PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (43)
 

Clipboard (0)
None

Select a Filter Below

Year of Publication
more »
1.  A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication 
Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6 × 10−6 for effect modification of current MHT use. The most significant interaction was observed for rs6707272 (P = 3 × 10−7) on chromosome 2 but was not replicated in the BCAC studies (P = 0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP × MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women.
doi:10.1007/s10549-013-2443-z
PMCID: PMC3781176  PMID: 23423446
Postmenopausal breast cancer risk; Menopausal hormone therapy; Polymorphisms; Gene-environment interaction; Genome-wide association study; Case-only study
2.  Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: When are these medications most helpful? 
Addiction (Abingdon, England)  2012;108(2):275-293.
Aims
Although debates over the efficacy of oral naltrexone and acamprosate in treating alcohol use disorders tend to focus on their global efficacy relative to placebo or their efficacy relative to each other, the underlying reality may be more nuanced. This meta-analysis examined when naltrexone and acamprosate are most helpful by testing: (1) the relative efficacy of each medication given its presumed mechanism of action (reducing heavy drinking versus fostering abstinence) and (2) whether different ways of implementing each medication (required abstinence before treatment, detoxification before treatment, goal of treatment, length of treatment, dosage) moderate its effects.
Methods
A systematic literature search identified 64 randomized, placebo-controlled, English-language clinical trials completed between 1970 and 2009 focused on acamprosate or naltrexone.
Results
Acamprosate had a significantly larger effect size than naltrexone on the maintenance of abstinence, and naltrexone had a larger effect size than acamprosate on the reduction of heavy drinking and craving. For naltrexone, requiring abstinence before the trial was associated with larger effect sizes for abstinence maintenance and reduced heavy drinking compared to placebo. For acamprosate, detoxification before medication administration was associated with better abstinence outcomes compared to placebo.
Conclusions
In treatment for alcohol use disorders, acamprosate has been found to be slightly more efficacious in promoting abstinence and naltrexone slightly more efficacious in reducing heavy drinking and craving. Detoxification before treatment or a longer period of required abstinence before treatment is associated with larger medication effects for acamprosate and naltrexone, respectively.
doi:10.1111/j.1360-0443.2012.04054.x
PMCID: PMC3970823  PMID: 23075288
3.  Association of CYP2D6 metabolizer status with mammographic density change in response to tamoxifen treatment 
Introduction
Not all breast cancer patients respond to tamoxifen treatment, possibly due to genetic predisposition. As tamoxifen-induced reductions in percent mammographic density (PMD) have been linked to the risk and prognosis of breast cancer, we conducted a candidate gene study to investigate the association between germline CYP2D6 polymorphisms and PMD change.
Methods
Baseline and follow-up mammograms were retrieved for 278 tamoxifen-treated subjects with CYP2D6 metabolizer status (extensive (EM), heterozygous extensive/intermediate (hetEM/IM) or poor metabolizer (PM)). Logistic regression analyses were conducted comparing subjects who experienced >10% reduction in PMD to those who experienced ≤10% reduction or increase.
Results
After multivariate adjustment, PMD change was found to be significantly associated with the degree of CYP2D6 enzyme functionality (Ptrend = 0.021). Compared with EM, hetEM/IM and PM were 72% (95% confidence interval (CI): 0.10 to 0.79) and 71% (0.03 to 2.62) less likely to experience a >10% reduction, respectively.
Conclusions
Tamoxifen-induced change in PMD appears to have a genetic component.
doi:10.1186/bcr3495
PMCID: PMC3979120  PMID: 24088226
4.  Change of mammographic density predicts the risk of contralateral breast cancer - a case-control study 
Introduction
Mammographic density is a strong risk factor for breast cancer, but it is unknown whether density at first breast cancer diagnosis and changes during follow-up influences risk of non-simultaneous contralateral breast cancer (CBC).
Methods
We collected mammograms for CBC-patients (cases, N = 211) and unilateral breast cancer patients (controls, N = 211), individually matched on age and calendar period of first breast cancer diagnosis, type of adjuvant therapy and length of follow-up (mean follow-up time: 8.25 years). The odds of CBC as a function of changes of density during follow-up were investigated using conditional logistic regression, adjusting for non-dense area at diagnosis.
Results
Patients who experienced ≥10% absolute decrease in percent density had a 55% decreased odds of CBC (OR = 0.45 95% CI: 0.24 to 0.84) relative to patients who had little or no change in density from baseline to first follow-up mammogram (mean = 1.6 (SD = 0.6) years after diagnosis), whereas among those who experienced an absolute increase in percent density we could not detect any effect on the odds of CBC (OR = 0.83 95% CI: 0.24 to 2.87).
Conclusion
Decrease of mammographic density within the first two years after first diagnosis is associated with a significantly reduced risk of CBC, this potential new risk predictor can thus contribute to decision-making in follow-up strategies and treatment.
doi:10.1186/bcr3451
PMCID: PMC3978478  PMID: 23876209
Contralateral breast cancer; mammographic density; risk; breast density; epidemiology
5.  Possible influence of mammographic density on local and locoregional recurrence of breast cancer 
Introduction
It is debated whether mammographic density gives rise to more aggressive cancers. We therefore aimed to study the influence of mammographic density on prognosis.
Methods
This is a case-only study within a population-based case-control study. Cases were all postmenopausal women in Sweden with incident breast cancer, diagnosed 1993-1995, and aged 50-74 years. Women with pre-diagnostic/diagnostic mammograms were included (n = 1774). Mammographic density of the unaffected breast was assessed using a computer-assisted thresholding technique. The Cox proportional hazards model was used to study recurrence and survival with and without stratification on surgical procedure (breast-conserving surgery vs. mastectomy).
