Publications by authors named "Peter Kraft"

713 Publications

Risk of Late-Onset Breast Cancer in Genetically Predisposed Women.

J Clin Oncol 2021 Jul 22:JCO2100531. Epub 2021 Jul 22.

Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose: The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years.

Methods: A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs.

Results: The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in , , and were found in 3.42% of women diagnosed with estrogen receptor (ER)-negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in , , , and were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in , , and .

Conclusion: This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with and PVs and perhaps with and PVs should be considered for magnetic resonance imaging screening.
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http://dx.doi.org/10.1200/JCO.21.00531DOI Listing
July 2021

Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies.

Am J Clin Nutr 2021 Jul 13. Epub 2021 Jul 13.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis.

Objectives: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC.

Methods: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs.

Results: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association.

Conclusions: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.
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http://dx.doi.org/10.1093/ajcn/nqab217DOI Listing
July 2021

Obesity, Adiposity, and Risk of Symptomatic Gallstone Disease According to Genetic Susceptibility.

Clin Gastroenterol Hepatol 2021 Jul 2. Epub 2021 Jul 2.

Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background & Aims: Adiposity has been consistently associated with gallstone disease risk. We aimed to characterize associations of anthropometric measures (body mass index [BMI], recent weight change, long-term weight change, waist circumference, and waist-to-hip ratio) with symptomatic gallstone disease according to strata of gallstone disease polygenic risk score (PRS).

Methods: We conducted analysis among 34,626 participants with available genome-wide genetic data within 3 large, prospective, U.S. cohorts-the Nurses' Health Study (NHS), Health Professionals Follow-Up Study, and NHS II. We characterized joint associations of PRS and anthropometric measures and tested for interactions on the relative and absolute risk scales.

Results: Women in the highest BMI and PRS categories (BMI ≥30 kg/m and PRS ≥1 SD above mean) had odds ratio for gallstone disease of 5.55 (95% confidence interval, 5.29 to 5.81) compared with those in the lowest BMI and PRS categories (BMI <25 kg/m and PRS <1 SD below the mean). The corresponding odds ratio among men was 1.65 (95% confidence interval, 1.02 to 2.29). Associations for BMI did not vary within strata of PRS on the relative risk scale. On the absolute risk scale, the incidence rate difference between obese and normal-weight individuals was 1086 per 100,000 person-years within the highest PRS category, compared with 666 per 100,000 person-years in the lowest PRS category, with strong evidence for interaction with the ABCG8 locus.

Conclusions: While maintenance of a healthy body weight reduces gallstone disease risk among all individuals, risk reduction is higher among the subset with greater genetic susceptibility to gallstone disease.
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http://dx.doi.org/10.1016/j.cgh.2021.06.044DOI Listing
July 2021

Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.

Am J Hum Genet 2021 Jul 18;108(7):1190-1203. Epub 2021 Jun 18.

Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10).
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http://dx.doi.org/10.1016/j.ajhg.2021.05.013DOI Listing
July 2021

Risk of Breast Cancer Among Carriers of Pathogenic Variants in Breast Cancer Predisposition Genes Varies by Polygenic Risk Score.

J Clin Oncol 2021 Jun 8:JCO2001992. Epub 2021 Jun 8.

Population Health Sciences Department, Weill Cornell Medicine, New York, NY.

Purpose: This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population.

Methods: A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in , , , , , , , , and . PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor-specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC.

Results: The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of , , and carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of and carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk.

Conclusion: PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of and nearly half of carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.
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http://dx.doi.org/10.1200/JCO.20.01992DOI Listing
June 2021

Multitrait transcriptome-wide association study (TWAS) tests.

Genet Epidemiol 2021 Jun 3. Epub 2021 Jun 3.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Multitrait tests can improve power to detect associations between individual single-nucleotide polymorphisms (SNPs) and several related traits. Here, we develop methods for multi-SNP transcriptome-wide association (TWAS) tests to test the association between predicted gene expression levels and multiple phenotypes. We show that the correlation in TWAS test statistics for multiple phenotypes has the same form as multitrait statistics for the single-SNP setting. Thus, established methods for combining single-SNP test statistics across multiple traits can be extended directly to the TWAS setting. We performed an extensive evaluation across eight multitrait methods in simulations that varied gene-phenotype effect sizes in addition to the underlying covariance structure among the phenotypes. We found that all multitrait TWAS tests have well-calibrated Type I error (except ASSET, which can have a slightly elevated or depressed Type I error rate). Our results show that multitrait TWAS can improve statistical power compared with multiple single-trait TWAS followed by Bonferroni correction. To illustrate our approach to real data, we conducted a multitrait TWAS of four circulating lipid traits from the Global Lipids Genetics Consortium. We found that our multitrait Wald TWAS approach identified 506 genes associated with lipid levels compared with 87 identified through Bonferroni-corrected single-trait TWAS. Overall, we find that our proposed multitrait TWAS framework outperforms single-trait approaches to identify new genetic associations, especially for functionally correlated phenotypes and phenotypes with overlapping genome-wide association studies samples, leading to insights into the genetic architecture of multiple phenotypes.
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http://dx.doi.org/10.1002/gepi.22391DOI Listing
June 2021

