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1.
Endocrinology ; 163(4)2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35192695

RESUMO

OBJECTIVE: Concentrations of circulating sex hormones have been associated with a variety of diseases in women and are strongly influenced by menopausal status. We investigated the genetic architectures of circulating concentrations of estradiol, testosterone, and SHBG by menopausal status in women of European and African ancestry. METHODS: Using data on 229 966 women from the UK Biobank, we conducted genome-wide association studies (GWASs) of circulating concentrations of estradiol, testosterone, and SHBG in premenopausal and postmenopausal women. We tested for evidence of heterogeneity of genetic effects by menopausal status and genetic ancestry. We conducted gene-based enrichment analyses to identify tissues in which genes with GWAS-enriched signals were expressed. RESULTS: We identified 4 loci (5q35.2, 12q14.3, 19q13.42, 20p12.3) that were associated with detectable concentrations of estradiol in both pre- and postmenopausal women of European ancestry. Heterogeneity analysis identified 1 locus for testosterone (7q22.1) in the CYP3A7 gene and 1 locus that was strongly associated with concentrations of SHBG in premenopausal women only (10q15.1) near the AKR1C4 gene. Gene-based analysis of testosterone revealed evidence of enrichment of GWAS signals in genes expressed in adipose tissue for postmenopausal women. We did not find any evidence of ancestry-specific genetic effects for concentrations of estradiol, testosterone, or SHBG. CONCLUSIONS: We identified specific loci that showed genome-wide significant evidence of heterogeneity by menopausal status for testosterone and SHBG. We also observed support for a more prominent role of genetic variants located near genes expressed in adipose tissue in determining testosterone concentrations among postmenopausal women.


Assuntos
Estudo de Associação Genômica Ampla , Pós-Menopausa , Estradiol , Feminino , Hormônios Esteroides Gonadais , Humanos , Pós-Menopausa/genética , Globulina de Ligação a Hormônio Sexual/genética , Testosterona
2.
Menopause ; 29(3): 293-303, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013060

RESUMO

OBJECTIVE: Oral postmenopausal hormone therapy (HT) has been shown to be associated with venous thromboembolism (VTE), but whether this association is modified by VTE-associated genetic susceptibility is unknown. We examined interactions between oral HT use and a genetic risk score (GRS) of VTE. METHOD: Eligible women were postmenopausal women who had data on oral HT use, VTE incidence between 1990 and 2012, and genetic data in the Nurses' Health Study. We built a GRS aggregating 16 VTE-related genetic variants. We used Cox regression to estimate associations of HT use with incident VTE and assessed interactions between HT use and VTE GRS. We also estimated incidence of VTE between age 50 and 79 years for groups of women defined by HT use and VTE GRS. RESULTS: We identified 432 incident VTE cases. Current HT users were at higher risk of VTE than never users (HR: 1.9, 95% CI: 1.5-2.6), with slightly higher risk for estrogen plus progestin HT than estrogen only (HR: 2.4 vs 1.9). The GRS was associated with VTE risk (HR comparing 4th quartile to 1st: 2.0, 95% CI: 1.2-3.4). We did not observe significant multiplicative interactions between HT use and GRS. The estimated VTE risk difference (per 10,000 person-years) comparing 50-year-old current HT users to never users was 22.5 for women in the highest GRS quartile and 9.8 for women in the lowest GRS quartile. CONCLUSION: The VTE GRS might inform clinical guidance regarding the balance of risks and benefits of HT use, especially among younger women.


Assuntos
Terapia de Reposição de Estrogênios , Tromboembolia Venosa , Idoso , Terapia de Reposição de Estrogênios/efeitos adversos , Estrogênios/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Estudos Prospectivos , Fatores de Risco , Tromboembolia Venosa/induzido quimicamente , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/genética
3.
Int J Cancer ; 150(9): 1447-1454, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-34888857

