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1.
Maturitas ; 166: 35-40, 2022 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-36055009

RESUMO

BACKGROUND: Menopausal hormone therapy (MHT) has been associated with a decreased risk of gastric cancer (GC) and colorectal cancer (CRC); however, few studies have been conducted in diverse ethnic groups, particularly in the Asian population. Therefore, the current study evaluated if MHT is inversely associated with GC and CRC in East Asia using a representative population-based study in Korea. METHODS: This retrospective cohort study was conducted using the National Health Insurance Service-National Sample Cohort 2.0 in South Korea from 2002 to 2015. A total of 196,095 women aged ≥40 years were included in the study. The numbers of participants who did and did not use MHT were 19,063 (9.7 %) and 177,032 (90.3 %), respectively. Hazard ratios (HRs) and the corresponding 95 % confidence intervals (CIs) were estimated using a time-dependent Cox proportional hazards model. Age was considered as a time scale, and other confounding factors, including income levels based on insurance premiums, region of residence, and comorbidities, were included in the multivariable-adjusted model. RESULTS: The total number of incident cases of GC and CRC were 1339 (0.68 %) and 1428 (0.73 %), respectively. We observed an inverse association of the use of estrogen replacement therapy (ERT; estrogen-containing therapy regardless of other regimen types) with GC [HR (95 % CI):0.68 (0.51-0.90)], CRC [0.57 (0.42-0.78)] and gastrointestinal cancer [GI, 0.63 (0.51-0.77)]. In the analyses by CRC subsite, the risks of both colon and rectal cancers were associated with ERT. In addition, both estrogen and combined estrogen and progestogen regimens were significantly associated with CRC and GI cancer. CONCLUSION: ERT was associated with a decreased risk of GC and CRC. Our findings support the protective effect of estrogen against GC and CRC in Korean women.

2.
Eur J Cancer ; 173: 178-193, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35933885

RESUMO

BACKGROUND: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2). METHOD: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance. RESULTS: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0.902 for patients with ER-positive tumours (p = 2.3 × 10-6) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted. CONCLUSION: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predictions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration.


Assuntos
Neoplasias da Mama , Receptores de Progesterona , Neoplasias da Mama/patologia , Feminino , Humanos , Progesterona , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo
3.
Breast Cancer ; 29(5): 869-879, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35543923

RESUMO

BACKGROUND: Human leukocyte antigen (HLA) genes play critical roles in immune surveillance, an important defence against tumors. Imputing HLA genotypes from existing single-nucleotide polymorphism datasets is low-cost and efficient. We investigate the relevance of the major histocompatibility complex region in breast cancer susceptibility, using imputed class I and II HLA alleles, in 25,484 women of Asian ancestry. METHODS: A total of 12,901 breast cancer cases and 12,583 controls from 12 case-control studies were included in our pooled analysis. HLA imputation was performed using SNP2HLA on 10,886 quality-controlled variants within the 15-55 Mb region on chromosome 6. HLA alleles (n = 175) with info scores greater than 0.8 and frequencies greater than 0.01 were included (resolution at two-digit level: 71; four-digit level: 104). We studied the associations between HLA alleles and breast cancer risk using logistic regression, adjusting for population structure and age. Associations between HLA alleles and the risk of subtypes of breast cancer (ER-positive, ER-negative, HER2-positive, HER2-negative, early-stage, and late-stage) were examined. RESULTS: We did not observe associations between any HLA allele and breast cancer risk at P < 5e-8; the smallest p value was observed for HLA-C*12:03 (OR = 1.29, P = 1.08e-3). Ninety-five percent of the effect sizes (OR) observed were between 0.90 and 1.23. Similar results were observed when different subtypes of breast cancer were studied (95% of ORs were between 0.85 and 1.18). CONCLUSIONS: No imputed HLA allele was associated with breast cancer risk in our large Asian study. Direct measurement of HLA gene expressions may be required to further explore the associations between HLA genes and breast cancer risk.