Leveraging expression from multiple tissues using sparse canonical correlation analysis and aggregate tests improves the power of transcriptome-wide association studies.

PLoS Genet 2021 Apr 8;17(4):e1008973. Epub 2021 Apr 8.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.

Transcriptome-wide association studies (TWAS) test the association between traits and genetically predicted gene expression levels. The power of a TWAS depends in part on the strength of the correlation between a genetic predictor of gene expression and the causally relevant gene expression values. Consequently, TWAS power can be low when expression quantitative trait locus (eQTL) data used to train the genetic predictors have small sample sizes, or when data from causally relevant tissues are not available. Here, we propose to address these issues by integrating multiple tissues in the TWAS using sparse canonical correlation analysis (sCCA). We show that sCCA-TWAS combined with single-tissue TWAS using an aggregate Cauchy association test (ACAT) outperforms traditional single-tissue TWAS. In empirically motivated simulations, the sCCA+ACAT approach yielded the highest power to detect a gene associated with phenotype, even when expression in the causal tissue was not directly measured, while controlling the Type I error when there is no association between gene expression and phenotype. For example, when gene expression explains 2% of the variability in outcome, and the GWAS sample size is 20,000, the average power difference between the ACAT combined test of sCCA features and single-tissue, versus single-tissue combined with Generalized Berk-Jones (GBJ) method, single-tissue combined with S-MultiXcan, UTMOST, or summarizing cross-tissue expression patterns using Principal Component Analysis (PCA) approaches was 5%, 8%, 5% and 38%, respectively. The gain in power is likely due to sCCA cross-tissue features being more likely to be detectably heritable. When applied to publicly available summary statistics from 10 complex traits, the sCCA+ACAT test was able to increase the number of testable genes and identify on average an additional 400 additional gene-trait associations that single-trait TWAS missed. Our results suggest that aggregating eQTL data across multiple tissues using sCCA can improve the sensitivity of TWAS while controlling for the false positive rate.
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http://dx.doi.org/10.1371/journal.pgen.1008973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057593PMC
April 2021

Evaluation of a Multiethnic Polygenic Risk Score Model for Prostate Cancer.

J Natl Cancer Inst 2021 Apr 1. Epub 2021 Apr 1.

Urology Division, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Polygenic risk scores (PRS) of common genetic variants have shown promise in prostate cancer risk stratification, but their validity across populations has yet to be confirmed. We evaluated a multiethnic PRS model based on 269 germline genetic risk variants (261 were available for analysis) using an independent population of 13,628 U.S. men. The PRS was strongly associated with prostate cancer, but not with any other disease. Comparing men in the top PRS decile to those at average risk (40%-60%), the odds ratio of prostate cancer was 3.89 (95% confidence interval = 3.24 to 4.68) for men of European ancestry and 3.81 (95% confidence interval = 1.48 to 10.19) for men of African ancestry. By age 85, the cumulative incidence of prostate cancer for European American men was 7.1% in the bottom and 54.1% in the top decile. This suggests that the PRS can be used to identify a substantial proportion of men at high risk for prostate cancer.
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http://dx.doi.org/10.1093/jnci/djab058DOI Listing
April 2021

Prospective evaluation of a breast-cancer risk model integrating classical risk factors and polygenic risk in 15 cohorts from six countries.

Int J Epidemiol 2021 Mar 23. Epub 2021 Mar 23.

Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.

Background: Rigorous evaluation of the calibration and discrimination of breast-cancer risk-prediction models in prospective cohorts is critical for applications under clinical guidelines. We comprehensively evaluated an integrated model incorporating classical risk factors and a 313-variant polygenic risk score (PRS) to predict breast-cancer risk.