RESUMO

Elevated blood levels of C-reactive protein (CRP) have been linked to colorectal cancer (CRC) survival. We evaluated genetic variants associated with CRP levels and their interactions with sex and lifestyle factors in association with CRC-specific mortality. Our study included 16 142 CRC cases from the International Survival Analysis in Colorectal Cancer Consortium. We identified 618 common single nucleotide polymorphisms (SNPs) associated with CRP levels from the NHGRI-EBI GWAS Catalog. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between SNPs and CRC-specific mortality adjusting for age, sex, genotyping platform/study and principal components. We investigated their interactions with sex and lifestyle factors using likelihood ratio tests. Of 5472 (33.9%) deaths accrued over up to 10 years of follow-up, 3547 (64.8%) were due to CRC. No variants were associated with CRC-specific mortality after multiple comparison correction. We observed strong evidence of interaction between variant rs1933736 at FRK gene and sex in relation to CRC-specific mortality (corrected Pinteraction  = .0004); women had higher CRC-specific mortality associated with the minor allele (HR = 1.11, 95% CI = 1.04-1.19) whereas an inverse association was observed for men (HR = 0.88, 95% CI = 0.82-0.94). There was no evidence of interactions between CRP-associated SNPs and alcohol, obesity or smoking. Our study observed a significant interaction between sex and a CRP-associated variant in relation to CRC-specific mortality. Future replication of this association and functional annotation of the variant are needed.


Assuntos
Proteína C-Reativa , Neoplasias Colorretais , Proteína C-Reativa/análise , Proteína C-Reativa/genética , Feminino , Humanos , Estilo de Vida , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Análise de Sobrevida
4.
Crit Care Explor ; 3(12): e0602, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34957408

RESUMO

To assess if genetic predictors for C-reactive protein and risk of venous thromboembolism are associated with severe outcomes among individuals who tested positive for severe acute respiratory syndrome coronavirus 2. DESIGN: Retrospective cohort study. SETTING: U.K. Biobank. PATIENTS OR SUBJECTS: U.K. Biobank participants with European ancestry who were recorded to have a positive polymerase chain reaction test result for severe acute respiratory syndrome coronavirus 2 between March 16, 2020, and August 14, 2020. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: We constructed separate genetic risk scores for C-reactive protein and venous thromboembolism consisting of 56 and 37 genetic variants that have been significantly associated with venous thromboembolism and C-reactive protein, respectively. Among 1,126 individuals who were diagnosed with coronavirus disease 2019, 48% had a coronavirus disease 2019-related hospitalization, 16% received critical care support, 10% had critical respiratory support, and 21% died from coronavirus disease 2019. Genetic predisposition to high C-reactive protein concentrations was marginally associated with a lower risk of death from coronavirus disease 2019 (odds ratio, 0.85; 95% CI, 0.73-1.00; p = 0.05). No other associations were significant. CONCLUSIONS: Our results do not support associations between polygenic risk for elevated blood C-reactive protein concentrations or venous thromboembolism and severe coronavirus disease 2019 health outcomes. Thus, considering genetic predisposition associated with C-reactive protein concentrations or venous thromboembolism risk is not meaningful for predicting severe coronavirus disease 2019 health outcomes.

5.
Arch Suicide Res ; : 1-14, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34821208

RESUMO

INTRODUCTION: The aim was to investigate psychiatric health care utilization two years before death by suicide among individuals with previous suicide attempts (PSA) compared with those without (NSA). METHOD: A retrospective population-based cohort study was conducted including 484 individuals who died by suicide in Sweden in 2015 and were in contact with psychiatric services within the two years preceding death, identified through the Cause of Death register. Data on psychiatric health care two years before death, including suicide attempts according to notes in the medical record was used. Associations between having at least one PSA vs. NSA and health care utilization were estimated as odds ratios (OR) with 95% confidence intervals (CI) by logistic regression analyses. RESULTS: Of the 484 individuals included, 51% had PSA. Those with PSA were more likely than NSA to have received a psychiatric diagnosis [OR 1.96 (CI 95% 1.17-3.30)], to have ongoing psychotropic medication [OR 1.96 (CI 95% 1.15-3.36)] and to have been absent from appointments during the last three months [1.97 (1.25-3.13)]. In addition, elevated suicide risk was more often noted in the psychiatric case records of those with a PSA than those without [OR 2.17 (CI 95% 1.24-3.79)]. CONCLUSION: The results underline the importance of improved suicide risk assessment as well as thorough diagnostic assessment and when indicated, psychiatric treatment as suicide preventive interventions regardless of PSA. Furthermore, the larger proportion of absence from appointments in individuals with PSA may indicate a need of improved alliance between psychiatric care providers and individuals with PSA.HIGHLIGHTSBeing assessed with elevated suicide risk was more common among those with previous attempt/s (PSA).One-fifth of all with no previous attempt (NSA) had no psychiatric diagnosis, compared to one in ten in those with PSA.Receiving psychotropic medication was more common among those with PSA.