Assuntos
Neoplasias da Mama , Antígenos HLA , Alelos , Asiáticos/genética , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Genótipo , Antígenos HLA/genética , Humanos , Polimorfismo de Nucleotídeo Único
5.
JAMA Netw Open ; 5(3): e2149030, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35311964

RESUMO

Importance: Polygenic risk scores (PRSs) have shown promise in breast cancer risk prediction; however, limited studies have been conducted among Asian women. Objective: To develop breast cancer risk prediction models for Asian women incorporating PRSs and nongenetic risk factors. Design, Setting, and Participants: This diagnostic study included women of Asian ancestry from the Asia Breast Cancer Consortium. PRSs were developed using data from genomewide association studies (GWASs) of breast cancer conducted among 123 041 women with Asian ancestry (including 18 650 women with breast cancer) using 3 approaches: (1) reported PRS for women with European ancestry; (2) breast cancer-associated single-nucleotide variations (SNVs) identified by fine-mapping of GWAS-identified risk loci; and (3) genomewide risk prediction algorithms. A nongenetic risk score (NGRS) was built, including 7 well-established nongenetic risk factors, using data of 416 case participants and 1558 control participants from a prospective cohort study. PRSs were initially validated in an independent data set including 1426 case participants and 1323 control participants and further evaluated, along with the NGRS, in the second data set including 368 case participants and 736 control participants nested within a prospective cohort study. Main Outcomes and Measures: Logistic regression was used to examine associations of risk scores with breast cancer risk to estimate odds ratios (ORs) with 95% CIs and area under the receiver operating characteristic curve (AUC). Results: A total of 126 894 women of Asian ancestry were included; 20 444 (16.1%) had breast cancer. The mean (SD) age ranged from 49.1 (10.8) to 54.4 (10.4) years for case participants and 50.6 (9.5) to 54.0 (7.4) years for control participants among studies that provided demographic characteristics. In the prospective cohort, a PRS with 111 SNVs developed using the fine-mapping approach (PRS111) showed a prediction performance comparable with a genomewide PRS that included more than 855 000 SNVs. The OR per SD increase of PRS111 score was 1.67 (95% CI, 1.46-1.92), with an AUC of 0.639 (95% CI, 0.604-0.674). The NGRS had a limited predictive ability (AUC, 0.565; 95% CI, 0.529-0.601). Compared with the average risk group (40th-60th percentile), women in the top 5% of PRS111 and NGRS were at a 3.84-fold (95% CI, 2.30-6.46) and 2.10-fold (95% CI, 1.22-3.62) higher risk of breast cancer, respectively. The prediction model including both PRS111 and NGRS achieved the highest prediction accuracy (AUC, 0.648; 95% CI, 0.613-0.682). Conclusions and Relevance: In this study, PRSs derived using breast cancer risk-associated SNVs had similar predictive performance in Asian and European women. Including nongenetic risk factors in models further improved prediction accuracy. These findings support the utility of these models in developing personalized screening and prevention strategies.


Assuntos
Neoplasias da Mama , /genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
6.
Prev Med ; 155: 106949, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34974070

RESUMO

The socioecological approach emphasises that health promotion should focus on a variety of factors that surround individuals simultaneously, yet there is little evidence on how these factors relatively affect physical activity (PA). The main objective was to identify relevant determinants of PA by examining the associations between factors within multilayered socioecological categories and PA. A prospective analysis was conducted with 84,052 participants participating in the accelerometer measurement from the UK Biobank. Time spent in moderate-to-vigorous PA (MVPA) was calculated from participants who wore a wrist-worn accelerometer for seven days; a questionnaire-based self-reported leisure-time physical activity was also assessed. A categorical principal component analysis was conducted to reduce the dimensions of 184 variables. The associations between principal components (PCs) and PA were evaluated using general linear models. A network of PCs was constructed to assess the comprehensive association with PA. PCs related to body composition and chronic diseases were suggested as key determinants of objectively measured MVPA and found to be clustered in the network. PCs related to body composition and socio-economic status were proposed as the key regulatory hubs in the network because they exhibited the highest level of indirect linkages with other components. In the environmental category, PCs related to greenness and air pollution were revealed to be key factors in the self-reported walking for pleasure. Using a socioecological approach, it was discovered that obesity and disease-related factors were the most important determinants, and they had an integrative influence with other factors in different categories.


Assuntos
Acelerometria , Bancos de Espécimes Biológicos , Exercício Físico , Humanos , Estudos Prospectivos , Reino Unido
7.
Genet Med ; 24(3): 586-600, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34906514

RESUMO

PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.