Methods: Fifteen prospective cohorts from six countries with 239 340 women (7646 incident breast-cancer cases) of European ancestry aged 19-75 years were included. Calibration of 5-year risk was assessed by comparing expected and observed proportions of cases overall and within risk categories. Risk stratification for women of European ancestry aged 50-70 years in those countries was evaluated by the proportion of women and future cases crossing clinically relevant risk thresholds.

Results: Among women <50 years old, the median (range) expected-to-observed ratio for the integrated model across 15 cohorts was 0.9 (0.7-1.0) overall and 0.9 (0.7-1.4) at the highest-risk decile; among women ≥50 years old, these were 1.0 (0.7-1.3) and 1.2 (0.7-1.6), respectively. The proportion of women identified above a 3% 5-year risk threshold (used for recommending risk-reducing medications in the USA) ranged from 7.0% in Germany (∼841 000 of 12 million) to 17.7% in the USA (∼5.3 of 30 million). At this threshold, 14.7% of US women were reclassified by adding the PRS to classical risk factors, with identification of 12.2% of additional future cases.

Conclusion: Integrating a 313-variant PRS with classical risk factors can improve the identification of European-ancestry women at elevated risk who could benefit from targeted risk-reducing strategies under current clinical guidelines.
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http://dx.doi.org/10.1093/ije/dyab036DOI Listing
March 2021

Prediagnostic Inflammation and Pancreatic Cancer Survival.

J Natl Cancer Inst 2021 Mar 19. Epub 2021 Mar 19.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.

Background: Chronic inflammation may promote initiation and progression of pancreatic cancer, but no studies have examined the association between inflammation in the period before diagnosis and pancreatic cancer survival.

Methods: We prospectively examined the association of prediagnostic plasma levels of C-reactive protein, interleukin-6, and tumor necrosis factor-α receptor 2 with survival among 492 participants from 5 large US prospective cohort studies who developed pancreatic cancer. Using an empirical dietary inflammatory pattern (EDIP) score, we evaluated whether long-term proinflammatory diets were associated with survival among 1153 patients from 2 of the 5 cohorts. Cox proportional hazards regression was used to estimate hazard ratios for death with adjustment for potential confounders.

Results: Higher prediagnostic levels of C-reactive protein, interleukin-6, and tumor necrosis factor-α receptor 2 were individually associated with reduced survival (Ptrend = .03, .01, and .04, respectively). Compared to patients with a combined inflammatory biomarker score of 0 (all 3 markers levels below medians), those with a score of 3 (all 3 markers levels above medians) had a hazard ratio for death of 1.57 (95% confidence interval = 1.16 to 2.12; Ptrend = .003), corresponding to median overall survival times of 8 versus 5 months. Patients consuming the most proinflammatory diets (EDIP quartile 4) in the prediagnostic period had a hazard ratio for death of 1.34 (95% confidence interval = 1.13 to 1.59; Ptrend = .01), compared to those consuming the least proinflammatory diets (EDIP quartile 1).

Conclusion: Prediagnostic levels of inflammatory biomarkers and long-term proinflammatory diets were inversely associated with pancreatic cancer survival.
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http://dx.doi.org/10.1093/jnci/djab040DOI Listing
March 2021

Estimating the effective sample size in association studies of quantitative traits.

G3 (Bethesda) 2021 Mar 18. Epub 2021 Mar 18.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

The effective sample size (ESS) is a metric used to summarize in a single term the amount of correlation in a sample. It is of particular interest when predicting the statistical power of genome-wide association studies (GWAS) based on linear mixed models. Here, we introduce an analytical form of the ESS for mixed-model GWAS of quantitative traits and relate it to empirical estimators recently proposed. Using our framework, we derived approximations of the ESS for analyses of related and unrelated samples and for both marginal genetic and gene-environment interaction tests. We conducted simulations to validate our approximations and to provide a quantitative perspective on the statistical power of various scenarios, including power loss due to family relatedness and power gains due to conditioning on the polygenic signal. Our analyses also demonstrate that the power of gene-environment interaction GWAS in related individuals strongly depends on the family structure and exposure distribution. Finally, we performed a series of mixed-model GWAS on data from the UK Biobank and confirmed the simulation results. We notably found that the expected power drop due to family relatedness in the UK Biobank is negligible.
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http://dx.doi.org/10.1093/g3journal/jkab057DOI Listing
March 2021

Improving reporting standards for polygenic scores in risk prediction studies.