Results
Percentage density (PD) was associated with both local and locoregional recurrence even after adjustment for established prognosticators; hazards ratio (HR) 1.92, p = 0.039, for local recurrence and HR 1.67, p = 0.033, for locoregional recurrence for women with PD≥25% compared to PD<25%. Stratification on surgical procedure showed that the associations were also present in mastectomized women. PD was neither associated with distant recurrence nor survival.
Conclusions
High mammographic density is an independent risk factor of local and locoregional recurrence but is neither associated with distant metastasis nor survival. The relationships with local and locoregional recurrences were also present in women treated with mastectomy, indicating that they are not merely explained by density masking residual disease in women treated with breast-conserving surgery. Rather there appears to be a true association. Thus, mammographic density should possibly influence adjuvant therapy decisions in the future.
doi:10.1186/bcr3450
PMCID: PMC3979151  PMID: 23844592
6.  Ultra-Brief Intervention for Problem Drinkers: Results from a Randomized Controlled Trial 
PLoS ONE  2012;7(10):e48003.
Background
There are a number of evidence-based, in-person clinical inteventions for problem drinkers, but most problem drinkers will never seek such treatments. Reaching the population of non-treatment seeking problem drinkers will require a different approach. Accordingly, this randomized clinical trial evaluated an intervention that has been validated in clinical settings and then modified into an ultra-brief format suitable for use as an indicated public health intervention (i.e., targeting the population of non-treatment seeking problem drinkers).
Methodology/Principal Findings
Problem drinkers (N = 1767) completed a baseline population telephone survey and then were randomized to one of three conditions – a personalized feedback pamphlet condition, a control pamphlet condition, or a no intervention control condition. In the week after the baseline survey, households in the two pamphlet conditions were sent their respective interventions by postal mail addressed to ‘Check Your Drinking.’ Changes in drinking were assessed post intervention at three-month and six-month follow-ups. The follow-up rate was 86% at three-months and 76% at six-months. There was a small effect (p = .04) in one of three outcome variables (reduction in AUDIT-C, a composite measure of quantity and frequency of drinking) observed for the personalized feedback pamphlet compared to the no intervention control. No significant differences (p>.05) between groups were observed for the other two outcome variables – number of drinks consumed in the past seven days and highest number of drinks on one occasion.
Conclusions/Significance
Based on the results of this study, we tentatively conclude that a brief intervention, modified to an ultra-brief, public health format can have a meaningful impact.
Trial Registration
ClinicalTrials.gov NCT00688584.
doi:10.1371/journal.pone.0048003
PMCID: PMC3480504  PMID: 23110157
7.  Who uses online interventions for problem drinkers? 
The goal of this research was to understand why some people use online interventions for drinking problems while others with comparable access to the interventions do not. As part of a randomized controlled trial, 92 participants in the experimental condition were provided access to a password protected version of a web-based personalized feedback intervention (the Check Your Drinking screener; CYD; www.CheckYourDrinking.net). Information collected at baseline was compared between those who accessed the website and those who did not. Those who accessed the website tended to be more frequent users of the Internet, to drink less, and to perceive that others of the same age and sex drank less as compared to those who did not access the intervention. Some of these results are troubling as the preferred target of this type of intervention would be those who drink more and perceive that others are also heavy alcohol consumers.
doi:10.1016/j.jsat.2011.03.003
PMCID: PMC3166539  PMID: 21632197
Alcohol; Internet; brief intervention; adherence
8.  A meta-analysis of genome-wide association studies of follicular lymphoma 
BMC Genomics  2012;13:516.
Background
B-cell non-Hodgkin lymphoma represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is one of the most common subtypes. Family and epidemiological studies suggest an important genetic role in the etiology of FL. In recent genome-wide association studies (GWAS) of FL, several genetic susceptibility loci have been identified on chromosome 6p21.33 (rs6457327) and 6p21.32 (rs10484561, rs2647012) in the human leukocyte antigen class I and class II regions. To identify new genetic variants and further elucidate the genetic basis of FL, a meta-analysis was performed of the top 1000 SNPs associated with FL risk from two GWAS in the US, Denmark and Sweden (592 cases, 1541 controls), with independent validation in 107 cases and 681 controls.
Results
rs9275517 and rs3117222 in the HLA class II region were validated and inversely associated with FL risk (rs9275517: OR = 0.63, 95% CI = 0.55-0.73, p = 4.03 × 10-11; rs3117222: OR = 0.66, 95% CI = 0.57-0.77, p = 1.45 × 10-7). rs9275517, which is in high linkage disequilibrium with rs2647012 (r2 = 0.9), was no longer associated with FL after conditioning on rs2647012. The rs3117222 association was independent of established FL SNPs, but not of the HLA-DPB1*0301 allele. Using publicly available gene expression profiles with matching genotype information, we found that rs3117222 also was significantly correlated with increased HLA-DPB1 expression.
Conclusions
By performing a meta-analysis of two GWAS of FL, we further validated the relevance of HLA-DPB1*0301 as a protective allele in the pathogenesis of FL. Moreover, the protective rs3117222 A allele correlated with increased levels of HLA-DPB1, suggesting a possible disease mechanism involving HLA-DPB1 expression regulation. Our results add further support to the major role of HLA genetic variation in the pathogenesis of FL.
doi:10.1186/1471-2164-13-516
PMCID: PMC3534234  PMID: 23025665
Follicular lymphoma (FL); Genome-wide association studies (GWAS); Human leukocyte antigen (HLA); Meta-analysis
9.  Genetic Variants in ER Cofactor Genes and Endometrial Cancer Risk 
PLoS ONE  2012;7(8):e42445.