Assuntos
Neoplasias da Mama , Teorema de Bayes , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Fatores de Risco
8.
Epidemiol Health ; 43: e2021061, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34525501

RESUMO

OBJECTIVES: During the coronavirus disease 2019 (COVID-19) pandemic, crude incidence and mortality rates have been widely reported; however, age-standardized rates are more suitable for comparisons. In this study, we estimated and compared the age-standardized incidence, mortality, and case fatality rates (CFRs) among countries and investigated the relationship between these rates and factors associated with healthcare resources: gross domestic product per capita, number of hospital beds per population, and number of doctors per population. METHODS: The incidence, mortality, and CFRs of 79 countries were age-standardized using the World Health Organization standard population. The rates for persons 60 years or older were also calculated. The relationships among the rates were analysed using trend lines and coefficients of determination (R2). Pearson correlation coefficients between the rates and the healthcare resource-related factors were calculated. RESULTS: The countries with the highest age-standardized incidence, mortality, and CFRs were Czechia (14,253 cases/100,000), Mexico (182 deaths/100,000), and Mexico (6.7%), respectively. The R2 between the incidence and mortality rates was 0.852 for all ages and 0.945 for those 60 years or older. The healthcare resources-related factors were associated positively with incidence rates and negatively with CFRs, with weaker correlations among the elderly. CONCLUSIONS: Compared to age-standardized rates, crude rates showed greater variation among countries. Medical resources may be important in preventing COVID-19-related deaths; however, considering the small variation in fatality among the elderly, preventive measures such as vaccination are more important, especially for the elderly population, to minimize the mortality rates.


Assuntos
COVID-19 , Idoso , Estudos Transversais , Humanos , Incidência , Lactente , Mortalidade , Pandemias , SARS-CoV-2
9.
Am J Cancer Res ; 11(8): 3921-3934, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522458

RESUMO

The causal relationship between body mass index (BMI) and type 2 diabetes (T2D) and breast cancer prognosis is still ambiguous. The aim of this study was to investigate the prognostic effect of BMI and T2D on breast cancer disease-free survival (DFS) among Asian individuals. In this two-sample Mendelian randomization (MR) study, the instrumental variables (IVs) were identified using a genome-wide association study (GWAS) among 24,000 participants in the Taiwan Biobank. Importantly, the validity of these IVs was confirmed with a previous large-scale GWAS (Biobank Japan Project, BBJ). In this study, we found that a genetic predisposition toward higher BMI (as indicated by BMI IVs, F = 86.88) was associated with poor breast cancer DFS (hazard ratio [HR] = 6.11; P < 0.001). Furthermore, higher level of genetically predicted T2D (as indicated by T2D IVs) was associated with an increased risk of recurrence of and mortality from breast cancer (HR = 1.43; P < 0.001). Sensitivity analyses, including the weighted-median approach, MR-Egger regression, Radial regression and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) supported the consistency of our findings. Finally, the causal relationship between BMI and poor breast cancer prognosis was confirmed in a prospective cohort study. Our MR analyses demonstrated the causal relationship between the genetic prediction of elevated BMI and a greater risk of T2D with poor breast cancer prognosis. BMI and T2D have important clinical implications and may be used as prognostic indicators of breast cancer.

10.
Menopause ; 28(11): 1225-1232, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34520413

RESUMO

OBJECTIVE: Although menopausal hormone therapy (MHT) is the most effective treatment for menopausal symptoms, menopausal women hesitate to start MHT due to concerns about adverse events. Recently, however, it has been recommended to use it for appropriate patients who have been evaluated for baseline diseases, age, and timing of initiation. We aimed to investigate the association of MHT with cardiovascular diseases (CVDs) and type 2 diabetes among middle-aged postmenopausal women in Korea. METHODS: Data were collected from the National Health Insurance Service database in Korea from 2002 to 2016. A total of 58,060 postmenopausal women (including 8,013 [13.8%] MHT users and 50,047 [86.2%] nonusers) were included. The time-dependent Cox regression model with a 1-year latency period was used to evaluate the hazard ratio (HR) and 95% confidence interval (CI) of the associations of MHT with CVDs and type 2 diabetes outcomes. Subgroup analyses by regimen type and cumulative duration were conducted. RESULTS: In the multivariate-adjusted model, MHT was not significantly associated with CVDs (HR = 1.085, 95% CI: 0.899-1.310) or type 2 diabetes (HR = 1.104, 95% CI: 0.998-1.221). Differential effects were not observed by regimen type, cumulative duration, and years since menopause subgroups. Sensitivity analyses also did not show adverse events by MHT on CVDs and type 2 diabetes. CONCLUSIONS: Although protective effects of MHT against CVDs or type 2 diabetes were not observed among postmenopausal women who had screened underlying diseases, our results may contribute to reducing the current concerns about the use of MHT for middle-aged postmenopausal women in Korea.