Nature 2021 03 10;591(7849):211-219. Epub 2021 Mar 10.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical applications for the estimation of disease risk using genetics. However, there is notable heterogeneity in the application and reporting of these risk scores, which hinders the translation of PRSs into clinical care. Here, in a collaboration between the Clinical Genome Resource (ClinGen) Complex Disease Working Group and the Polygenic Score (PGS) Catalog, we present the Polygenic Risk Score Reporting Standards (PRS-RS), in which we update the Genetic Risk Prediction Studies (GRIPS) Statement to reflect the present state of the field. Drawing on the input of experts in epidemiology, statistics, disease-specific applications, implementation and policy, this comprehensive reporting framework defines the minimal information that is needed to interpret and evaluate PRSs, especially with respect to downstream clinical applications. Items span detailed descriptions of study populations, statistical methods for the development and validation of PRSs and considerations for the potential limitations of these scores. In addition, we emphasize the need for data availability and transparency, and we encourage researchers to deposit and share PRSs through the PGS Catalog to facilitate reproducibility and comparative benchmarking. By providing these criteria in a structured format that builds on existing standards and ontologies, the use of this framework in publishing PRSs will facilitate translation into clinical care and progress towards defining best practice.
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http://dx.doi.org/10.1038/s41586-021-03243-6DOI Listing
March 2021

Genome-wide association study in almost 195,000 individuals identifies 50 previously unidentified genetic loci for eye color.

Sci Adv 2021 Mar 10;7(11). Epub 2021 Mar 10.

Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.

Human eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.
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http://dx.doi.org/10.1126/sciadv.abd1239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946369PMC
March 2021

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

Nat Commun 2021 02 24;12(1):1258. Epub 2021 Feb 24.

Faculty of Medicine, University of Southampton, Southampton, UK.

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.
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http://dx.doi.org/10.1038/s41467-020-20851-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904932PMC
February 2021

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Nat Commun 2021 02 17;12(1):1078. Epub 2021 Feb 17.

Copenhagen General Population Study, Herlev and Gentofte Hospital Copenhagen University Hospital, Herlev, Denmark.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
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http://dx.doi.org/10.1038/s41467-020-20496-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890067PMC
February 2021

Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3.

Cancer Res 2021 Jun 11;81(11):3134-3143. Epub 2021 Feb 11.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and < 5 × 10 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, = 3.08 × 10). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 ( = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178175PMC
June 2021

The Use Of Genetic Correlation And Mendelian Randomization Studies To Increase Our Understanding of Relationships Between Complex Traits.

Curr Epidemiol Rep 2020 Jun 16;7(2):104-112. Epub 2020 May 16.

Department of Epidemiology, University of Washington, Seattle, WA.

Purpose Of The Review: Increasing access to large-scale genetic datasets in population-based studies allows for genetic association studies as a means to examine previously known and novel relationships among complex traits. In this review, we discuss two widely used approaches to leverage genetic data to study the links between traits: Genome-wide genetic correlation and Mendelian Randomization (MR) studies.

Recent Findings: Both genetic correlation and MR studies have provided important novel insights. However, although they are less sensitive to many sources of bias present in traditional, observational epidemiology, they still rely on assumptions that in practice might be difficult to assess. To overcome this, development of novel methods less sensitive to these assumptions is an active area of research.

Summary: We believe that as population-based genetic datasets grow larger and novel methods allowing for weaker forms of current assumptions become available, genetic correlation and MR studies will become an integral part of genetic epidemiology studies.
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http://dx.doi.org/10.1007/s40471-020-00233-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863746PMC
June 2020

Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium.

Cancer Epidemiol Biomarkers Prev 2021 Apr 26;30(4):623-642. Epub 2021 Jan 26.

Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype.

Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.

Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype ( > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking.

Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype.

Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026532PMC
April 2021

Temporal changes in total and hippocampal brain volume and cognitive function in patients with chronic heart failure-the COGNITION.MATTERS-HF cohort study.

Eur Heart J 2021 04;42(16):1569-1578

Comprehensive Heart Failure Center Würzburg, University and University Hospital Würzburg, Am Schwarzenberg 15, 97078 Würzburg, Germany.

Aims: We quantified the concurring dynamics affecting total and hippocampal brain volume and cognitive function in patients with chronic heart failure (HF) over a period of three years.

