| 1. |
- Escala-Garcia, Maria, et al.
(författare)
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A network analysis to identify mediators of germline-driven differences in breast cancer prognosis
- 2020
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies similar to 7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
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| 2. |
- Kapoor, Pooja Middha, et al.
(författare)
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Combined associations of a polygenic risk score and classical risk factors with breast cancer risk
- 2021
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 113:3, s. 329-337
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
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| 3. |
- Ahearn, Thomas U., et al.
(författare)
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Common variants in breast cancer risk loci predispose to distinct tumor subtypes
- 2022
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Ingår i: Breast Cancer Research. - : Springer Nature. - 1465-5411 .- 1465-542X. ; 24:1
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Dixon-Suen, Suzanne C, et al.
(författare)
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Physical activity, sedentary time and breast cancer risk : a Mendelian randomisation study
- 2022
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Ingår i: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 56:20, s. 1157-1170
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Chew, Christine, et al.
(författare)
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Lower vitamin D is associated with metabolic syndrome and insulin resistance in systemic lupus : Data from an international inception cohort
- 2021
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Ingår i: Rheumatology (United Kingdom). - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 60:10, s. 4737-4747
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Vitamin D (25(OH)D) deficiency and metabolic syndrome (MetS) may both contribute to increased cardiovascular risk in SLE. We aimed to examine the association of demographic factors, SLE phenotype, therapy and vitamin D levels with MetS and insulin resistance. Methods: The Systemic Lupus International Collaborating Clinics (SLICC) enrolled patients recently diagnosed with SLE (<15 months) from 33 centres across 11 countries from 2000. Clinical, laboratory and therapeutic data were collected. Vitamin D level was defined according to tertiles based on distribution across this cohort, which were set at T1 (10-36 nmol/l), T2 (37-60 nmol/l) and T3 (61-174 nmol/l). MetS was defined according to the 2009 consensus statement from the International Diabetes Federation. Insulin resistance was determined using the HOMA-IR model. Linear and logistic regressions were used to assess the association of variables with vitamin D levels. Results: Of the 1847 patients, 1163 (63%) had vitamin D measured and 398 (34.2%) subjects were in the lowest 25(OH)D tertile. MetS was present in 286 of 860 (33%) patients whose status could be determined. Patients with lower 25(OH)D were more likely to have MetS and higher HOMA-IR. The MetS components, hypertension, hypertriglyceridemia and decreased high-density lipoprotein (HDL) were all significantly associated with lower 25(OH)D. Increased average glucocorticoid exposure was associated with higher insulin resistance. Conclusions: MetS and insulin resistance are associated with lower vitamin D in patients with SLE. Further studies could determine whether vitamin D repletion confers better control of these cardiovascular risk factors and improve long-term outcomes in SLE.
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| 6. |
- Elkhalifa, Marwa, et al.
(författare)
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Anti-beta 2 glycoprotein I IgA in the SLICC classification criteria dataset
- 2021
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Ingår i: Lupus. - : SAGE Publications. - 0961-2033 .- 1477-0962. ; 30:8, s. 1283-1288
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Anti-beta 2 glycoprotein I IgA is a common isotype of anti-beta 2 glycoprotein I in SLE. Anti-beta 2 glycoprotein I was not included in the American College of Rheumatology (ACR) SLE classification criteria, but was included in the Systemic Lupus International Collaborating Clinics (SLICC) criteria. We aimed to evaluate the prevalence of anti-beta 2-glycoprotein I IgA in SLE versus other rheumatic diseases. In addition, we examined the association between anti-beta 2 glycoprotein I IgA and disease manifestations in SLE. Methods: The dataset consisted of 1384 patients, 657 with a consensus physician diagnosis of SLE and 727 controls with other rheumatic diseases. Anti-beta 2 glycoprotein I isotypes were measured by ELISA. Patients with a consensus diagnosis of SLE were compared to controls with respect to presence of anti-beta 2 glycoprotein I. Among patients with SLE, we assessed the association between anti-beta 2 glycoprotein I IgA and clinical manifestations. Results: The prevalence of anti-beta 2 glycoprotein I IgA was 14% in SLE patients and 7% in rheumatic disease controls (odds ratio, OR 2.3, 95% CI: 1.6, 3.3). It was more common in SLE patients who were younger patients and of African descent (p = 0.019). Eleven percent of SLE patients had anti-beta 2 glycoprotein I IgA alone (no anti-beta 2 glycoprotein I IgG or IgM). There was a significant association between anti-beta 2 glycoprotein I IgA and anti-dsDNA (p = 0.001) and the other antiphospholipid antibodies (p = 0.0004). There was no significant correlation of anti-beta 2 glycoprotein I IgA with any of the other ACR or SLICC clinical criteria for SLE. Those with anti-beta 2 glycoprotein I IgA tended to have a history of thrombosis (12% vs 6%, p = 0.071), but the difference was not statistically significant. Conclusion: We found the anti-beta 2 glycoprotein I IgA isotype to be more common in patients with SLE and in particular, with African descent. It could occur alone without other isotypes.
