Publications by authors named "Ji-Yeob Choi"

151 Publications

Enhanced eosinophil-mediated inflammation associated with antibody and complement-dependent pneumonic insults in critical COVID-19.

Cell Rep 2021 10 20;37(1):109798. Epub 2021 Sep 20.

Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul 06351, Republic of Korea; Geninus Inc., Seoul 05836, Republic of Korea.

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.
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http://dx.doi.org/10.1016/j.celrep.2021.109798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450316PMC
October 2021

The age-standardized incidence, mortality, and case fatality rates of COVID-19 among 79 countries: cross-sectional comparison and their correlation with associated factors.

Epidemiol Health 2021 Sep 8:e2021061. Epub 2021 Sep 8.

Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.

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 comparison. In this study, we estimated and compared the age-standardized incidence, mortality, and case fatality rates 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 case fatality rates of 79 countries were age-standardized using the WHO 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). The Pearson's correlation coefficients between the rates and the healthcare resource-related factors were calculated.

Results: The countries with the highest age-standardized incidence, mortality, and case fatality rates 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 0.8520 for all ages and 0.9452 for those 60 years or older. The healthcare resources-related factors were associated positively with incidence rates, and negatively with case fatality rates: the correlations were weaker among the elderly.

Conclusion: Compared to age-standardized rates, crude rates showed greater variation between countries. Medical resources may be important in preventing COVID-19-related deaths; however, considering the small variation in fatality among the elderly, prevention such as vaccination is more important especially for the elderly population to minimize the mortality rates in the elderly population.
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http://dx.doi.org/10.4178/epih.e2021061DOI Listing
September 2021

Body mass index and type 2 diabetes and breast cancer survival: a Mendelian randomization study.

Am J Cancer Res 2021 15;11(8):3921-3934. Epub 2021 Aug 15.

Institute of Biomedical Sciences, Academia Sinica Taipei, Taiwan.

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414374PMC
August 2021

Effects of menopausal hormone therapy on cardiovascular diseases and type 2 diabetes in middle-aged postmenopausal women: analysis of the Korea National Health Insurance Service Database.

Menopause 2021 Sep 13. Epub 2021 Sep 13.

Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea BK21plus Biomedical Science Project, Seoul National University College of Medicine, Seoul, Korea Institute of Health Policy and Management, Seoul National University Medical Research Center, Seoul, Korea Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea Cancer Research Institute, Seoul National University, Seoul, Korea Department of Health Convergence, Ewha Womans University, Seoul, Korea.

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.
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http://dx.doi.org/10.1097/GME.0000000000001848DOI Listing
September 2021

Network Analysis in Systems Epidemiology.

J Prev Med Public Health 2021 Jul 7;54(4):259-564. Epub 2021 Jul 7.

Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.

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.
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http://dx.doi.org/10.3961/jpmph.21.190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357545PMC
July 2021

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

Am J Hum Genet 2021 07 18;108(7):1190-1203. Epub 2021 Jun 18.

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

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10).
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http://dx.doi.org/10.1016/j.ajhg.2021.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322933PMC
July 2021

Network of biomarkers and their mediation effects on the associations between regular exercise and the incidence of cardiovascular & metabolic diseases.

Sci Rep 2021 06 17;11(1):12802. Epub 2021 Jun 17.

Department of Biomedical Sciences, Seoul National University Graduate School, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.

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.
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http://dx.doi.org/10.1038/s41598-021-92312-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211674PMC
June 2021

Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?

Cancers (Basel) 2021 May 14;13(10). Epub 2021 May 14.

Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark.

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 (-2df = 1.2 × 10). 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 (-2df = 1.1 × 10). 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.
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http://dx.doi.org/10.3390/cancers13102370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156547PMC
May 2021

Breast Cancer-Related Low Penetrance Genes.

Adv Exp Med Biol 2021 ;1187:419-434

Seoul National University, Seoul, South Korea.

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.
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http://dx.doi.org/10.1007/978-981-32-9620-6_22DOI Listing
May 2021

Association between BMI variability and risk of fracture among Korean men and women: a population based study.

Arch Osteoporos 2021 04 10;16(1):67. Epub 2021 Apr 10.

Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea.

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.
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http://dx.doi.org/10.1007/s11657-021-00918-5DOI Listing
April 2021

Integrative analysis of genetic and clinical risk factors for bone loss in a Korean population.