Methods And Results: A total of 148 patients with mild stable HF entered this monocentric prospective cohort study: mean age 64.5 (10.8) years; 16.2% female; 77% in New York Heart Association functional classes I-II; 128 and 105 patients attended follow-up visits after 1 and 3 years, respectively. The assessment included cardiological, neurological, psychological work-up, and brain magnetic resonance imaging. Total and regional brain volumes were quantified using an operator-independent fully automated approach and reported normalized to the mean estimated intracranial volume. At baseline, the mean hippocampal volume was ∼13% lower than expected. However, the 3-year progressive hippocampal volume loss was small: -62 mm3 [95% confidence interval (CI) -81 to -42, P < 0.0001). This corresponded to a relative change of -1.8% (95% CI -2.3 to -1.2), which was similar in magnitude as observed with physiological aging. Moreover, the load of white matter hypointensities increased within the limits of normal aging. Cognitive function during the 3-year observation period remained stable, with 'intensity of attention' as the only domain declining (LSmean -1.82 points, 95% CI -3.05 to -0.58, P = 0.004). After 3 years, performance in all domains of cognition remained associated with hippocampal volume (r ≥ 0.29).

Conclusion: In patients with predominantly mild HF, the markedly reduced hippocampal volume observed at baseline was associated with impaired cognitive function, but no accelerated deterioration in cognition and brain atrophy became evident over a mid-term period of three years.
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http://dx.doi.org/10.1093/eurheartj/ehab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060058PMC
April 2021

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers.

Br J Cancer 2021 02 26;124(4):842-854. Epub 2021 Jan 26.

Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.

Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.

Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10).

Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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http://dx.doi.org/10.1038/s41416-020-01185-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884683PMC
February 2021

A Genome-Wide Association Study of Childhood Body Fatness.

Obesity (Silver Spring) 2021 02;29(2):446-453

Department of Epidemiology, University of Washington, Seattle, Washington, USA.

Objective: This study aimed to uncover genetic contributors to adiposity in early life.

Methods: A genome-wide association study of childhood body fatness in 34,401 individuals within the Nurses' Health Studies and the Health Professionals Follow-up Study was conducted. Data were imputed to the 1000 Genomes Phase 3 version 5 reference panel.

Results: A total of 1,354 single-nucleotide polymorphisms (P < 10 ) were selected for replication in a previously published genome-wide association study of childhood BMI. Nineteen significant genome-wide (P < 5 × 10 ) regions were observed, fourteen of which were previously associated with childhood obesity and five were novel: BNDF (P = 7.58 × 10 ), PRKD1 (P = 1.43 × 10 ), 20p13 (P = 2.05 × 10 ), FHIT (P = 1.77 × 10 ), and LOC101927575 (P = 3.22 × 10 ). The BNDF, FHIT, and PRKD1 regions were previously associated with adult BMI. LOC101927575 and 20p13 regions have not previously been associated with adiposity phenotypes. In a transcriptome-wide analysis, associations for POMC at 2p23.3 (P = 3.36 × 10 ) and with TMEM18 at 2p25.3 (P = 3.53 × 10 ) were observed. Childhood body fatness was genetically correlated with hip (r = 0.42, P = 4.44 × 10 ) and waist circumference (r = 0.39, P = 5.56 × 10 ), as well as age at menarche (r = -0.37, P = 7.96 × 10 ).

Conclusions: Additional loci that contribute to childhood adiposity were identified, further explicating its genetic architecture.
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http://dx.doi.org/10.1002/oby.23070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842657PMC
February 2021

A Population-Based Study of Genes Previously Implicated in Breast Cancer.

N Engl J Med 2021 02 20;384(5):440-451. Epub 2021 Jan 20.