Given that the transcriptional regulatory activity of estrogen receptor (ER) is modulated by its biochemical cofactors, genetic variation within the ER cofactor genes may alter cellular response to estrogen exposure and consequently modify the risk for endometrial cancer. We genotyped 685 tagging SNPs within 60 ER cofactor genes in 564 endometrial cancer cases and 1,510 controls from Sweden, and tested their associations with the risk of endometrial cancer. We investigated the associations of individual SNPs by using a trend test as well as multiple SNPs within a gene or gene complex by using multi-variant association analysis. No significant association was observed for any individual SNPs or genes, but a marginal association of the cumulative genetic variation of the NCOA2 complex as a whole (NCOA2, CARM1, CREBBP, PRMT1 and EP300) with endometrial cancer risk was observed (Padjusted = 0.033). However, the association failed to be replicated in an independent European dataset of 1265 cases and 5190 controls (P = 0.71). The results indicate that common genetic variants within ER cofactor genes are unlikely to play a significant role in endometrial cancer risk in European population.
doi:10.1371/journal.pone.0042445
PMCID: PMC3411617  PMID: 22876322
10.  High-throughput mammographic-density measurement: a tool for risk prediction of breast cancer 
Breast Cancer Research : BCR  2012;14(4):R114.
Introduction
Mammographic density (MD) is a strong, independent risk factor for breast cancer, but measuring MD is time consuming and reader dependent. Objective MD measurement in a high-throughput fashion would enable its wider use as a biomarker for breast cancer. We use a public domain image-processing software for the fully automated analysis of MD and penalized regression to construct a measure that mimics a well-established semiautomated measure (Cumulus). We also describe measures that incorporate additional features of mammographic images for improving the risk associations of MD and breast cancer risk.
Methods
We randomly partitioned our dataset into a training set for model building (733 cases, 748 controls) and a test set for model assessment (765 cases, 747 controls). The Pearson product-moment correlation coefficient (r) was used to compare the MD measurements by Cumulus and our automated measure, which mimics Cumulus. The likelihood ratio test was used to validate the performance of logistic regression models for breast cancer risk, which included our measure capturing additional information in mammographic images.
Results
We observed a high correlation between the Cumulus measure and our measure mimicking Cumulus (r = 0.884; 95% CI, 0.872 to 0.894) in an external test set. Adding a variable, which includes extra information to percentage density, significantly improved the fit of the logistic regression model of breast cancer risk (P = 0.0002).
Conclusions
Our results demonstrate the potential to facilitate the integration of mammographic density measurements into large-scale research studies and subsequently into clinical practice.
doi:10.1186/bcr3238
PMCID: PMC3680940  PMID: 22846386
11.  Predictors of Attrition from a National Sample of Methadone Maintenance Patients 
Background
Methadone substitution therapy is an effective harm reduction treatment method for opioid dependent persons. Ability to retain patients in methadone treatment is an accepted predictor of treatment outcomes.
Objectives
The current study evaluates the roles of psychiatric comorbidity, medical comorbidity, and sociodemographic characteristics as predictors of retention in methadone treatment utilizing retrospective analysis of data from a nationwide sample of patients in methadone treatment in the VA.
Methods
Data were gathered using the VA’s national health services use database. A cohort of veterans with a new episode of “opiate substitution” in fiscal year 1999 was identified, and their continuous service use was tracked through fiscal year 2002. The sample included a total of 2,363 patients in 23 VA medical centers. Survival analysis was used to explore factors associated with retention in methadone treatment.
Results
Younger age, having a serious mental illness, being African American, or having race recorded as unknown were associated with lower rates of retention in methadone treatment programs in this population of veterans (controlling for site).
Conclusion
Given that extended methadone treatment is associated with improved outcomes while patients remain in treatment, more longitudinal studies using primary data collection are needed to fully explore factors related to retention. For the VA population specifically, further research is necessary to fully understand the relationship between race/ethnicity and treatment retention.
Scientific Significance
This is the first retention study the authors are aware of that utilizes data from a nationwide, multisite, population of participants in methadone treatment.
doi:10.3109/00952991003736389
PMCID: PMC3314423  PMID: 20465373
methadone maintenance; veterans; treatment retention; national sample
12.  Breast cancer risk prediction and individualised screening based on common genetic variation and breast density measurement 
Introduction
Over the last decade several breast cancer risk alleles have been identified which has led to an increased interest in individualised risk prediction for clinical purposes.
Methods
We investigate the performance of an up-to-date 18 breast cancer risk single-nucleotide polymorphisms (SNPs), together with mammographic percentage density (PD), body mass index (BMI) and clinical risk factors in predicting absolute risk of breast cancer, empirically, in a well characterised Swedish case-control study of postmenopausal women. We examined the efficiency of various prediction models at a population level for individualised screening by extending a recently proposed analytical approach for estimating number of cases captured.
Results
The performance of a risk prediction model based on an initial set of seven breast cancer risk SNPs is improved by additionally including eleven more recently established breast cancer risk SNPs (P = 4.69 × 10-4). Adding mammographic PD, BMI and all 18 SNPs to a Swedish Gail model improved the discriminatory accuracy (the AUC statistic) from 55% to 62%. The net reclassification improvement was used to assess improvement in classification of women into low, intermediate, and high categories of 5-year risk (P = 8.93 × 10-9). For scenarios we considered, we estimated that an individualised screening strategy based on risk models incorporating clinical risk factors, mammographic density and SNPs, captures 10% more cases than a screening strategy using the same resources, based on age alone. Estimates of numbers of cases captured by screening stratified by age provide insight into how individualised screening programs might appear in practice.