Video Summary:http://links.lww.com/MENO/A807.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Terapia de Reposição de Estrogênios , Feminino , Humanos , Menopausa , Pessoa de Meia-Idade , Programas Nacionais de Saúde , Pós-Menopausa , República da Coreia/epidemiologia
11.
Cell Rep ; 37(1): 109798, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34587481

RESUMO

Despite the worldwide effect of the coronavirus disease 2019 (COVID-19) pandemic, the underlying mechanisms of fatal viral pneumonia remain elusive. Here, we show that critical COVID-19 is associated with enhanced eosinophil-mediated inflammation when compared to non-critical cases. In addition, we confirm increased T helper (Th)2-biased adaptive immune responses, accompanying overt complement activation, in the critical group. Moreover, enhanced antibody responses and complement activation are associated with disease pathogenesis as evidenced by formation of immune complexes and membrane attack complexes in airways and vasculature of lung biopsies from six fatal cases, as well as by enhanced hallmark gene set signatures of Fcγ receptor (FcγR) signaling and complement activation in myeloid cells of respiratory specimens from critical COVID-19 patients. These results suggest that SARS-CoV-2 infection may drive specific innate immune responses, including eosinophil-mediated inflammation, and subsequent pulmonary pathogenesis via enhanced Th2-biased immune responses, which might be crucial drivers of critical disease in COVID-19 patients.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , Proteínas do Sistema Complemento/imunologia , Eosinófilos/imunologia , Inflamação/imunologia , Pneumonia Viral/imunologia , SARS-CoV-2/imunologia , Imunidade Adaptativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Complexo Antígeno-Anticorpo/metabolismo , COVID-19/metabolismo , COVID-19/virologia , Ativação do Complemento , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Eosinófilos/virologia , Feminino , Humanos , Inflamação/metabolismo , Inflamação/virologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/patologia , Lesão Pulmonar/virologia , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/metabolismo , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais , Células Th2/imunologia , Carga Viral , Adulto Jovem
12.
J Prev Med Public Health ; 54(4): 259-564, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34370939

RESUMO

Traditional epidemiological studies have identified a number of risk factors for various diseases using regression-based methods that examine the association between an exposure and an outcome (i.e., one-to-one correspondences). One of the major limitations of this approach is the "black-box" aspect of the analysis, in the sense that this approach cannot fully explain complex relationships such as biological pathways. With high-throughput data in current epidemiology, comprehensive analyses are needed. The network approach can help to integrate multi-omics data, visualize their interactions or relationships, and make inferences in the context of biological mechanisms. This review aims to introduce network analysis for systems epidemiology, its procedures, and how to interpret its findings.


Assuntos
Epidemiologia , Humanos , Metanálise em Rede
13.
Sci Rep ; 11(1): 12802, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140622

RESUMO

This study aimed to understand the biological process related to the prevention of cardiovascular & metabolic diseases (CMD), including diabetes, hypertension, and dyslipidemia via regular exercise. This study included 17,053 subjects aged 40-69 years in the Health Examinees Study from 2004 to 2012. Participation in regular exercise was investigated by questionnaires. Data on 42 biomarkers were collected from anthropometric measures and laboratory tests. We examined the associations between regular exercise and biomarkers using general linear models, between biomarkers and the risk of CMD using cox proportional hazard models, and the mediation effect of biomarkers using mediation analyses. Biomarker networks were constructed based on the significant differential correlations (p < 0.05) between the exercise and non-exercise groups in men and women, respectively. We observed significant mediators in 14 and 16 of the biomarkers in men and women, respectively. Triglyceride level was a noteworthy mediator in decreasing the risk of CMD with exercise, explaining 23.79% in men and 58.20% in women. The biomarker network showed comprehensive relationships and associations among exercise, biomarkers, and CMD. Body composition-related biomarkers were likely to play major roles in men, while obesity-related biomarkers seemed to be key factors in women.