From Mayo Clinic, Rochester, MN (C. Hu, S.N.H., R.G., K.Y.L., J.N., J.L., S. Yadav, N.J.B., T.L., J.E.O., C.S., C.M.V., E.C.P., F.J.C.); Harvard University T.H. Chan School of Public Health (H.H., C.G., D.J.H., P.K.), Slone Epidemiology Center at Boston University (K.A.B., J.R.P., L.R.), and Brigham and Women's Hospital (H.E.) - all in Boston; Qiagen, Hilden, Germany (R.S., J.K.); Roswell Park Comprehensive Cancer Center, Buffalo (C.B.A., S. Yao), and Weill Cornell Medicine, New York (R.T.) - both in New York; the University of California, Irvine (H.A.-C., A.Z.), Beckman Research Institute of City of Hope, Duarte (L.B., H.M., S.N., J.N.W.), Keck School of Medicine, University of Southern California, Los Angeles (C. Haiman), and Stanford University School of Medicine, Stanford (E.M.J., A.W.K.) - all in California; the University of Wisconsin-Milwaukee Joseph J. Zilber School of Public Health, Milwaukee (P.A.), and the University of Wisconsin-Madison, Madison (E.S.B., I.M.O., A.T.-D.); the Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, State University of New Jersey, New Brunswick (E.V.B.); the Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta (B.D.C., S.M.G., M.G., J.M.H., E.J.J., A.V.P.); the University of Oxford, Oxford, United Kingdom (D.J.H.); the Fred Hutchinson Cancer Research Center (C.K., P.A.N.) and the Department of Epidemiology, University of Washington (S.L.) - both in Seattle; the Epidemiology Program, University of Hawaii Cancer Center, Honolulu (L.L.M.); the National Institute of Environmental Health Sciences, Durham, NC (K.M.O., D.P.S., J.A.T., C.W.); Vanderbilt University, Nashville (T.P., S.R.); the University of Utah, Salt Lake City (D.E.G.); and the Department of Medicine and the Basser Center for BRCA, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (S.M.D., K.L.N.).

Background: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants.

Methods: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed.

Results: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in and were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in , , and were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in , , and were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in , were not associated with an increased risk of breast cancer.

Conclusions: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).
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http://dx.doi.org/10.1056/NEJMoa2005936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127622PMC
February 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

Prevalence and determinants of systolic and diastolic cardiac dysfunction and heart failure in acute ischemic stroke patients: The SICFAIL study.

ESC Heart Fail 2021 04 22;8(2):1117-1129. Epub 2020 Dec 22.

Department of Neurology, University Hospital Essen, Essen, Germany.

Aims: Ischaemic stroke (IS) might induce alterations of cardiac function. Prospective data on frequency of cardiac dysfunction and heart failure (HF) after IS are lacking. We assessed prevalence and determinants of diastolic dysfunction (DD), systolic dysfunction (SD), and HF in patients with acute IS.

Methods And Results: The Stroke-Induced Cardiac FAILure in mice and men (SICFAIL) study is a prospective, hospital-based cohort study. Patients with IS underwent a comprehensive assessment of cardiac function in the acute phase (median 4 days after IS) including clinical examination, standardized transthoracic echocardiography by expert sonographers, and determination of blood-based biomarkers. Information on demographics, lifestyle, risk factors, symptoms suggestive of HF, and medical history was collected by a standardized personal interview. Applying current guidelines, cardiac dysfunction was classified based on echocardiographic criteria into SD (left ventricular ejection fraction < 52% in men or <54% in women) and DD (≥3 signs of DD in patients without SD). Clinically overt HF was classified into HF with reduced, mid-range, or preserved ejection fraction. Between January 2014 and February 2017, 696 IS patients were enrolled. Of them, patients with sufficient echocardiographic data on SD were included in the analyses {n = 644 patients [median age 71 years (interquartile range 60-78), 61.5% male]}. In these patients, full assessment of DD was feasible in 549 patients without SD (94%). Prevalence of cardiac dysfunction and HF was as follows: SD 9.6% [95% confidence interval (CI) 7.6-12.2%]; DD in patients without SD 23.3% (95% CI 20.0-27.0%); and clinically overt HF 5.4% (95% CI 3.9-7.5%) with subcategories of HF with preserved ejection fraction 4.35%, HF with mid-range ejection fraction 0.31%, and HF with reduced ejection fraction 0.78%. In multivariable analysis, SD and fulfilment of HF criteria were associated with history of coronary heart disease [SD: odds ratio (OR) 3.87, 95% CI 1.93-7.75, P = 0.0001; HF: OR 2.29, 95% CI 1.04-5.05, P = 0.0406] and high-sensitive troponin T at baseline (SD: OR 1.78, 95% CI 1.31-2.42, P = 0.0003; HF: OR 1.66, 95% CI 1.17-2.33, P = 0.004); DD was associated with older age (OR 1.08, 95% CI 1.05-1.11, P < 0.0001) and treated hypertension vs. no hypertension (OR 2.84, 95% CI 1.23-6.54, P = 0.0405).