Conclusions
Taken together, genetic risk factors and mammographic density offer moderate improvements to clinical risk factor models for predicting breast cancer.
doi:10.1186/bcr3110
PMCID: PMC3496143  PMID: 22314178
13.  Associations of Breast Cancer Risk Factors With Tumor Subtypes: A Pooled Analysis From the Breast Cancer Association Consortium Studies 
Yang, Xiaohong R. | Chang-Claude, Jenny | Goode, Ellen L. | Couch, Fergus J. | Nevanlinna, Heli | Milne, Roger L. | Gaudet, Mia | Schmidt, Marjanka K. | Broeks, Annegien | Cox, Angela | Fasching, Peter A. | Hein, Rebecca | Spurdle, Amanda B. | Blows, Fiona | Driver, Kristy | Flesch-Janys, Dieter | Heinz, Judith | Sinn, Peter | Vrieling, Alina | Heikkinen, Tuomas | Aittomäki, Kristiina | Heikkilä, Päivi | Blomqvist, Carl | Lissowska, Jolanta | Peplonska, Beata | Chanock, Stephen | Figueroa, Jonine | Brinton, Louise | Hall, Per | Czene, Kamila | Humphreys, Keith | Darabi, Hatef | Liu, Jianjun | Van ‘t Veer, Laura J. | van Leeuwen, Flora E. | Andrulis, Irene L. | Glendon, Gord | Knight, Julia A. | Mulligan, Anna Marie | O’Malley, Frances P. | Weerasooriya, Nayana | John, Esther M. | Beckmann, Matthias W. | Hartmann, Arndt | Weihbrecht, Sebastian B. | Wachter, David L. | Jud, Sebastian M. | Loehberg, Christian R. | Baglietto, Laura | English, Dallas R. | Giles, Graham G. | McLean, Catriona A. | Severi, Gianluca | Lambrechts, Diether | Vandorpe, Thijs | Weltens, Caroline | Paridaens, Robert | Smeets, Ann | Neven, Patrick | Wildiers, Hans | Wang, Xianshu | Olson, Janet E. | Cafourek, Victoria | Fredericksen, Zachary | Kosel, Matthew | Vachon, Celine | Cramp, Helen E. | Connley, Daniel | Cross, Simon S. | Balasubramanian, Sabapathy P. | Reed, Malcolm W. R. | Dörk, Thilo | Bremer, Michael | Meyer, Andreas | Karstens, Johann H. | Ay, Aysun | Park-Simon, Tjoung-Won | Hillemanns, Peter | Arias Pérez, Jose Ignacio | Rodríguez, Primitiva Menéndez | Zamora, Pilar | Benítez, Javier | Ko, Yon-Dschun | Fischer, Hans-Peter | Hamann, Ute | Pesch, Beate | Brüning, Thomas | Justenhoven, Christina | Brauch, Hiltrud | Eccles, Diana M. | Tapper, William J. | Gerty, Sue M. | Sawyer, Elinor J. | Tomlinson, Ian P. | Jones, Angela | Kerin, Michael | Miller, Nicola | McInerney, Niall | Anton-Culver, Hoda | Ziogas, Argyrios | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Yang, Show-Lin | Yu, Jyh-Cherng | Chen, Shou-Tung | Hsu, Giu-Cheng | Haiman, Christopher A. | Henderson, Brian E. | Le Marchand, Loic | Kolonel, Laurence N. | Lindblom, Annika | Margolin, Sara | Jakubowska, Anna | Lubiński, Jan | Huzarski, Tomasz | Byrski, Tomasz | Górski, Bohdan | Gronwald, Jacek | Hooning, Maartje J. | Hollestelle, Antoinette | van den Ouweland, Ans M. W. | Jager, Agnes | Kriege, Mieke | Tilanus-Linthorst, Madeleine M. A. | Collée, Margriet | Wang-Gohrke, Shan | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Mononen, Kari | Grip, Mervi | Hirvikoski, Pasi | Winqvist, Robert | Mannermaa, Arto | Kosma, Veli-Matti | Kauppinen, Jaana | Kataja, Vesa | Auvinen, Päivi | Soini, Ylermi | Sironen, Reijo | Bojesen, Stig E. | Dynnes Ørsted, David | Kaur-Knudsen, Diljit | Flyger, Henrik | Nordestgaard, Børge G. | Holland, Helene | Chenevix-Trench, Georgia | Manoukian, Siranoush | Barile, Monica | Radice, Paolo | Hankinson, Susan E. | Hunter, David J. | Tamimi, Rulla | Sangrajrang, Suleeporn | Brennan, Paul | McKay, James | Odefrey, Fabrice | Gaborieau, Valerie | Devilee, Peter | Huijts, P.E.A. | Tollenaar, RAEM. | Seynaeve, C. | Dite, Gillian S. | Apicella, Carmel | Hopper, John L. | Hammet, Fleur | Tsimiklis, Helen | Smith, Letitia D. | Southey, Melissa C. | Humphreys, Manjeet K. | Easton, Douglas | Pharoah, Paul | Sherman, Mark E. | Garcia-Closas, Montserrat
Background
Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.
Methods
We pooled tumor marker and epidemiological risk factor data from 35 568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case–case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case–control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided.
Results
In case–case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR− than PR+ tumors (P = .001). Nulliparity (P = 3 × 10−6) and increasing age at first birth (P = 2 × 10−9) were less frequent in ER− than in ER+ tumors. Obesity (body mass index [BMI] ≥ 30 kg/m2) in younger women (≤50 years) was more frequent in ER−/PR− than in ER+/PR+ tumors (P = 1 × 10−7), whereas obesity in older women (>50 years) was less frequent in PR− than in PR+ tumors (P = 6 × 10−4). The triple-negative (ER−/PR−/HER2−) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6+ and/or epidermal growth factor receptor [EGFR]+) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case–control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER+ or PR+ tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors.