Bone 2021 06 17;147:115910. Epub 2021 Mar 17.

Department of Preventive Medicine, Ajou University School of Medicine, Suwon, Republic of Korea. Electronic address:

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 (β = 0.127, P = 0.007) and TNFSF11 rs7325635 (β = 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.
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http://dx.doi.org/10.1016/j.bone.2021.115910DOI Listing
June 2021

Optimal cutoff values for anthropometric indices of obesity as discriminators of metabolic abnormalities in Korea: results from a Health Examinees study.

BMC Public Health 2021 03 6;21(1):459. Epub 2021 Mar 6.

Department of Family Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.

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/m 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 m/kg for the conicity index among men, and 23.4 kg/m 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 m/kg 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.
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http://dx.doi.org/10.1186/s12889-021-10490-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937287PMC
March 2021

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

Cancer Epidemiol Biomarkers Prev 2021 04 26;30(4):623-642. Epub 2021 Jan 26.

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

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

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

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

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

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

A systematic review and meta-analysis of effects of menopausal hormone therapy on cardiovascular diseases.

Sci Rep 2020 11 26;10(1):20631. Epub 2020 Nov 26.

Department of Biomedical Sciences, Seoul National University Graduate School, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.

A systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies was conducted to assess the association between menopausal hormone therapy and cardiovascular disease. The PubMed and EMBASE databases were searched for articles published from 2000 to 2019, using review methods based on a previous Cochrane review. Quality assessment of RCTs and observational studies was conducted using the Jadad scale and the Newcastle-Ottawa Scale, respectively. A total of 26 RCTs and 47 observational studies were identified. The study populations in the RCTs were older and had more underlying diseases than those in the observational studies. Increased risks of venous thromboembolism [summary estimate (SE), 95% confidence interval (CI): RCTs, 1.70, 1.33-2.16; observational studies, 1.32, 1.13-1.54] were consistently identified in both study types, whereas an increased risk of stroke in RCTs (SE: 1.14, 95% CI: 1.04-1.25) and a decreased risk of myocardial infarction in observational studies (SE: 0.79, 95% CI: 0.75-0.84) were observed. Differential clinical effects depending on timing of initiation, underlying disease, regimen type, and route of administration were identified through subgroup analyses. These findings suggest that underlying disease and timing of initiation should be carefully considered before starting therapy in postmenopausal women.
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http://dx.doi.org/10.1038/s41598-020-77534-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691511PMC
November 2020

Effect of Citric Acid Cycle Genetic Variants and Their Interactions with Obesity, Physical Activity and Energy Intake on the Risk of Colorectal Cancer: Results from a Nested Case-Control Study in the UK Biobank.

Cancers (Basel) 2020 Oct 12;12(10). Epub 2020 Oct 12.

Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Korea.

Colorectal cancer is a common malignancy worldwide. Physical activity and a healthy diet contribute to energy balance and have been recommended for the prevention of colorectal cancer. We suggest that the individual differences in energy balance can be explained by genetic polymorphisms involved in mitochondria, which play a central role in energy metabolism at the cellular level. This study aimed to evaluate the association between genetic variants of the mitochondrial citric acid cycle and colorectal cancer. Study participants comprised 3523 colorectal cancer cases and 10,522 matched controls from the UK Biobank study. Odds ratios (ORs) and 95% confidence intervals (CIs) for colorectal cancer were estimated using a conditional logistic regression model. We found a significant association between the gene rs35494829 and colon cancer (ORs [95% CIs] per increment of the minor allele, 0.82 [0.74-0.92]). Statistical significance was observed in the interactions of the citric acid cycle variants with obesity, energy intake, and vigorous physical activity in colorectal cancer. We also identified significant SNP-SNP interactions among citric acid cycle SNPs in colorectal cancer. The results of this study may provide evidence for bioenergetics in the development of colorectal cancer and for establishing a precise prevention strategy.
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http://dx.doi.org/10.3390/cancers12102939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601149PMC
October 2020

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Am J Hum Genet 2020 11 5;107(5):837-848. Epub 2020 Oct 5.

Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong; Hong Kong Sanatorium and Hospital, Department of Pathology, Happy Valley, Hong Kong.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS was quantified using Cox regression analyses. We assessed PRS interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10 percentile and 20.5% at the 90 percentile of PRS. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675034PMC
November 2020

Sustained Responses of Neutralizing Antibodies Against Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Recovered Patients and Their Therapeutic Applicability.