Conclusions: A substantial proportion of the study population exhibited subclinical and clinical cardiac dysfunction. SICFAIL provides reliable data on prevalence and determinants of SD, DD, and clinically overt HF in patients with acute IS according to current guidelines, enabling further clarification of its aetiological and prognostic role.
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http://dx.doi.org/10.1002/ehf2.13145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006617PMC
April 2021

Number of Patients with Ischemic Stroke did not Decline in a Regional Stroke Unit After the Implementation of Mechanical Thrombectomy.

J Stroke Cerebrovasc Dis 2021 Feb 8;30(2):105498. Epub 2020 Dec 8.

Department of Neurology, Hospital Main-Spessart, Grafen-von-Rieneck-Str. 5, 97816 Lohr, Germany; Department of Neurology, University Clinic Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany. Electronic address:

Objectives: Since the implementation of mechanical thrombectomy (MT) in 2015 for patients with ischemic stroke and large-vessel occlusion, the question arose as to whether patients should be primarily admitted to the nearest regional stroke unit (SU) for prompt intravenous thrombolysis (IVT) or to a more distant supraregional SU performing MT, to avoid secondary-transfer delays in MT. Although an evidence-based answer is still lacking, a discrepant discussion with potential consequences for the regional flow of stroke patients arose. We aimed to assess if MT implementation was associated with the number and characteristics of patients with stroke/transient ischemic attack (TIA) admitted to a regional SU not offering endovascular treatment.

Materials And Methods: Patients with acute stroke/TIA treated at the Klinikum Main-Spessart Lohr, Germany, in 2013/2014 or 2017/2018 were included in this retrospective study. Data were derived from the clinical information system and mandatory stroke quality assessment. We assessed the catchment area using a region-based approach. For each region, the number of patients treated in our hospital, including data regarding clinical severity, demographic characteristics, and changes over time, were analyzed.

Results: The number of patients with acute stroke/TIA increased from 890 (2013/2014) to 1016 (2017/2018). Aggregated demographic and clinical data of the whole catchment area showed no differences between 2013/2014 and 2017/2018 (P > 0.05) besides duration of hospitalization (P < 0.01), IVT rate (P < 0.01), and secondary transfer for MT. A region-based analysis revealed an increase in younger and more severely affected patients admitted from the periphery of the catchment area between 2013/2014 and 2017/2018.

Conclusion: Despite the implementation of MT in the supraregional SUs around our regional SU (not offering MT), more patients with stroke/TIA were admitted to our hospital, especially younger and more severely affected patients, from the border regions of the catchment area.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105498DOI Listing
February 2021

The NLRP3 inflammasome drives inflammation in ischemia/reperfusion injury after transient middle cerebral artery occlusion in mice.

Brain Behav Immun 2021 02 9;92:223-233. Epub 2020 Dec 9.

Department of Neurology, University Hospital Würzburg, Josef-Schneider-Straße 11, 97080 Würzburg, Germany. Electronic address:

Purpose: Cerebral ischemia induces a profound neuro-inflammatory response, but the underlying molecular mechanisms are poorly understood. Inflammasomes (NLRP1, NLRP3, NLRC4, AIM2) are intracellular multi-protein complexes which can induce sets of pro-inflammatory cyto- and chemokines, and thereby guide inflammation. We, here, assessed the functional role of NLRP3 in ischemia/reperfusion (I/R) injury in a mouse model of transient cerebral ischemia.

Methods: Ischemic stroke was induced in C57Bl/6 mice by 60 min transient middle cerebral artery occlusion (tMCAO) and 3, 7 or 23 h of reperfusion, a paradigm of I/R injury. The expression patterns of inflammasomes in the ischemic hemispheres were evaluated by semiquantitative real-time PCR and Western Blot analysis accompanied by protein localization using immunocytochemistry. Finally, animals were treated with the inflammasome inhibitors Sulforaphane, Genipin, MCC950 or vehicle, directly before or upon recanalization after tMCAO. Stroke outcome was assessed, including infarct size and functional deficits, local inflammatory response, neuronal survival as well as blood-brain barrier function on day 1 after tMCAO.

Results: After tMCAO the relative gene expression levels of NLRP3 increased 20-30x within 1 day in the ischemic hemisphere which translated into an increased expression of NLRP3 in neurons. Accordingly, the gene expression levels of the NLRP3-modulator, Bruton's Tyrosine Kinase (BTK), and the NLRP3-inducible cytokine IL-1β significantly rose. Lesser or non-significant changes were seen for the other inflammasomes. Application of inflammasome inhibitors covering all inflammasomes or specifically NLRP3 significantly reduced infarct volumes when given before or after tMCAO and was accompanied by clear evidence for reduced activation of caspase 1. This stroke attenuating effect coincided with less immune cell infiltration in the ischemic hemisphere and preservation of the blood-brain barrier integrity.