Conclusions
This study shows that reproductive factors and BMI are most clearly associated with hormone receptor–positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.
doi:10.1093/jnci/djq526
PMCID: PMC3107570  PMID: 21191117
14.  NordicDB: a Nordic pool and portal for genome-wide control data 
European Journal of Human Genetics  2010;18(12):1322-1326.
A cost-efficient way to increase power in a genetic association study is to pool controls from different sources. The genotyping effort can then be directed to large case series. The Nordic Control database, NordicDB, has been set up as a unique resource in the Nordic area and the data are available for authorized users through the web portal (http://www.nordicdb.org). The current version of NordicDB pools together high-density genome-wide SNP information from ∼5000 controls originating from Finnish, Swedish and Danish studies and shows country-specific allele frequencies for SNP markers. The genetic homogeneity of the samples was investigated using multidimensional scaling (MDS) analysis and pairwise allele frequency differences between the studies. The plot of the first two MDS components showed excellent resemblance to the geographical placement of the samples, with a clear NW–SE gradient. We advise researchers to assess the impact of population structure when incorporating NordicDB controls in association studies. This harmonized Nordic database presents a unique genome-wide resource for future genetic association studies in the Nordic countries.
doi:10.1038/ejhg.2010.112
PMCID: PMC3002853  PMID: 20664631
common controls; genome-wide data; Nordic Control Database; population stratification
15.  Normative Misperceptions about Alcohol Use in a General Population Sample of Problem Drinkers from a Large Metropolitan City 
Aims: Heavy drinkers tend to overestimate how much others drink (normative fallacy), at least in college samples. Little research has been conducted to evaluate whether normative misperceptions about drinking extend beyond the college population. The present study explored normative misperceptions in an adult general population sample of drinkers. Methods: As part of a larger study, in Toronto, Canada, a random digit dialling telephone survey was conducted with 14,009 participants who drank alcohol at least once per month. Respondents with Alcohol Use Disorders Identification Test of eight or more (n = 2757) were asked to estimate what percent of Canadians of their same sex: (a) drank more than they do; (b) were abstinent and (c) drank seven or more drinks per week. Respondents' estimates of these population drinking norms were then compared with the actual levels of alcohol consumption in the Canadian population. Results: A substantial level of normative misperception was observed for estimates of levels of drinking in the general population. Estimates of the proportion of Canadians who were abstinent were fairly accurate. There was some evidence of a positive relationship between the respondents' own drinking severity and the extent of normative misperceptions. Little evidence was found of a relationship between degree of normative misperceptions and age. Conclusion: Normative misperceptions have been successfully targeted in social norms media campaigns as well as in personalized feedback interventions for problem drinkers. The present research solidifies the empirical bases for extending these interventions more widely into the general population.
doi:10.1093/alcalc/agr125
PMCID: PMC3243438  PMID: 22028458
16.  The Genetic Structure of the Swedish Population 
PLoS ONE  2011;6(8):e22547.
Patterns of genetic diversity have previously been shown to mirror geography on a global scale and within continents and individual countries. Using genome-wide SNP data on 5174 Swedes with extensive geographical coverage, we analyzed the genetic structure of the Swedish population. We observed strong differences between the far northern counties and the remaining counties. The population of Dalarna county, in north middle Sweden, which borders southern Norway, also appears to differ markedly from other counties, possibly due to this county having more individuals with remote Finnish or Norwegian ancestry than other counties. An analysis of genetic differentiation (based on pairwise Fst) indicated that the population of Sweden's southernmost counties are genetically closer to the HapMap CEU samples of Northern European ancestry than to the populations of Sweden's northernmost counties. In a comparison of extended homozygous segments, we detected a clear divide between southern and northern Sweden with small differences between the southern counties and considerably more segments in northern Sweden. Both the increased degree of homozygosity in the north and the large genetic differences between the south and the north may have arisen due to a small population in the north and the vast geographical distances between towns and villages in the north, in contrast to the more densely settled southern parts of Sweden. Our findings have implications for future genome-wide association studies (GWAS) with respect to the matching of cases and controls and the need for within-county matching. We have shown that genetic differences within a single country may be substantial, even when viewed on a European scale. Thus, population stratification needs to be accounted for, even within a country like Sweden, which is often perceived to be relatively homogenous and a favourable resource for genetic mapping, otherwise inferences based on genetic data may lead to false conclusions.
doi:10.1371/journal.pone.0022547
PMCID: PMC3150368  PMID: 21829632
17.  Coffee consumption modifies risk of estrogen-receptor negative breast cancer 
Introduction
Breast cancer is a complex disease and may be sub-divided into hormone-responsive (estrogen receptor (ER) positive) and non-hormone-responsive subtypes (ER-negative). Some evidence suggests that heterogeneity exists in the associations between coffee consumption and breast cancer risk, according to different estrogen receptor subtypes. We assessed the association between coffee consumption and postmenopausal breast cancer risk in a large population-based study (2,818 cases and 3,111 controls), overall, and stratified by ER tumour subtypes.
Methods
Odds ratios (OR) and corresponding 95% confidence intervals (CI) were estimated using the multivariate logistic regression models fitted to examine breast cancer risk in a stratified case-control analysis. Heterogeneity among ER subtypes was evaluated in a case-only analysis, by fitting binary logistic regression models, treating ER status as a dependent variable, with coffee consumption included as a covariate.