Clin Infect Dis 2021 08;73(3):e550-e558

Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul, Republic of Korea.

Background: Zoonotic coronaviruses have emerged as a global threat by causing fatal respiratory infections. Given the lack of specific antiviral therapies, application of human convalescent plasma retaining neutralizing activity could be a viable therapeutic option that can bridges this gap.

Methods: We traced antibody responses and memory B cells in peripheral blood collected from 70 recovered Middle East respiratory syndrome coronavirus (MERS-CoV) patients for 3 years after the 2015 outbreak in South Korea. We also used a mouse infection model to examine whether the neutralizing activity of collected sera could provide therapeutic benefit in vivo upon lethal MERS-CoV challenge.

Results: Anti-spike-specific IgG responses, including neutralizing activity and antibody-secreting memory B cells, persisted for up to 3 years, especially in MERS patients who suffered from severe pneumonia. Mean antibody titers gradually decreased annually by less than 2-fold. Levels of antibody responses were significantly correlated with fever duration, viral shedding periods, and maximum viral loads observed during infection periods. In a transgenic mice model challenged with lethal doses of MERS-CoV, a significant reduction in viral loads and enhanced survival was observed when therapeutically treated with human plasma retaining a high neutralizing titer (> 1/5000). However, this failed to reduce pulmonary pathogenesis, as revealed by pathological changes in lungs and initial weight loss.

Conclusions: High titers of neutralizing activity are required for suppressive effect on the viral replication but may not be sufficient to reduce inflammatory lesions upon fatal infection. Therefore, immune sera with high neutralizing activity must be carefully selected for plasma therapy of zoonotic coronavirus infection.
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http://dx.doi.org/10.1093/cid/ciaa1345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499518PMC
August 2021

Adherence to the Recommended Intake of Calcium and Colorectal Cancer Risk in the HEXA Study.

Cancer Res Treat 2021 Jan 25;53(1):140-147. Epub 2020 Aug 25.

JW LEE Center for Global Medicine, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Dietary calcium intake has been suggested to be protective against the development of colorectal cancer. The mean dietary calcium intake of Koreans is 490 mg/day, which is far below the recommended calcium intake of 700-800 mg/day. In this study, we explored the relationship between dietary calcium intake and colorectal cancer development in Koreans with relatively low calcium intake compared with individuals in Western countries.

Materials And Methods: The Health Examinees Study, a large-scale genomic community-based prospective cohort study, was designed to identify the general characteristics of major chronic diseases in Koreans. A total of 119,501 participants aged 40-69 years recruited between 2004 and 2013 were included in this analysis. The calcium intake level was categorized using the Dietary Reference Intakes for Koreans (KDRIs). The Cox proportional hazards regression model was used to estimate the hazard ratio (HR) and the corresponding 95% confidence intervals (CIs) for colorectal cancer risk, adjusting for potential confounders.

Results: In the multivariable-adjusted model, compared with the group that consumed less than the recommended amount of calcium, the group that consumed more than the recommended intake of calcium showed a significant reduction in the risk of colorectal cancer in women. (HR, 0.54; 95% CI, 0.31 to 0.95). Among men, however, no significant association was observed between dietary calcium intake and colorectal cancer risk (HR, 0.89; 95% CI, 0.54 to 1.45).

Conclusion: Korean women who adhere to the recommended intake of calcium showed a reduced risk of colorectal cancer.
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http://dx.doi.org/10.4143/crt.2020.480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812010PMC
January 2021

Association of sleep duration and quality with elevated hs-CRP among healthy Korean adults.

PLoS One 2020 25;15(8):e0238053. Epub 2020 Aug 25.

Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.