Conclusions: Our data show that induction of the NLRP3 inflammasome in neurons drives neuroinflammation in acute ischemic stroke. Early blockade of NLRP3 protects from I/R injury by mitigating inflammation and stabilizing the blood-brain barrier.
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http://dx.doi.org/10.1016/j.bbi.2020.12.009DOI Listing
February 2021

Simplified Breast Risk Tool Integrating Questionnaire Risk Factors, Mammographic Density, and Polygenic Risk Score: Development and Validation.

Cancer Epidemiol Biomarkers Prev 2021 Apr 4;30(4):600-607. Epub 2020 Dec 4.

Alvin J. Siteman Cancer Center and Department of Surgery, Division of Public Health Sciences, School of Medicine, Washington University in St. Louis, St. Louis, Missouri.

Background: Clinical use of breast cancer risk prediction requires simplified models. We evaluate a simplified version of the validated Rosner-Colditz model and add percent mammographic density (MD) and polygenic risk score (PRS), to assess performance from ages 45-74. We validate using the Mayo Mammography Health Study (MMHS).

Methods: We derived the model in the Nurses' Health Study (NHS) based on: MD, 77 SNP PRS and a questionnaire score (QS; lifestyle and reproductive factors). A total of 2,799 invasive breast cancer cases were diagnosed from 1990-2000. MD (using Cumulus software) and PRS were assessed in a nested case-control study. We assess model performance using this case-control dataset and evaluate 10-year absolute breast cancer risk. The prospective MMHS validation dataset includes 21.8% of women age <50, and 434 incident cases identified over 10 years of follow-up.

Results: In the NHS, MD has the highest odds ratio (OR) for 10-year risk prediction: OR = 1.48 [95% confidence interval (CI): 1.31-1.68], followed by PRS, OR = 1.37 (95% CI: 1.21-1.55) and QS, OR = 1.25 (95% CI: 1.11-1.41). In MMHS, the AUC adjusted for age + MD + QS 0.650; for age + MD + QS + PRS 0.687, and the NRI was 6% in cases and 16% in controls.

Conclusion: A simplified assessment of QS, MD, and PRS performs consistently to discriminate those at high 10-year breast cancer risk.

Impact: This simplified model provides accurate estimation of 10-year risk of invasive breast cancer that can be used in a clinical setting to identify women who may benefit from chemopreventive intervention..
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026588PMC
April 2021

Circulating carotenoids and breast cancer among high-risk individuals.

Am J Clin Nutr 2021 03;113(3):525-533

Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.

Background: Carotenoids represent 1 of few modifiable factors to reduce breast cancer risk. Elucidation of interactions between circulating carotenoids and genetic predispositions or mammographic density (MD) may help inform more effective primary preventive strategies in high-risk populations.

Objectives: We tested whether women at high risk for breast cancer due to genetic predispositions or high MD would experience meaningful and greater risk reduction from higher circulating levels of carotenoids in a nested case-control study in the Nurses' Health Studies (NHS and NHSII).

Methods: This study included 1919 cases and 1695 controls in a nested case-control study in the NHS and NHSII. We assessed both multiplicative and additive interactions. RR reductions and 95% CIs were calculated using unconditional logistic regressions, adjusting for matching factors and breast cancer risk factors. Absolute risk reductions (ARR) were calculated based on Surveillance, Epidemiology, and End Results incidence rates.

Results: We showed that compared with women at low genetic risk or low MD, those with higher genetic risk scores or high MD had greater ARRs for breast cancer as circulating carotenoid levels increase (additive P-interaction = 0.05). Among women with a high polygenic risk score, those in the highest quartile of circulating carotenoids had a significant ARR (28.6%; 95% CI, 14.8-42.1%) compared to those in the lowest quartile of carotenoids. For women with a high percentage MD (≥50%), circulating carotenoids were associated with a 37.1% ARR (95% CI, 21.7-52.1%) when comparing the highest to the lowest quartiles of circulating carotenoids.

Conclusions: The inverse associations between circulating carotenoids and breast cancer risk appeared to be more pronounced in high-risk women, as defined by germline genetic makeup or MD.
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http://dx.doi.org/10.1093/ajcn/nqaa316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948839PMC
March 2021
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