Results
In the Swedish study, coffee consumption was associated with a modest decrease in overall breast cancer risk in the age-adjusted model (OR> 5 cups/day compared to OR≤ 1 cup/day: 0.80, 95% CI: 0.64, 0.99, P trend = 0.028). In the stratified case-control analyses, a significant reduction in the risk of ER-negative breast cancer was observed in heavy coffee drinkers (OR> 5 cups/day compared to OR≤ 1 cup/day : 0.43, 95% CI: 0.25, 0.72, P trend = 0.0003) in a multivariate-adjusted model. The breast cancer risk reduction associated with higher coffee consumption was significantly higher for ER-negative compared to ER-positive tumours (P heterogeneity (age-adjusted) = 0.004).
Conclusions
A high daily intake of coffee was found to be associated with a statistically significant decrease in ER-negative breast cancer among postmenopausal women.
doi:10.1186/bcr2879
PMCID: PMC3218935  PMID: 21569535
18.  Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls 
Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Orr, Nick | Ashworth, Alan | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Burwinkel, Barbara | Bartram, Claus R. | Meindl, Alfons | Schmutzler, Rita K. | Cox, Angela | Brock, Ian | Elliott, Graeme | Reed, Malcolm W. R. | Southey, Melissa C. | Smith, Letitia | Spurdle, Amanda B. | Hopper, John L. | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Fredericksen, Zachary | Schürmann, Peter | Waltes, Regina | Bremer, Michael | Dörk, Thilo | Devilee, Peter | van Asperen, Christie J. | Tollenaar, Rob A.E.M. | Seynaeve, Caroline | Hall, Per | Czene, Kamila | Humphreys, Keith | Liu, Jianjun | Ahmed, Shahana | Dunning, Alison M. | Maranian, Melanie | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Beesley, Jonathan | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Zalutsky, Iosif V. | Anton-Culver, Hoda | Ziogas, Argyrios | Brauch, Hiltrud | Ko, Yon-Dschun | Hamann, Ute | Fasching, Peter A. | Strick, Reiner | Ekici, Arif B. | Beckmann, Matthias W. | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | English, Dallas R. | Milne, Roger L. | Benítez, Javier | Arias, José Ignacio | Pita, Guillermo | Nordestgaard, Børge G. | Bojesen, Stig E. | Flyger, Henrik | Kang, Daehee | Yoo, Keun-Young | Noh, Dong Young | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | García-Closas, Montserrat | Chanock, Stephen | Lissowska, Jolanta | Brinton, Louise A. | Chang-Claude, Jenny | Wang- Gohrke, Shan | Broeks, Annegien | Schmidt, Marjanka K | van Leeuwen, Flora E | Van 't Veer, Laura J | Margolin, Sara | Lindblom, Annika | Humphreys, Manjeet K. | Morrison, Jonathan | Platte, Radka | Easton, Douglas F. | Peto, Julian
Background
Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious.
Methods
We have genotyped five polymorphic (MAF 0.9% to 2.6%) missense single nucleotide polymorphisms (SNPs) in ATM (S49C, S707P, F858L, P1054R, L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium (BCAC).
Results
Combining data from all five SNPs, the OR was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR=1.06 (Ptrend=0.04). The trend OR among bilateral and familial cases was 1.12 (95% CI 1.02-1.23; Ptrend=0.02).
Conclusions
In this large combined analysis, these 5 missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer.
Impact
Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility.
doi:10.1158/1055-9965.EPI-10-0374
PMCID: PMC2938473  PMID: 20826828
19.  Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls 
Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Orr, Nick | Ashworth, Alan | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Burwinkel, Barbara | Bartram, Claus R. | Meindl, Alfons | Schmutzler, Rita K. | Cox, Angela | Brock, Ian | Elliott, Graeme | Reed, Malcolm W. R. | Southey, Melissa C. | Smith, Letitia | Spurdle, Amanda B. | Hopper, John L. | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Fredericksen, Zachary | Schürmann, Peter | Waltes, Regina | Bremer, Michael | Dörk, Thilo | Devilee, Peter | van Asperen, Christie J. | Tollenaar, Rob A.E.M. | Seynaeve, Caroline | Hall, Per | Czene, Kamila | Humphreys, Keith | Liu, Jianjun | Ahmed, Shahana | Dunning, Alison M. | Maranian, Melanie | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Beesley, Jonathan | Investigators, kConFab | Group, AOCS | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Zalutsky, Iosif V. | Anton-Culver, Hoda | Ziogas, Argyrios | Brauch, Hiltrud | Ko, Yon-Dschun | Hamann, Ute | Fasching, Peter A. | Strick, Reiner | Ekici, Arif B. | Beckmann, Matthias W. | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | English, Dallas R. | Milne, Roger L. | Benítez, Javier | Arias, José Ignacio | Pita, Guillermo | Nordestgaard, Børge G. | Bojesen, Stig E. | Flyger, Henrik | Kang, Daehee | Yoo, Keun-Young | Noh, Dong Young | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | García-Closas, Montserrat | Chanock, Stephen | Lissowska, Jolanta | Brinton, Louise A. | Chang-Claude, Jenny | Wang- Gohrke, Shan | Broeks, Annegien | Schmidt, Marjanka K | van Leeuwen, Flora E | Van ‘t Veer, Laura J | Margolin, Sara | Lindblom, Annika | Humphreys, Manjeet K. | Morrison, Jonathan | Platte, Radka | Easton, Douglas F. | Peto, Julian
Background
Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious.
