0.001). The mean EQ-5D change was -0.036 for group i), 0.091 for group ii), and 0.127 for group iii), compared to 0.021, 0.023 and 0.053 on the SF-6D. These change scores were significantly different according to the EQ-5D (p < 0.001), but not the SF-6D.
Conclusion
The EQ-5D and SF-6D had largely comparable practicality and construct validity. However, in contrast to the EQ-5D, the SF-6D could not discriminate between those who improved post-intervention, and those who did not. This suggests that it is more appropriate to use the EQ-5D in future cost-effectiveness analyses of interventions which are designed to alleviate knee pain.
Trial registration
Current Controlled Trials ISRCTN93206785
doi:10.1186/1478-7547-7-12
PMCID: PMC2720915  PMID: 19615052
17.  Identification of new genetic risk factors for prostate cancer 
Asian Journal of Andrology  2008;11(1):49-55.
There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.
doi:10.1038/aja.2008.18
PMCID: PMC3735221  PMID: 19050691
prostate cancer; genetics; susceptibility loci; SNPs; relative risks

Results 1-17 (17)