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- Dixon-Suen, Suzanne C, et al.
(author)
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Physical activity, sedentary time and breast cancer risk : a Mendelian randomisation study
- 2022
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In: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 56:20, s. 1157-1170
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Journal article (peer-reviewed)abstract
- OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.
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- Saevarsdottir, S., et al.
(author)
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Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
- 2022
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:8
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Journal article (peer-reviewed)abstract
- Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
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- Ahearn, Thomas U., et al.
(author)
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Common variants in breast cancer risk loci predispose to distinct tumor subtypes
- 2022
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In: Breast Cancer Research. - : Springer Nature. - 1465-5411 .- 1465-542X. ; 24:1
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Journal article (peer-reviewed)abstract
- BackgroundGenome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.MethodsAmong 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.ResultsEighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.ConclusionThis report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
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- Dennis, J, et al.
(author)
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Rare germline copy number variants (CNVs) and breast cancer risk
- 2022
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In: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 65-
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Journal article (peer-reviewed)abstract
- Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E−18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.
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- McDonald, C. M., et al.
(author)
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Ataluren delays loss of ambulation and respiratory decline in nonsense mutation Duchenne muscular dystrophy patients
- 2022
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In: Journal of Comparative Effectiveness Research. - : Becaris Publishing Limited. - 2042-6305 .- 2042-6313. ; 11:3
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Journal article (peer-reviewed)abstract
- Aim: We investigated the effect of ataluren plus standard of care (SoC) on age at loss of ambulation (LoA) and respiratory decline in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) versus patients with DMD on SoC alone. Patients & methods: Study 019 was a long-term Phase III study of ataluren safety in nmDMD patients with a history of ataluren exposure. Propensity score matching identified Study 019 and CINRG DNHS patients similar in disease progression predictors. Results & conclusion: Ataluren plus SoC was associated with a 2.2-year delay in age at LoA (p = 0.0006), and a 3.0-year delay in decline of predicted forced vital capacity to <60% in nonambulatory patients (p = 0.0004), versus SoC. Ataluren plus SoC delays disease progression and benefits ambulatory and nonambulatory patients with nmDMD. ClinicalTrials.gov: .
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- Seidler, Y, et al.
(author)
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KNOWING WHAT TO DO WITH THE DATA - A QUALITATIVE STUDY ON CHALLENGES OF USING SMARTPHONE-BASED EPROS IN RHEUMATOID ARTHRITIS
- 2022
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In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 1081-1081
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Conference paper (other academic/artistic)abstract
- Using patient-reported outcomes (PROs) has a long tradition in rheumatology, and PRO measurement is included in many composite indices evaluating disease progression and treatment response [1]. However, little is known about patients´ and health professionals´ (HPs) perceptions of using digitally collected PROs, the so-called ePROs, with a personal smartphone app.ObjectivesTo identify main challenges in utilising ePROs for management and treatment of rheumatoid arthritis from patients’ and HPs’ perspectives.MethodsWe interviewed 25 people with rheumatoid arthritis (RA) and 17 HPs (nurses, rheumatologists, and physiotherapists) from Austria and Denmark. We used the RheumaBuddy app as a practical example to illustrate the digital data collection and the feedback that patients would get from entering their self-reported outcomes. Interviews were recorded and transcribed. We applied a qualitative thematic analysis to identify major themes using a procedure of rigorous coding. Analysis was done by two researchers, and conflicts were solved by consensus. Ethical approval was obtained in both countries.ResultsThree main themes emerged: 1) Being simple yet comprehensive; 2) Resources to interpret, use and act upon the collected data; and 3) Being reminded of the disease. Within the first theme, many valued the intuitiveness and simplicity of ePROs, especially when used as a monitoring tool in between clinical visits. HPs were concerned about not to overwhelm the patients with too many questions. On the other hand, the short ePROs asked in the app were not comprehensive enough to capture psychosocial and lifestyle aspects of the disease which were considered important both by patients and HPs. Within the second theme, patients and HPs expressed that ePROs could be the basis for shared decision making. Nevertheless, some patients had clearer ideas on making use of the feedback they could get from their self-reported data than the others. Participants from Denmark, who experienced a higher level of digital health maturity in official institutions, expressed more proactive use of the data than participants from Austria who were on average younger than their Danish counterparts. One patient in Austria even asserted having no idea what to do with the collected data but believed that the “doctor will make good use of it”. HPs in both countries, however, indicated that they needed more resources, skills, and time to make sense of the ePRO data and act accordingly. Under the third theme, patients considered the collection of ePROs to be very important when pain and disease activity were high. HPs, on the other hand, were more concerned that the regular collection of ePROs might constantly remind patients that they are living with the disease.ConclusionThe potential adoption of ePROs in practice depends on both patients and HPs’ motivations and ideas to use the feedback they would get from the collected data. This might be influenced by the level of digital health maturity of a country, as well as available resources. In addition, ePROs need to be intuitive and simple, but at the same time comprehensive and reliable enough so that they can be used for shared decision making. Challenges remain for the ePROs to be used as supporting and empowering tools, and not as reminders of the disease and pain.Table 1.Demographic data of the participants (N=42)DemographicAustriaDenmarkTotalDataPatientHPPatientHPPatientHPN14101172517Women (%)10(71)6(60)7(64)5(71)17(68)11(65)Men (%)4(29)4(40)4(36)2(29)8(32)6(35)AgeMean (Range)54(30-76)41(29-63)65(37-77)47(31-59)60(30-77)44(29-63)References[1]T Stamm, I Parodis, and P Studenic. Patient-reported outcomes with anifrolumab in patients with systemic lupus erythematosus, Lancet Rheumatol, (2022), in Press.AcknowledgementsWe would like to express our particular thank you to all those who have taken part in the interview study and for their valuable inputs.Disclosure of InterestsYuki Seidler: None declared, Tanja Schjødt Jørgensen Speakers bureau: AbbVie, Pfizer, Roche, Novartis, UCB, Biogen and Eli Lilly., Consultant of: AbbVie, Pfizer, Roche, Novartis, UCB, Biogen and Eli Lilly, Paul Studenic: None declared, Helga Radner Speakers bureau: Gilead, Merck Sharp, Pfizer, Abbvie, Consultant of: Gilead, Merck Sharp, Pfizer, Abbvie, Thomas Nygaard: None declared, Nadine Weibrecht: None declared, Nikolas Popper Speakers bureau: Roche, Consultant of: dwh GmbH (as CSO), Lars Erik Kristensen Speakers bureau: Pfizer, AbbVie, Amgen, UCB, Gilead, Biogen, BMS, MSD, Novartis, Eli Lilly, and Janssen pharmaceuticals, Consultant of: Pfizer, AbbVie, Amgen, UCB, Gilead, Biogen, BMS, MSD, Novartis, Eli Lilly, and Janssen pharmaceuticals, Grant/research support from: IIT research grants from Novo, UCB, Eli Lilly; Novartis and Abbvie, Tanita-Christina Wilhelmer: None declared, James Rickmann: None declared, Erika Mosor: None declared, Valentin Ritschl: None declared, Tanja Stamm Speakers bureau: AbbVie, Novartis, Roche, Sanofi, and Takeda., Consultant of: AbbVie and Sanofi Genzyme., Grant/research support from: AbbVie and Roche.
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