Methods
We have genotyped five polymorphic (MAF 0.9% to 2.6%) missense single nucleotide polymorphisms (SNPs) in ATM (S49C, S707P, F858L, P1054R, L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium (BCAC).
Results
Combining data from all five SNPs, the OR was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR=1.06 (Ptrend=0.04). The trend OR among bilateral and familial cases was 1.12 (95% CI 1.02-1.23; Ptrend=0.02).
Conclusions
In this large combined analysis, these 5 missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer.
Impact
Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility.
doi:10.1158/1055-9965.EPI-10-0374
PMCID: PMC2938473  PMID: 20826828
20.  Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32 
Nature genetics  2010;42(8):661-664.
To identify susceptibility loci for non-Hodgkin lymphoma (NHL) subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma (FL) in 1,465 FL cases/6,958 controls at 6p21.32 (rs10484561, rs7755224, r2=1.0; combined p-values=1.12×10-29, 2.00×10-19), providing further support that MHC genetic variation influences FL susceptibility. Confirmatory evidence of a previously reported association was also found between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined p-value=4.24×10-9).
doi:10.1038/ng.626
PMCID: PMC2913472  PMID: 20639881
21.  Genetic variation of ESR1 and its co-activator PPARGC1B is synergistic in augmenting the risk of estrogen receptor-positive breast cancer 
Introduction
Given the role of estrogen in breast carcinogenesis and the modification of estrogen receptor (ER) activity by its biochemical cofactors, we hypothesize that genetic variation within ER cofactor genes alters cellular response to estrogen exposure and consequently modifies the risk for ER-positive breast cancer.
Methods
We genotyped 790 tagging SNPs within 60 ER cofactor genes in 1,257 cases and 1,464 controls from Sweden and in 2,215 cases and 1,265 controls from Finland, and tested their associations with either ER-positive or ER-negative breast cancer.
Results
Seven SNPs showed consistent association with ER-positive breast cancer in the two independent samples, and six of them were located within PPARGC1B, encoding an ER co-activator, with the strongest association at rs741581 (odds ratio = 1.41, P = 4.84 × 10-5) that survived Bonferroni correction for multiple testing in the combined ER-positive breast cancer sample (Pcorrected = 0.03). Moreover, we also observed significant synergistic interaction (Pinteraction = 0.008) between the genetic polymorphisms within PPARGC1B and ESR1 in ER-positive breast cancer. By contrast, no consistent association was observed in ER-negative breast cancer. Furthermore, we found that administration of estrogen in the MCF-7 cell line induced PPARGC1B expression and enhanced occupancies of ER and RNA polymerase II within the region of SNP association, suggesting the upregulation of PPARGC1B expression by ESR1 activation.
Conclusions
Our study revealed that DNA polymorphisms of PPARGC1B, coding a bona fide ER co-activator, are associated with ER-positive breast cancer risk. The feed-forward transcriptional regulatory loop between PPARGC1B and ESR1 further augments their protein interaction, which provides a plausible mechanistic explanation for the synergistic genetic interaction between PPARGC1B and ESR1 in ER-positive breast cancer. Our study also highlights that biochemically and genomically informed candidate gene studies can enhance the discovery of interactive disease susceptibility genes.
doi:10.1186/bcr2817
PMCID: PMC3109578  PMID: 21269472
22.  A genome-wide association scan on estrogen receptor-negative breast cancer 
Introduction
Breast cancer is a heterogeneous disease and may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells. ER status of breast cancer is important clinically, and is used both as a prognostic indicator and treatment predictor. In this study, we focused on identifying genetic markers associated with ER-negative breast cancer risk.
Methods
We conducted a genome-wide association analysis of 285,984 single nucleotide polymorphisms (SNPs) genotyped in 617 ER-negative breast cancer cases and 4,583 controls. We also conducted a genome-wide pathway analysis on the discovery dataset using permutation-based tests on pre-defined pathways. The extent of shared polygenic variation between ER-negative and ER-positive breast cancers was assessed by relating risk scores, derived using ER-positive breast cancer samples, to disease state in independent, ER-negative breast cancer cases.
Results
Association with ER-negative breast cancer was not validated for any of the five most strongly associated SNPs followed up in independent studies (1,011 ER-negative breast cancer cases, 7,604 controls). However, an excess of small P-values for SNPs with known regulatory functions in cancer-related pathways was found (global P = 0.052). We found no evidence to suggest that ER-negative breast cancer shares a polygenic basis to disease with ER-positive breast cancer.
Conclusions
ER-negative breast cancer is a distinct breast cancer subtype that merits independent analyses. Given the clinical importance of this phenotype and the likelihood that genetic effect sizes are small, greater sample sizes and further studies are required to understand the etiology of ER-negative breast cancers.
doi:10.1186/bcr2772
PMCID: PMC3046434  PMID: 21062454
23.  Multi-Variant Pathway Association Analysis Reveals the Importance of Genetic Determinants of Estrogen Metabolism in Breast and Endometrial Cancer Susceptibility 
PLoS Genetics  2010;6(7):e1001012.