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| 7. |
- Petri, Michelle, et al.
(författare)
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Comparison of the 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology Systemic Lupus Erythematosus Classification Criteria With Two Sets of Earlier Systemic Lupus Erythematosus Classification Criteria
- 2021
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Ingår i: Arthritis Care and Research. - : Wiley. - 2151-464X .- 2151-4658. ; 73:9, s. 1231-1235
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The Systemic Lupus International Collaborating Clinics (SLICC) 2012 systemic lupus erythematosus (SLE) classification criteria and the revised American College of Rheumatology (ACR) 1997 criteria are list based, counting each SLE manifestation equally. We derived a classification rule based on giving variable weights to the SLICC criteria and compared its performance to the revised ACR 1997, the unweighted SLICC 2012, and the newly reported European Alliance of Associations for Rheumatology (EULAR)/ACR 2019 criteria sets. Methods: The physician-rated patient scenarios used to develop the SLICC 2012 classification criteria were reemployed to devise a new weighted classification rule using multiple linear regression. The performance of the rule was evaluated on an independent set of expert-diagnosed patient scenarios and compared to the performance of the previously reported classification rules. Results: The weighted SLICC criteria and the EULAR/ACR 2019 criteria had less sensitivity but better specificity compared to the list-based revised ACR 1997 and SLICC 2012 classification criteria. There were no statistically significant differences between any pair of rules with respect to overall agreement with the physician diagnosis. Conclusion: The 2 new weighted classification rules did not perform better than the existing list-based rules in terms of overall agreement on a data set originally generated to assess the SLICC criteria. Given the added complexity of summing weights, researchers may prefer the unweighted SLICC criteria. However, the performance of a classification rule will always depend on the populations from which the cases and non-cases are derived and whether the goal is to prioritize sensitivity or specificity.
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| 8. |
- Almeida-Brasil, Celline C., et al.
(författare)
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Flares after hydroxychloroquine reduction or discontinuation : results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort
- 2022
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 81:3, s. 370-378
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To evaluate systemic lupus erythematosus (SLE) flares following hydroxychloroquine (HCQ) reduction or discontinuation versus HCQ maintenance. METHODS: We analysed prospective data from the Systemic Lupus International Collaborating Clinics (SLICC) cohort, enrolled from 33 sites within 15 months of SLE diagnosis and followed annually (1999-2019). We evaluated person-time contributed while on the initial HCQ dose ('maintenance'), comparing this with person-time contributed after a first dose reduction, and after a first HCQ discontinuation. We estimated time to first flare, defined as either subsequent need for therapy augmentation, increase of ≥4 points in the SLE Disease Activity Index-2000, or hospitalisation for SLE. We estimated adjusted HRs (aHRs) with 95% CIs associated with reducing/discontinuing HCQ (vs maintenance). We also conducted separate multivariable hazard regressions in each HCQ subcohort to identify factors associated with flare. RESULTS: We studied 1460 (90% female) patients initiating HCQ. aHRs for first SLE flare were 1.20 (95% CI 1.04 to 1.38) and 1.56 (95% CI 1.31 to 1.86) for the HCQ reduction and discontinuation groups, respectively, versus HCQ maintenance. Patients with low educational level were at particular risk of flaring after HCQ discontinuation (aHR 1.43, 95% CI 1.09 to 1.87). Prednisone use at time-zero was associated with over 1.5-fold increase in flare risk in all HCQ subcohorts. CONCLUSIONS: SLE flare risk was higher after HCQ taper/discontinuation versus HCQ maintenance. Decisions to maintain, reduce or stop HCQ may affect specific subgroups differently, including those on prednisone and/or with low education. Further study of special groups (eg, seniors) may be helpful.