Assuntos
Biomarcadores/metabolismo , Doenças Cardiovasculares/metabolismo , Exercício Físico/fisiologia , Doenças Metabólicas/metabolismo , Adulto , Idoso , Doenças Cardiovasculares/epidemiologia , Feminino , Humanos , Incidência , Masculino , Doenças Metabólicas/epidemiologia , Pessoa de Meia-Idade , Fatores de Risco
14.
Cancers (Basel) ; 13(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069208

RESUMO

In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10-3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10-4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

15.
Am J Hum Genet ; 108(7): 1190-1203, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34146516

RESUMO

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 × 10-31).


Assuntos
Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Anotação de Sequência Molecular , Regiões Promotoras Genéticas , Neoplasias da Mama/genética , Sistemas CRISPR-Cas , Linhagem Celular , Mapeamento Cromossômico , Cromossomos Humanos Par 2 , Feminino , Estudos de Associação Genética , Variação Genética , Humanos , Fatores de Risco , Deleção de Sequência
16.
Adv Exp Med Biol ; 1187: 419-434, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33983592

RESUMO

Susceptibility genes involved in disease etiology and prognosis are categorized into two groups: high penetrance genes (i.e., BRCA1, CHEK2, ATM, etc.) and low penetrance genes (i.e., NATs, GSTs, CYPs, etc., and variants identified by genome-wide association studies). Since low penetrance genes have high population attributable risk, the usefulness of those genes to research on breast cancer prevention is not small. In this chapter, the previous studies on low-penetrance genetic susceptibility through a candidate gene approach and genome-wide association of breast cancer were summarized. The contribution of low-penetrance susceptibility genes to the breast cancer risk prediction models will also be discussed on the utility in clinical or public health application.


Assuntos
Neoplasias da Mama , Estudo de Associação Genômica Ampla , Neoplasias da Mama/genética , Predisposição Genética para Doença , Humanos , Penetrância
17.
Arch Osteoporos ; 16(1): 67, 2021 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-33839996

RESUMO

In Korean adults aged 50 years and older, the overall risk of fractures increased with greater BMI variability among both men and women, specifically, spinal fractures for men and both spinal and hip fractures for women. PURPOSE: The bone-health-related outcome, such as fractures due to BMI fluctuation, has been understudied within Asian populations. In this large-scale, population-based cohort study in Korea, we aimed to investigate the relationship between variability in body mass index (BMI) and the risk of fractures. METHODS: The study included 166,932 subjects aged ≥ 50 years from the National Health Insurance Service-Health Screening Cohort. The BMI variability value from three follow-up examinations during 2002-2007 was categorized into quartiles. The hazard ratios (HRs) with 95% confidence intervals (CIs) for the effects of BMI variability on the risk of admission from hip, spine, and upper extremity fractures during 2008-2015 were evaluated using a Cox proportional hazards regression analysis. RESULTS: Compared to those in the lowest BMI variability (1st quartile), men in the highest BMI variability (4th quartile) showed an increased risk of spinal fractures (aHR 1.21, 95% CI 1.07-1.36) with a significant linear trend (P for trend = 0.021). Compared to those in the lowest BMI variability (1st quartile), women in the highest BMI variability (4th quartile) showed an increased risk of hip and spinal fractures (aHR 1.35, 95% CI 1.05-1.69; aHR 1.16, 95% CI 1.05-1.28) with significant linear trends (P for trend = 0.021; P for trend = 0.003, respectively). There was no association between BMI variability and incidents of upper extremity fractures for men or women. CONCLUSION: Association between BMI variability and increased fracture risk depended on sex and fracture types. BMI maintenance, instead of high BMI fluctuation, may be beneficial in terms of lowering the overall fracture risk for Korean adults over 50 years old.


Assuntos
Fraturas do Quadril , Adulto , Idoso , Índice de Massa Corporal , Estudos de Coortes , Feminino , Fraturas do Quadril/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Fatores de Risco
18.
Bone ; 147: 115910, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33722773