Despite the central role of estrogen exposure in breast and endometrial cancer development and numerous studies of genes in the estrogen metabolic pathway, polymorphisms within the pathway have not been consistently associated with these cancers. We posit that this is due to the complexity of multiple weak genetic effects within the metabolic pathway that can only be effectively detected through multi-variant analysis. We conducted a comprehensive association analysis of the estrogen metabolic pathway by interrogating 239 tagSNPs within 35 genes of the pathway in three tumor samples. The discovery sample consisted of 1,596 breast cancer cases, 719 endometrial cancer cases, and 1,730 controls from Sweden; and the validation sample included 2,245 breast cancer cases and 1,287 controls from Finland. We performed admixture maximum likelihood (AML)–based global tests to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three sub-pathways for androgen synthesis, androgen-to-estrogen conversion, and estrogen removal. In the discovery sample, although no single polymorphism was significant after correction for multiple testing, the pathway-based AML global test suggested association with both breast (pglobal = 0.034) and endometrial (pglobal = 0.052) cancers. Further testing revealed the association to be focused on polymorphisms within the androgen-to-estrogen conversion sub-pathway, for both breast (pglobal = 0.008) and endometrial cancer (pglobal = 0.014). The sub-pathway association was validated in the Finnish sample of breast cancer (pglobal = 0.015). Further tumor subtype analysis demonstrated that the association of the androgen-to-estrogen conversion sub-pathway was confined to postmenopausal women with sporadic estrogen receptor positive tumors (pglobal = 0.0003). Gene-based AML analysis suggested CYP19A1 and UGT2B4 to be the major players within the sub-pathway. Our study indicates that the composite genetic determinants related to the androgen–estrogen conversion are important for the induction of two hormone-associated cancers, particularly for the hormone-driven breast tumour subtypes.
Author Summary
Estrogen exposure is the most important risk factor for breast and endometrial cancers. Genetic variation of the genes involved in estrogen metabolism has, however, not been consistently associated with these two cancers. We posited that the genetic risk associated with the estrogen metabolic genes is likely to be carried by multiple variants and is therefore most effectively detected by multi-variant analysis. We carried out a comprehensive association analysis of the estrogen metabolic pathway by interrogating SNPs within 35 genes of the pathway in three tumor samples from Sweden and Finland. Through pathway-based multi-variant association analysis, we showed that the genetic variation within the estrogen metabolic pathway is associated with risk for breast and endometrial cancers and that the genetic variation within the genes involved in androgen-to-estrogen conversion is particularly important for the development of ER–positive and sporadic breast tumors in postmenopausal women. Our study has demonstrated that the influence of genetic variation on hormone exposure has an impact on breast cancer development, especially on the development of hormone-driven breast tumor subtypes. Our study has also highlighted that future genetic studies of the estrogen metabolic genes should focus on the androgen-to-estrogen conversion process.
doi:10.1371/journal.pgen.1001012
PMCID: PMC2895650  PMID: 20617168
24.  Effects of childhood body size on breast cancer tumour characteristics 
Introduction
Although a role of childhood body size in postmenopausal breast cancer risk has been established, less is known about its influence on tumour characteristics.
Methods
We studied the relationships between childhood body size and tumour characteristics in a Swedish population-based case-control study consisting of 2,818 breast cancer cases and 3,111 controls. Our classification of childhood body size was derived from a nine-level somatotype. Relative risks were estimated by odds ratios with 95% confidence intervals, derived from fitting unconditional logistic regression models. Association between somatotype at age 7 and tumour characteristics were evaluated in a case-only analysis where P values for heterogeneity were obtained by performing one degree of freedom trend tests.
Results
A large somatotype at age 7 was found to be associated with decreased postmenopausal breast cancer risk. Although strongly associated with other risk factors such as age of menarche, adult body mass index and mammographic density, somatotype at age 7 remained a significant protective factor (odds ratio (OR) comparing large to lean somatotype at age 7 = 0.73, 95% confidence interval (CI) = 0.58-0.91, P trend = 0.004) after adjustment. The significant protective effect was observed within all subgroups defined by estrogen receptor (ER) and progesterone receptor (PR) status, with a stronger effect for ER-negative (0.40, 95% CI = 0.21-0.75, P trend = 0.002), than for ER-positive (0.80, 95% CI = 0.62-1.05, P trend = 0.062), tumours (P heterogeneity = 0.046). Somatotype at age 7 was not associated with tumour size, histology, grade or the presence or absence of metastatic nodes.
Conclusions
Greater body size at age 7 is associated with a decreased risk of postmenopausal breast cancer, and the associated protective effect is stronger for the ER-negative breast cancer subtype than for the ER-positive subtype.
doi:10.1186/bcr2564
PMCID: PMC2879571  PMID: 20398298
25.  Genetic variation in the estrogen metabolic pathway and mammographic density as an intermediate phenotype of breast cancer 
Introduction
Several studies have examined the effect of genetic variants in genes involved in the estrogen metabolic pathway on mammographic density, but the number of loci studied and the sample sizes evaluated have been small and pathways have not been evaluated comprehensively. In this study, we evaluate the association between mammographic density and genetic variants of the estrogen metabolic pathway.
Methods
A total of 239 SNPs in 34 estrogen metabolic genes were studied in 1,731 Swedish women who participated in a breast cancer case-control study, of which 891 were cases and 840 were controls. Film mammograms of the medio-lateral oblique view were digitalized and the software Cumulus was used for computer-assisted semi-automated thresholding of mammographic density. Generalized linear models controlling for possible confounders were used to evaluate the effects of SNPs on mammographic density. Results found to be nominally significant were examined in two independent populations. The admixture maximum likelihood-based global test was performed to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three subpathways for androgen synthesis, androgen-to-estrogen conversion and estrogen removal.
Results
Genetic variants of genes involved in estrogen metabolism exhibited no appreciable effect on mammographic density. None of the nominally significant findings were validated. In addition, global analyses on the overall estrogen metabolic pathway and its subpathways did not yield statistically significant results.
Conclusions
Overall, there is no conclusive evidence that genetic variants in genes involved in the estrogen metabolic pathway are associated with mammographic density in postmenopausal women.
doi:10.1186/bcr2488
PMCID: PMC2879563  PMID: 20214802

Results 1-25 (43)