6.
J Clin Oncol ; 39(35): 3918-3926, 2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34672684

RESUMO

PURPOSE: To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS: The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS: The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION: The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Predisposição Genética para Doença , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
7.
J Clin Oncol ; 39(31): 3430-3440, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34292776

RESUMO

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 BRCA1, BRCA2, and PALB2 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 CHEK2, PALB2, BRCA2, and BRCA1 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 BRCA1, BRCA2, and PALB2. 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 BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Quinase do Ponto de Checagem 2/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Testes Genéticos , Humanos , Prognóstico
8.
Br J Cancer ; 125(6): 806-815, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34230610

RESUMO

BACKGROUND: Biomarker studies on colorectal cancer (CRC) prognosis are limited to pre-diagnostic or pre-operative measures. Post-treatment biomarkers are not well understood for their associations with CRC survival. METHODS: We included 306 eligible incident stage II-III CRC cases from the population-based Seattle Colon Cancer Family Registry. Concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), adiponectin, and leptin were measured using post-treatment plasma samples. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and CRC-specific mortality were calculated using Cox proportional hazard models. RESULTS: Elevated levels of CRP, IL-6, MCP-1, and adiponectin were significantly associated with a higher risk of all-cause mortality within 10 years post blood draw with HRs (95% CI) of 1.32 (1.10-2.59), 2.72 (2.07-3.56), 1.97 (1.18-3.28) and 1.71 (1.14-2.58), respectively. IL-6 and adiponectin had a dose-response effect (Ptrend < 0.0001). For CRC-specific mortality, we observed positive associations for CRP (HR = 1.75, 95% CI: 1.2-2.56), IL-6 (HR = 5.02, 95% CI: 2.92-8.59), MCP-1 (HR = 3.78, 95% CI: 1.41-10.08), and adiponectin (HR = 3.16, 95% CI: 1.27-7.86), and inverse association for leptin (HR = 0.44, 95% CI: 0.29-0.68) within the first year of blood draw, whereas the association for IL-6 remained statistically significant over 10 years. CONCLUSION: Our results support the role of chronic inflammation in CRC progression and suggested several post-treatment inflammatory biomarkers, particularly IL-6, are promising prognostic markers for stage II-III CRC patients.


Assuntos
Adiponectina/sangue , Proteína C-Reativa/análise , Quimiocina CCL2/sangue , Neoplasias Colorretais/patologia , Interleucina-6/sangue , Leptina/sangue , Adulto , Idoso , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/mortalidade , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida
9.
J Clin Oncol ; 39(23): 2564-2573, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34101481

RESUMO

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 BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. 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 BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 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 CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.


Assuntos
Neoplasias da Mama/genética , Variação Genética/genética , Adulto , Idoso , Neoplasias da Mama/patologia , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Fatores de Risco
10.
Cancer Epidemiol Biomarkers Prev ; 30(7): 1349-1358, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33972368