RESUMO

PURPOSE: The relative contribution of genetic and clinical factors for bone loss is not well known. This study aimed to investigate the annualized percentage change in total hip bone mineral density (BMD) and the genetic and clinical risk factors for bone loss in a Korean prospective cohort study over a 6-year period. METHODS: We included 645 men aged ≥50 years and 683 postmenopausal women who had repeated BMD testing between 2007 and 2014. The association between covariates and annualized percentage change in hip BMD was analyzed through the multivariate linear regression analysis. A total of 2614 single-nucleotide polymorphisms (SNPs) from 23 known BMD-related candidate genes and genome-wise association study were investigated. RESULTS: Hip bone loss increased more rapidly in women than in men with advancing age. Hip bone loss in men increased with lean mass (LM) loss (%/year) (P < 0.001) and current smoking (P = 0.024) and decreased with increasing waist circumference (WC) (P < 0.001), alcohol consumption (P = 0.049), and increase in red blood cell counts (P = 0.031). Decreasing WC (P = 0.009), LM loss (%/year) (P < 0.001), and years since menopause ≤ 3 years (P = 0.003) significantly correlated with hip bone loss in women aged 45-59 years. Hip bone loss in women aged ≥60 years increased with advancing age (P = 0.012), alcohol consumption (P = 0.028), LM loss (%/year) (P = 0.031), and fat mass loss (%/year) (P < 0.001) and decreased with increasing WC (P = 0.025). LRP5 rs498830 (ß = 0.127, P = 0.007) and TNFSF11 rs7325635 (ß = 0.146, P = 0.001) were the top SNPs related to hip bone loss in men and postmenopausal women, respectively. However, none of the SNPs were associated with hip bone loss after Benjamini-Hochberg adjustment. CONCLUSION: In this study, decreasing WC and LM were significant risk factors for hip bone loss in both men and women. Those factors were also identified that had sex-specific or age-specific effects on hip bone loss. None of the SNPs were associated with hip bone loss after multiple testing adjustments. The understanding of the modifiable factors contributing to bone loss has been broadened, and this may have implications such as in developing individualized preventive strategy. Further studies are needed to better predict the risk for bone loss in men and women.


Assuntos
Densidade Óssea , Osteoporose , Densidade Óssea/genética , Feminino , Humanos , Masculino , Osteoporose/genética , Estudos Prospectivos , República da Coreia/epidemiologia , Fatores de Risco
19.
BMC Public Health ; 21(1): 459, 2021 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676466

RESUMO

BACKGROUND: Obesity is well known as a risk factor for cardiovascular disease. We aimed to determine the performance of and the optimal cutoff values for obesity indices to discriminate the presence of metabolic abnormalities as a primary risk factor for cardiovascular diseases in a Health Examinees study (HEXA). METHODS: The current study analyzed 134,195 participants with complete anthropometric and laboratory information in a Health Examinees study, consisting of the Korean population aged 40 to 69 years. The presence of metabolic abnormality was defined as having at least one of the following: hypertension, hyperglycemia, or dyslipidemia. The area under the receiver operating characteristic curve (AUC) and 95% confidence intervals (CIs) were calculated for body mass index, waist to hip ratio, waist to height ratio, waist circumference, and conicity index. RESULTS: The AUC of metabolic abnormalities was the highest for waist-to-height ratio (AUC [95% CIs], 0.677 [0.672-0.683] among men; 0.691 [0.687-0.694] among women), and the lowest for the C index (0.616 [0.611-0.622] among men; 0.645 [0.641-0.649] among women) among both men and women. The optimal cutoff values were 24.3 kg/m2 for the body mass index, 0.887 for the waist-to-hip ratio, 0.499 for the waist-to-height ratio, 84.4 cm for waist circumference and 1.20 m3/2/kg1/2 for the conicity index among men, and 23.4 kg/m2 for the body mass index, 0.832 for the waist-to-hip ratio, 0.496 for the waist-to-height ratio, 77.0 cm for the waist circumference and 1.18 m3/2/kg1/2 for the conicity index among women. CONCLUSION: The waist-to-height ratio is the best index to discriminate metabolic abnormalities among middle-aged Koreans. The optimal cutoff of obesity indices is lower than the international guidelines for obesity. It would be appropriate to use the indices for abdominal obesity rather than general obesity and to consider a lower level of body mass index and waist circumference than the current guidelines to determine obesity-related health problems in Koreans.


Assuntos
Obesidade , Razão Cintura-Estatura , Adulto , Idoso , Antropometria , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico , Obesidade/epidemiologia , Curva ROC , República da Coreia/epidemiologia , Fatores de Risco , Circunferência da Cintura , Relação Cintura-Quadril
20.
Cancer Epidemiol Biomarkers Prev ; 30(4): 623-642, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33500318

RESUMO

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 (P adj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m2 [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.


Assuntos
Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Estilo de Vida , Adulto , Idoso , Causas de Morte , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Estudos Prospectivos , Fatores de Risco , Análise de Sobrevida
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