This study aimed to investigate the association of sleep duration and quality with high-sensitivity C-reactive protein (hs-CRP) among middle-aged and elderly Koreans. Among a total of 74,867 participants (25,069 men and 49,798 women) recruited for the Health Examinees (HEXA) study, adjusted geometric means of hs-CRP level were compared across categories of sleep duration (<6, 6-7, 8-9, and ≥10 hours) and sleep quality (difficulty in initiating sleep and maintaining sleep) using ANCOVA models. Odds ratios (ORs) and 95% confidence intervals (CIs) for elevated hs-CRP (>3 mg/L) associated with sleep characteristics were estimated using multivariable-adjusted logistic regression models. Men who slept ≥10 hours per day were significantly associated with elevated hs-CRP (OR = 1.47, 95% CI 1.11-1.95). Whereas in women, difficulty in initiating sleep (OR = 1.28, 95% CI 1.04-1.57 for "Always"), and maintaining sleep was significantly associated with elevated hs-CRP levels (OR = 1.13, 95% CI 1.02-1.26 for "Often"; OR = 1.11, 95% CI 0.97-1.28 for "Always"). Additionally, women who experienced poor sleep quality presented an elevated level of hs-CRP (OR = 1.13, 95% CI 1.03-1.23). Our findings suggest that excessive sleep duration and poor sleep quality are significantly associated with the elevated inflammatory marker, specifically hs-CRP. Further research is needed to examine the effect of sleep interventions focused on these factors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238053PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446961PMC
October 2020

Relative effects of demographic, psychological, behavioral, and social factors on the initiation and maintenance of leisure-time physical activity: Results from a confirmatory path analysis in a longitudinal study.

J Epidemiol 2020 Aug 8. Epub 2020 Aug 8.

Department of Biomedical Sciences, Seoul National University Graduate School.

Background: There is a lack of evidence of the complicated pathways of underlying determinants in the phases of physical activity. The purpose of this study was to evaluate simultaneously a set of potential determinants on the initiation and maintenance phases of leisure-time physical activity (LTPA).

Methods: The longitudinal data of 54,359 Korean adults aged 40-69 years from the Health Examinees study were used. The median follow-up duration was 4.2 years. The self-reported durations per week of LTPA was repeatedly assessed. Based on previous longitudinal studies, the potential determinants were selected, and hypothetical models were constructed that consider the complex associations between the determinants. The standardized coefficients for direct and indirect effects were estimated by path analysis to differentiate contributions of mediation from the total effects.

Results: In the total population, age, education, chronic diseases, smoking, depression symptoms, and self-rated health were significantly associated with both initiation and maintenance phases. Income (B=0.025) and social supports (B=0.019) were associated only with the initiation phase. Waist-to-hip ratio (B=-0.042) and stress (B=-0.035) were associated only with the maintenance phase. After stratifying by sex, the significant effects of education, chronic diseases, and smoking were found only in men. The initiation phase-specific effects of income and social supports and the maintenance phase-specific effects of stress were found only in women. It was estimated that indirect effects contributed approximately 15% of the total effect.

Conclusion: The findings suggested that there were initiation- or maintenance-specific determinants of leisure-time physical activity according to sex.
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http://dx.doi.org/10.2188/jea.JE20200073DOI Listing
August 2020

European polygenic risk score for prediction of breast cancer shows similar performance in Asian women.

Nat Commun 2020 07 31;11(1):3833. Epub 2020 Jul 31.

Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore, Singapore.

Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.
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http://dx.doi.org/10.1038/s41467-020-17680-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395776PMC
July 2020

Patterns of leisure time and household physical activity and the risk of mortality among middle-aged Korean adults.

PLoS One 2020 18;15(6):e0234852. Epub 2020 Jun 18.

Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.

Background: Although many studies have focused on leisure time physical activity (LTPA), household physical activity (HPA) can contribute to health benefits. This study aimed to compare LTPA and HPA patterns and to examine the association of these types of activities with the risk of mortality in Korea.

Methods: A total of 125,299 participants 40 to 69 years old and enrolled in the Health Examinees (HEXA) study from 2004 to 2012 were included in this study. The sex-specific LTPA and HPA categories were defined based on a questionnaire. A multinomial logistic regression was used to examine the LTPA and HPA correlates. Hazard ratios (HR) with 95% confidence intervals (95% CIs) of all-cause mortality were estimated using the Cox proportional hazard model.

Results: Overall, the LTPA and HPA patterns differed by age, income, and history of chronic diseases. LTPA reduced the risk of death, and lower risks were observed in more time spent engaged in or a vigorous LTPA intensity. The subjects who participated only in HPA and were not involved in LTPA also had lower risks of mortality (HR = 0.72, 95% CIs: 0.60-0.85 for men, and HR = 0.84, 95% CIs: 0.69-1.02 for women) than those who did not participate in both LTPA and HPA.

Conclusions: HPA reduced the risks of mortality in middle-aged Korean adults and could even decrease the risk of death in those who did not participate in LTPA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234852PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302697PMC
September 2020

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk.

Sci Rep 2020 06 16;10(1):9688. Epub 2020 Jun 16.

Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.
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http://dx.doi.org/10.1038/s41598-020-65665-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297796PMC
June 2020

Marital status and the prevalence of obesity in a Korean population.

Obes Res Clin Pract 2020 May - Jun;14(3):217-224. Epub 2020 May 14.

JW LEE Center for Global Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Family Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Seoul Center for Infectious Disease Control, Seoul, Republic of Korea. Electronic address:

Objective: Previous studies have reported on marital status and the prevalence of obesity; however, few studies have assessed the prevalence of underweight in relation to marital status. This study aimed to explore the association of obesity and abdominal obesity with marital status among Koreans aged 40-69 years.

Methods: We selected a total of 137,608 participants from the Health Examinees Gem Study for the final analysis. Multinomial logistic regression models were used to estimate odds ratios (OR) and their 95% confidence intervals (CI) for the association of obesity with marital status, with controlling for potential confounders.

Results: The prevalence of underweight was higher in unmarried men (OR: 1.82, 95% CI: 1.25-2.63) and women (OR: 2.16, 95% CI: 1.79-2.61) than in married individuals. Compared to married individuals, a lower prevalence of BMI≥25kg/m was observed for those who were unmarried (men: OR: 0.71, 95% CI: 0.62-0.81, women: OR: 0.65, 95% CI: 0.58-0.73) or divorced/separated (men: OR: 0.80, 95% CI: 0.69-0.93, women: OR: 0.90, 95% CI: 0.83-0.98). Interestingly, widowed women showed higher prevalence of BMI≥25kg/m (OR: 1.17, 95% CI: 1.10-1.25) and abdominal obesity (OR: 1.23, 95% CI: 1.16-1.30) compared to married women, and the association persisted only among women in their 50s and 60s.

Conclusions: Married participants showed a higher prevalence of obesity and abdominal obesity than those in other marriage categories except for widowed women.
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http://dx.doi.org/10.1016/j.orcp.2020.04.003DOI Listing
April 2021

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants.

Nat Commun 2020 03 5;11(1):1217. Epub 2020 Mar 5.

Departments of Health Research and Policy, School of Medicine, Stanford University, California, CA, USA.

Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women.
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http://dx.doi.org/10.1038/s41467-020-15046-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057957PMC
March 2020

Altered expression of fucosylation pathway genes is associated with poor prognosis and tumor metastasis in non‑small cell lung cancer.

Int J Oncol 2020 Feb 24;56(2):559-567. Epub 2019 Dec 24.

Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.

Fucosylation is a post‑translational modification that attaches fucose residues to protein‑ or lipid‑bound oligosaccharides. Certain fucosylation pathway genes are aberrantly expressed in several types of cancer, including non‑small cell lung cancer (NSCLC), and this aberrant expression is associated with poor prognosis in patients with cancer. However, the molecular mechanism by which these fucosylation pathway genes promote tumor progression has not been well‑characterized. The present study analyzed public microarray data obtained from NSCLC samples. Multivariate analysis revealed that altered expression of fucosylation pathway genes, including fucosyltransferase 1 (FUT1), FUT2, FUT3, FUT6, FUT8 and GDP‑L‑fucose synthase (TSTA3), correlated with poor survival in patients with NSCLC. Inhibition of FUTs by 2F‑peracetyl‑fucose (2F‑PAF) suppressed transforming growth factor β (TGFβ)‑mediated Smad3 phosphorylation and nuclear translocation in NSCLC cells. In addition, wound‑healing and Transwell migration assays demonstrated that 2F‑PAF inhibited TGFβ‑induced NSCLC cell migration and invasion. Furthermore, in vivo bioluminescence imaging analysis revealed that 2F‑PAF attenuated the metastatic capacity of NSCLC cells. These results may help characterize the oncogenic role of fucosylation in NSCLC biology and highlight its potential for developing cancer therapeutics.
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http://dx.doi.org/10.3892/ijo.2019.4953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959459PMC
February 2020

Re-evaluating genetic variants identified in candidate gene studies of breast cancer risk using data from nearly 280,000 women of Asian and European ancestry.

EBioMedicine 2019 Oct 16;48:203-211. Epub 2019 Oct 16.

Department of Epidemiology, Cancer Prevention Institute of California, Fremont, CA, USA; Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.

Background: We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genome-wide association studies (GWAS) have accumulated data for hundreds of thousands of subjects. It's necessary to re-evaluate these variants in large GWAS datasets.