RESUMO

BACKGROUND: A positive association between circulating C-reactive protein (CRP) and colorectal cancer survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse causality. We used a Mendelian randomization approach to evaluate the association between genetically predicted CRP concentrations and colorectal cancer-specific survival. METHODS: We used individual-level data for 16,918 eligible colorectal cancer cases of European ancestry from 15 studies within the International Survival Analysis of Colorectal Cancer Consortium. We calculated a genetic-risk score based on 52 CRP-associated genetic variants identified from genome-wide association studies. Because of the non-collapsibility of hazard ratios from Cox proportional hazards models, we used the additive hazards model to calculate hazard differences (HD) and 95% confidence intervals (CI) for the association between genetically predicted CRP concentrations and colorectal cancer-specific survival, overall and by stage at diagnosis and tumor location. Analyses were adjusted for age at diagnosis, sex, body mass index, genotyping platform, study, and principal components. RESULTS: Of the 5,395 (32%) deaths accrued over up to 10 years of follow-up, 3,808 (23%) were due to colorectal cancer. Genetically predicted CRP concentration was not associated with colorectal cancer-specific survival (HD, -1.15; 95% CI, -2.76 to 0.47 per 100,000 person-years; P = 0.16). Similarly, no associations were observed in subgroup analyses by stage at diagnosis or tumor location. CONCLUSIONS: Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on colorectal cancer-specific survival. IMPACT: Future research evaluating genetically determined levels of other circulating inflammatory biomarkers (i.e., IL6) with colorectal cancer survival outcomes is needed.


Assuntos
Proteína C-Reativa/análise , Neoplasias Colorretais/mortalidade , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Feminino , Seguimentos , Variação Genética , Humanos , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fatores de Risco
11.
J Am Coll Cardiol ; 77(16): 2040-2052, 2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33888254

RESUMO

The National Heart, Lung, and Blood Institute and the Cardiovascular Medical Research and Education Fund held a workshop on the application of pulmonary vascular disease omics data to the understanding, prevention, and treatment of pulmonary vascular disease. Experts in pulmonary vascular disease, omics, and data analytics met to identify knowledge gaps and formulate ideas for future research priorities in pulmonary vascular disease in line with National Heart, Lung, and Blood Institute Strategic Vision goals. The group identified opportunities to develop analytic approaches to multiomic datasets, to identify molecular pathways in pulmonary vascular disease pathobiology, and to link novel phenotypes to meaningful clinical outcomes. The committee suggested support for interdisciplinary research teams to develop and validate analytic methods, a national effort to coordinate biosamples and data, a consortium of preclinical investigators to expedite target evaluation and drug development, longitudinal assessment of molecular biomarkers in clinical trials, and a task force to develop a master clinical trials protocol for pulmonary vascular disease.


Assuntos
Pesquisa Biomédica/tendências , Educação/tendências , Pneumopatias/classificação , National Heart, Lung, and Blood Institute (U.S.)/tendências , Relatório de Pesquisa/tendências , Doenças Vasculares/classificação , Doenças Cardiovasculares/classificação , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Biologia Computacional/métodos , Biologia Computacional/tendências , Humanos , Pneumopatias/diagnóstico , Pneumopatias/epidemiologia , Circulação Pulmonar/fisiologia , Literatura de Revisão como Assunto , Estados Unidos/epidemiologia , Doenças Vasculares/diagnóstico , Doenças Vasculares/epidemiologia
12.
Obesity (Silver Spring) ; 29(2): 446-453, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33491310

RESUMO

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 < 10-4 ) were selected for replication in a previously published genome-wide association study of childhood BMI. Nineteen significant genome-wide (P < 5 × 10-8 ) regions were observed, fourteen of which were previously associated with childhood obesity and five were novel: BNDF (P = 7.58 × 10-13 ), PRKD1 (P = 1.43 × 10-10 ), 20p13 (P = 2.05 × 10-10 ), FHIT (P = 1.77 × 10-8 ), and LOC101927575 (P = 3.22 × 10-8 ). 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 × 10-6 ) and with TMEM18 at 2p25.3 (P = 3.53 × 10-7 ) were observed. Childhood body fatness was genetically correlated with hip (rg = 0.42, P = 4.44 × 10-16 ) and waist circumference (rg = 0.39, P = 5.56 × 10-16 ), as well as age at menarche (rg = -0.37, P = 7.96 × 10-19 ). CONCLUSIONS: Additional loci that contribute to childhood adiposity were identified, further explicating its genetic architecture.