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| 9. |
- Almeida-Brasil, Celline C., et al.
(författare)
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Retinal toxicity in a multinational inception cohort of patients with systemic lupus on hydroxychloroquine
- 2022
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Ingår i: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective To evaluate hydroxychloroquine (HCQ)-related retinal toxicity in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort. Methods Data were collected at annual study visits between 1999 and 2019. We followed patients with incident SLE from first visit on HCQ (time zero) up to time of retinal toxicity (outcome), death, loss-to-follow-up or end of study. Potential retinal toxicity was identified from SLICC Damage Index scores; cases were confirmed with chart review. Using cumulative HCQ duration as the time axis, we constructed univariate Cox regression models to assess if covariates (ie, HCQ daily dose/kg, sex, race/ethnicity, age at SLE onset, education, body mass index, renal damage, chloroquine use) were associated with HCQ-related retinal toxicity. Results We studied 1460 patients (89% female, 52% white). Retinal toxicity was confirmed in 11 patients (incidence 1.0 per 1000 person-years, 0.8% overall). Average cumulative time on HCQ in those with retinal toxicity was 7.4 (SD 3.2) years; the first case was detected 4 years after HCQ initiation. Risk of retinal toxicity was numerically higher in older patients at SLE diagnosis (univariate HR 1.05, 95% CI 1.01 to 1.09). Conclusions This is the first assessment of HCQ and retinal disease in incident SLE. We did not see any cases of retinopathy within the first 4 years of HCQ. Cumulative HCQ may be associated with increased risk. Ophthalmology monitoring (and formal assessment of cases of potential toxicity, by a retinal specialist) remains important, especially in patients on HCQ for 10+ years, those needing higher doses and those of older age at SLE diagnosis.
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| 10. |
- Barber, Megan R.W., et al.
(författare)
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Economic Evaluation of Damage Accrual in an International Systemic Lupus Erythematosus Inception Cohort Using a Multistate Model Approach
- 2020
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Ingår i: Arthritis Care and Research. - : Wiley. - 2151-464X .- 2151-4658. ; 72:12, s. 1800-1808
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Tidskriftsartikel (refereegranskat)abstract
- Objective: There is a paucity of data regarding health care costs associated with damage accrual in systemic lupus erythematosus. The present study was undertaken to describe costs associated with damage states across the disease course using multistate modeling. Methods: Patients from 33 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. Annual data on demographics, disease activity, damage (SLICC/American College of Rheumatology Damage Index [SDI]), hospitalizations, medications, dialysis, and selected procedures were collected. Ten-year cumulative costs (Canadian dollars) were estimated by multiplying annual costs associated with each SDI state by the expected state duration using a multistate model. Results: A total of 1,687 patients participated; 88.7% were female, 49.0% were white, mean ± SD age at diagnosis was 34.6 ± 13.3 years, and mean time to follow-up was 8.9 years (range 0.6–18.5 years). Mean annual costs were higher for those with higher SDI scores as follows: $22,006 (Canadian) (95% confidence interval [95% CI] $16,662, $27,350) for SDI scores ≥5 versus $1,833 (95% CI $1,134, $2,532) for SDI scores of 0. Similarly, 10-year cumulative costs were higher for those with higher SDI scores at the beginning of the 10-year interval as follows: $189,073 (Canadian) (95% CI $142,318, $235,827) for SDI scores ≥5 versus $21,713 (95% CI $13,639, $29,788) for SDI scores of 0. Conclusion: Patients with the highest SDI scores incur 10-year cumulative costs that are ~9-fold higher than those with the lowest SDI scores. By estimating the damage trajectory and incorporating annual costs, data on damage can be used to estimate future costs, which is critical knowledge for evaluating the cost-effectiveness of novel therapies.
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