Methods: Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets.

Findings: Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P < 2·19 × 10. The associations for four variants reached P < 5 × 10 and have been reported by previous GWAS, including rs6435074 and rs6723097 (CASP8), rs17879961 (CHEK2) and rs2853669 (TERT). The remaining eight variants were rs676387 (HSD17B1), rs762551 (CYP1A2), rs1045485 (CASP8), rs9340799 (ESR1), rs7931342 (CHR11), rs1050450 (GPX1), rs13010627 (CASP10) and rs9344 (CCND1). Further investigating these 10 genes identified associations for two additional variants at P < 5 × 10, including rs4793090 (near HSD17B1), and rs9210 (near CYP1A2), which have not been identified by previous GWAS.

Interpretation: Though most candidate gene variants were not associated with breast cancer risk, we found 14 variants showing an association. Our findings warrant further functional investigation of these variants. FUND: National Institutes of Health.
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http://dx.doi.org/10.1016/j.ebiom.2019.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838373PMC
October 2019

IL-17A-Producing Innate Lymphoid Cells Promote Skin Inflammation by Inducing IL-33-Driven Type 2 Immune Responses.

J Invest Dermatol 2020 04 16;140(4):827-837.e9. Epub 2019 Oct 16.

Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea. Electronic address:

Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease characterized by type 2 cytokines secreted by T helper type 2 cells and group 2 innate lymphoid cells. Despite a high degree of heterogeneity, AD is still explained by type 2 immunity, and the role of IL-17A, which is increased in acute, pediatric, or Asian patients with AD, remains poorly understood. Here, we aimed to investigate the role of IL-17A-producing group 3 innate lymphoid cells (ILC3s), which are unexplored immune cells, in the pathogenesis of AD. We found that the numbers of ILC3s in the skin of AD-induced mice were increased, and that neutralizing IL-17A delayed development of AD. Moreover, adoptive transfer of ILC3s accelerated the symptoms of AD. Mechanically, ILC3s induced IL-33 production by nonimmune skin cells, keratinocytes, and fibroblasts, which promoted type 2 immune responses. Because AD has a complex pathophysiology and a broad spectrum of clinical phenotypes, the presence of ILC3s in the skin and their interaction with nonimmune skin cells could explain the pathogenesis of cutaneous AD.
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http://dx.doi.org/10.1016/j.jid.2019.08.447DOI Listing
April 2020

Strong association between herpes simplex virus-1 and chemotherapy-induced oral mucositis in patients with hematologic malignancies.

Korean J Intern Med 2020 09 9;35(5):1188-1198. Epub 2019 Sep 9.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Background/aims: A link between oral cavity infections and chemotherapy-induced oral mucositis (CIOM) in patients with hematological malignancies (HMs) undergoing intensive chemotherapy (IC) or hematopoietic stem cell transplantation (HSCT) has been suggested. However, conclusive data are lacking, and there are no current guidelines for the prophylactic use of antimicrobials to prevent CIOM in these populations.

Methods: The relationships between herpes simplex virus (HSV) reactivation and Candida colonization in the oral cavity and CIOM in patients with HMs undergoing IC or HSCT were evaluated. Patients aged ≥ 19 years with HMs undergoing IC or HSCT were enrolled. Each patient was evaluated for HSV and Candida in the oral cavity along with CIOM at baseline and during the 2nd, 3rd, and 4th weeks.

Results: Seventy presentations among 56 patients were analyzed. CIOM was observed in 23 presentations (32.9%), with a higher incidence associated with HSCT (17 of 35 presentations, 48.6%) than with IC (six of 35 presentations, 8.6%). The reactivation of HSV-1 was significantly associated with an increased incidence of CIOM after adjusting for age, sex, type of disease, and treatment stage. A higher HSV-1 viral load was associated with an increased incidence of CIOM. The presence of Candida was not associated with CIOM.

Conclusion: HSV-1 reactivation in the oral cavity was highly associated with CIOM in patients with HMs undergoing high-dose chemotherapy.
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http://dx.doi.org/10.3904/kjim.2018.469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487294PMC
September 2020

Two truncating variants in FANCC and breast cancer risk.

Sci Rep 2019 08 29;9(1):12524. Epub 2019 Aug 29.

Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
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http://dx.doi.org/10.1038/s41598-019-48804-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715680PMC
August 2019
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