Assuntos
Adiposidade/genética , Obesidade Pediátrica , Adulto , Idoso , Índice de Massa Corporal , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Pediátrica/epidemiologia , Obesidade Pediátrica/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Adulto Jovem
13.
J Natl Cancer Inst ; 113(3): 329-337, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32359158

RESUMO

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.


Assuntos
Neoplasias da Mama/genética , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Anamnese , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores de Estrogênio/metabolismo , Fatores de Risco
14.
Am J Epidemiol ; 190(1): 44-58, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-32639533

RESUMO

Previous studies suggest that the association between mammographic density (MD) and breast cancer risk might be modified by other breast cancer risk factors. In this study, we assessed multiplicative interactions between MD measures and established risk factors on the risk of invasive breast cancer overall and according to menopausal and estrogen receptor status. We used data on 2,137 cases and 4,346 controls from a nested case-control study within the Nurses' Health Study (1976-2004) and Nurses' Health Study II (1989-2007), whose data on percent mammographic density (PMD) and absolute area of dense tissue and nondense tissue (NDA) were available. No interaction remained statistically significant after adjusting for number of comparisons. For breast cancer overall, we observed nominally significant interactions (P < 0.05) between nulliparity and PMD/NDA, age at menarche and area of dense tissue, and body mass index and NDA. Individual nominally significant interactions across MD measures and risk factors were also observed in analyses stratified by either menopausal or estrogen receptor status. Our findings help provide further insights into potential mechanisms underlying the association between MD and breast cancer.


Assuntos
Densidade da Mama , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Adulto , Fatores Etários , Idoso , Índice de Massa Corporal , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Mamografia , Menarca , Menopausa , Pessoa de Meia-Idade , Enfermeiras e Enfermeiros , Paridade , Fenótipo , Estudos Prospectivos , Fatores de Risco , Estados Unidos/epidemiologia
15.
J Acquir Immune Defic Syndr ; 86(3): 339-343, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33148997

RESUMO

OBJECTIVES: Evaluate differences in weight change by regimen among people living with HIV (PLWH) initiating antiretroviral therapy (ART) in the current era. METHODS: Between 2012 and 2019, 3232 ART-naïve PLWH initiated ≥3-drug ART regimens in 8 Centers for AIDS Research Network of Integrated Clinical Systems sites. We estimated weight change by regimen for 11 regimens in the immediate (first 6 months) and extended (all follow-up on initial regimen) periods using linear mixed models adjusted for time on regimen, interaction between time and regimen, age, sex, race/ethnicity, hepatitis B/C coinfection, nadir CD4, smoking, diabetes, antipsychotic medication, and site. We included more recently approved regimens [eg, with tenofovir alafenamide fumarate (TAF)] only in the immediate period analyses to ensure comparable follow-up time. RESULTS: Mean follow-up was 1.9 years on initial ART regimen. In comparison to efavirenz/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), initiating bictegravir/TAF/FTC {3.9 kg [95% confidence interval (CI): 2.2 to 5.5]} and dolutegravir/TAF/FTC [4.4 kg (95% CI: 2.1 to 6.6)] were associated with the greatest weight gain in the immediate period, followed by darunavir/TDF/FTC [3.7 kg (95% CI: 2.1 to 5.2)] and dolutegravir/TDF/FTC [2.6 kg (95% CI: 1.3 to 3.9)]. In the extended period, compared with efavirenz/TDF/FTC, initiating darunavir/TDF/FTC was associated with a 1.0 kg (95% CI: 0.5 to 1.5) per 6-months greater weight gain, whereas dolutegravir/abacavir/FTC was associated with a 0.6-kg (95% CI: 0.3 to 0.9) and dolutegravir/TDF/FTC was associated with a 0.6-kg (95% CI: 0.1 to 1.1) per 6-months greater gain. Weight gain on dolutegravir/abacavir/FTC and darunavir/TDF/FTC was significantly greater than that for several integrase inhibitor-based regimens. CONCLUSIONS: There is heterogeneity between regimens in weight gain following ART initiation among previously ART-naïve PLWH; we observed greater gain among PLWH taking newer integrase strand transfer inhibitors (DTG, BIC) and DRV-based regimens.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Ganho de Peso/efeitos dos fármacos , Adulto , Alanina , Alcinos , Antirretrovirais/efeitos adversos , Benzoxazinas , Ciclopropanos , Didesoxinucleosídeos , Feminino , Inibidores de Integrase de HIV , Compostos Heterocíclicos com 3 Anéis , Humanos , Masculino , Pessoa de Meia-Idade , Oxazinas , Piperazinas , Piridonas , Tenofovir/análogos & derivados
16.
BMJ Open ; 10(10): e038794, 2020 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-33130567

RESUMO

OBJECTIVES: The overall aim of this study is to gain greater knowledge about the risk of suicide among suicide attempters in a very long-term perspective. Specifically, to investigate possible differences in clinical risk factors at short (≤5 years) versus long term (>5 years), with the hypothesis that risk factors differ in the shorter and longer perspective. DESIGN: Prospective study with register-based follow-up for 21-32 years. SETTING: Medical emergency inpatient unit in the south of Sweden. PARTICIPANTS: 1044 individuals assessed by psychiatric consultation when admitted to medical inpatient care for attempted suicide during 1987-1998. OUTCOME MEASURES: Suicide and all-cause mortality. RESULTS: At follow-up, 37.6% of the participants had died, 7.2% by suicide and 53% of these within 5 years of the suicide attempt. A diagnosis of psychosis at baseline represented the risk factor with the highest HR at long-term follow-up, that is, >5 years, followed by major depression and a history of attempted suicide before the index attempt. The severity of a suicide attempt as measured by SIS (Suicide Intent Scale) showed a non-proportional association with the hazard for suicide over time and was a relevant risk factor for suicide only within the first 5 years after an attempted suicide. CONCLUSIONS: The risk of suicide after a suicide attempt persists for up to 32 years after the index attempt. A baseline diagnosis of psychosis or major depression or earlier suicide attempts continued to be relevant risk factors in the very long term. The SIS score is a better predictor of suicide risk at short term, that is, within 5 years than at long term. This should be considered in the assessment of suicide risk and the implementation of care for these individuals.


Assuntos
Tentativa de Suicídio , Adulto , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Fatores de Risco , Suécia/epidemiologia
17.
Nord J Psychiatry ; 74(6): 429-438, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32129114

RESUMO

Background: The Self-Harm Antipathy Scale (SHAS) is a questionnaire designed to measure nurses' attitudes towards self-harm. This can be useful to improve the quality of care provided to individuals who self-harm.Aim: The purpose of this study was to revise and adapt the SHAS for use in Sweden and evaluate the psychometric properties of this Swedish version (Self-Harm Antipathy Scale - Swedish Revised; SHAS-SR).Methods: A sample of 596 employees within psychiatric healthcare was recruited (from a total of 3507, response rate 17.0%), the majority encountering self-harming individuals regularly at work. Participants completed the SHAS-SR questionnaire along with a scale assessing community attitudes towards individuals with mental illness (New CAMI-S). The sample was randomly split in half (n = 298 each). Exploratory factor analysis was performed on one subsample and confirmatory on the other. Confirmatory factor analysis on the original SHAS model, and convergent validity testing against New CAMI-S, used the whole sample.Results: The final version of the SHAS-SR included 17 items forming three factors. Convergent validity was established (r = -0.57, ρ = -0.48, p < 0.001). The SHAS-SR and all its subscales demonstrated acceptable internal consistency (α = 0.73-0.79, ω = 0.78-0.79).Conclusion: This study indicates that the SHAS-SR is reliable and valid when assessing attitudes towards self-harm among a sample of Swedish psychiatric healthcare staff. The scale could be useful for assessing the impact of attitude interventions to improve healthcare services. It may, however, have limited applicability for staff not working in caring roles.


Assuntos
Atitude do Pessoal de Saúde , Pessoal de Saúde/psicologia , Pessoal de Saúde/normas , Comportamento Autodestrutivo/epidemiologia , Comportamento Autodestrutivo/psicologia , Inquéritos e Questionários/normas , Adulto , Feminino , Humanos , Masculino , Transtornos Mentais/diagnóstico , Transtornos Mentais/epidemiologia , Transtornos Mentais/psicologia , Pessoa de Meia-Idade , Relações Enfermeiro-Paciente , Psicometria , Reprodutibilidade dos Testes , Comportamento Autodestrutivo/diagnóstico , Suécia
19.
Cancer Causes Control ; 31(3): 273-282, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006205

RESUMO

PURPOSE: The relationship of allergic diseases, such as asthma, hay fever, and eczema, with cancer is under debate. Observational studies have reported conflicting findings, but such studies are susceptible to confounding and reverse causation. Understanding the potential role of allergy in carcinogenesis may shed new light on the biological mechanisms underpinning intrinsic immunity and cancer. METHODS: We conducted a Mendelian randomization study, using germline genetic variants as instrumental variables, to determine the causal relevance of allergic disease and on two most common malignancies: breast cancer and prostate cancer. We used the summary statistics from the largest ever genome-wide association studies conducted on allergic disease (ncase = 180,129), asthma (ncase = 14,085), breast (ncase = 122,977), and prostate cancer (ncase = 79,148) and calculated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer for allergic disease. RESULTS: We did not observe any evidence to support a causal association between allergic disease and risk of breast cancer overall [OR 1.00 (95% CI 0.96-1.04), p = 0.95] or by subtype (estrogen receptor (ER)+ [0.99 (0.95-1.04), p = 0.71], ER- [1.05 (0.99-1.10), p = 0.11]). We also did not find any evidence for an association with prostate cancer [1.00 (0.94-1.05), p = 0.93] or advanced subtype [0.97 (0.90-1.05), p = 0.46]. Sensitivity analyses did not reveal directional pleiotropy. CONCLUSION: Our study does not support a causal effect of allergic disease on the risk of breast or prostate cancer. Future studies may be conducted to focus on understanding the causal role of allergic disease in cancer prognosis or drug responses (e.g., immunotherapy).


Assuntos
Asma/complicações , Neoplasias da Mama/imunologia , Neoplasias da Próstata/imunologia , Asma/genética , Neoplasias da Mama/genética , Estudos de Casos e Controles , Suscetibilidade a Doenças , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Razão de Chances , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética
20.
Am J Epidemiol ; 189(6): 554-563, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31712804

RESUMO

Hepatitis C virus (HCV) infection is common among people living with human immunodeficiency virus (PLWH). Extrahepatic manifestations of HCV, including myocardial infarction (MI), are a topic of active research. MI is classified into types, predominantly atheroembolic type 1 MI (T1MI) and supply-demand mismatch type 2 MI (T2MI). We examined the association between HCV and MI among patients in the Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems, a US multicenter clinical cohort of PLWH. MIs were centrally adjudicated and categorized by type using the Third Universal Definition of Myocardial Infarction. We estimated the association between chronic HCV (RNA+) and time to MI while adjusting for demographic characteristics, cardiovascular risk factors, clinical characteristics, and history of injecting drug use. Among 23,407 PLWH aged ≥18 years, there were 336 T1MIs and 330 T2MIs during a median of 4.7 years of follow-up between 1998 and 2016. HCV was associated with a 46% greater risk of T2MI (adjusted hazard ratio (aHR) = 1.46, 95% confidence interval (CI): 1.09, 1.97) but not T1MI (aHR = 0.87, 95% CI: 0.58, 1.29). In an exploratory cause-specific analysis of T2MI, HCV was associated with a 2-fold greater risk of T2MI attributed to sepsis (aHR = 2.01, 95% CI: 1.25, 3.24). Extrahepatic manifestations of HCV in this high-risk population are an important area for continued research.


Assuntos
Infecções por HIV/epidemiologia , Hepatite C Crônica/epidemiologia , Infarto do Miocárdio/epidemiologia , Adulto , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/classificação , Fatores de Risco , Fatores Socioeconômicos , Abuso de Substâncias por Via Intravenosa/epidemiologia , Estados Unidos/epidemiologia , Carga Viral
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