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Background The association between metabolic comorbidity and myocardial infarction (MI) among individuals with a family history of cardiovascular disease (CVD) is yet to be elucidated. We aimed to examine the combined effects of metabolic comorbidities, including diabetes mellitus, hypertension, and dyslipidemia, with a family history of CVD in first-degree on the risk of incident MI. Methods This cohort study consisted of 81,803 participants aged 40–89 years without a previous history of MI at baseline from the Korean Genome and Epidemiology Study. We performed Cox proportional hazard regression analysis to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for MI and early-onset MI risk associated with metabolic comorbidity in individuals with a family history of CVD. Results During a median follow-up of 5 years, 1,075 and 479 cases of total and early-onset MI were reported, respectively. According to the disease score, among individuals who had a positive family history of CVD, the HRs for MI were 1.92 (95% CI: 1.47–2.51) in individuals with one disease, 2.75 (95% CI: 2.09–3.61) in those with two diseases, and 3.74 (95% CI: 2.45–5.71) in those with three diseases at baseline compared to individuals without a family history of CVD and metabolic diseases. Similarly, an increase of the disease score among individuals with a positive family history of CVD was associated with an increase in early-onset MI risk. Conclusion Metabolic comorbidity was significantly associated with an increased risk of MI among individuals with a family history of CVD.

We aimed to summarize the cancer risk among patients with indication of group I pharmaceuticals as stated in monographs presented by the International Agency for Research on Cancer working groups. Following the PRISMA guidelines, a comprehensive literature search was conducted using the PubMed database. Pharmaceuticals with few studies on cancer risk were identified in systematic reviews; those with two or more studies were subjected to meta-analysis. For the meta-analysis, a random-effects model was used to calculate the summary relative risks (SRRs) and 95% confidence intervals (95% CIs). Heterogeneity across studies was presented using the Higgins I square value from Cochran’s Q test. Among the 12 group I pharmaceuticals selected, three involved a single study [etoposide, thiotepa, and mustargen + oncovin + procarbazine + prednisone (MOPP)], seven had two or more studies [busulfan, cyclosporine, azathioprine, cyclophosphamide, methoxsalen + ultraviolet (UV) radiation therapy, melphalan, and chlorambucil], and two did not have any studies [etoposide + bleomycin + cisplatin and treosulfan]. Cyclosporine and azathioprine reported increased skin cancer risk (SRR = 1.32, 95% CI 1.07–1.62; SRR = 1.56, 95% CI 1.25–1.93) compared to non-use. Cyclophosphamide increased bladder and hematologic cancer risk (SRR = 2.87, 95% CI 1.32–6.23; SRR = 2.43, 95% CI 1.65–3.58). Busulfan increased hematologic cancer risk (SRR = 6.71, 95% CI 2.49–18.08); melphalan was associated with hematologic cancer (SRR = 4.43, 95% CI 1.30–15.15). In the systematic review, methoxsalen + UV and MOPP were associated with an increased risk of skin and lung cancer, respectively. Our results can enhance persistent surveillance of group I pharmaceutical use, establish novel clinical strategies for patients with indications, and provide evidence for re-categorizing current group I pharmaceuticals into other groups.

An increased risk of gastric cancer for pickled vegetable and salted fish intake has been suggested, yet the lack of a dose-response association warrants a quantitative analysis. We conducted a meta-analysis, combining results from our analysis of two large Korean cohort studies and those from previous prospective cohort studies. We investigated the association of pickled vegetable and salted fish intake with gastric cancer in the Korean Genome Epidemiology Study and the Korean Multi-center Cancer Cohort Study using Cox proportional hazard models. We then searched for observational studies published until November 2019 and conducted both dose-response and categorical meta-analyses. The pooled relative risk (RR) of gastric cancer incidence was 1.15 (95% Confidence Interval (CI), 1.07–1.23) for 40 g/day increment in pickled vegetable intake in a dose-response manner (P for nonlinearity = 0.11). As for salted fish intake, the pooled risk of gastric cancer incidence was 1.17 (95% CI, 0.99–1.38) times higher, comparing the highest to the lowest intake. Our findings supported the evidence that high intake of pickled vegetable and salted fish is associated with elevated risk of gastric cancer incidence.

Background Fragmentomics, the investigation of fragmentation patterns of cell-free DNA (cfDNA), has emerged as a promising strategy for the early detection of multiple cancers in the field of liquid biopsy. However, the clinical application of this approach has been hindered by a limited understanding of cfDNA biology. Furthermore, the prevalence of hematopoietic cell-derived cfDNA in plasma complicates the in vivo investigation of tissue-specific cfDNA other than that of hematopoietic origin. While conventional two-dimensional cell lines have contributed to research on cfDNA biology, their limited representation of in vivo tissue contexts underscores the need for more robust models. In this study, we propose three-dimensional organoids as a novel in vitro model for studying cfDNA biology, focusing on multifaceted fragmentomic analyses. Results We established nine patient-derived organoid lines from normal lung airway, normal gastric, and gastric cancer tissues. We then extracted cfDNA from the culture medium of these organoids in both proliferative and apoptotic states. Using whole-genome sequencing data from cfDNA, we analyzed various fragmentomic features, including fragment size, footprints, end motifs, and repeat types at the end. The distribution of cfDNA fragment sizes in organoids, especially in apoptosis samples, was similar to that found in plasma, implying occupancy by mononucleosomes. The footprints determined by sequencing depth exhibited distinct patterns depending on fragment sizes, reflecting occupancy by a variety of DNA-binding proteins. Notably, we discovered that short fragments (< 118 bp) were exclusively enriched in the proliferative state and exhibited distinct fragmentomic profiles, characterized by 3 bp palindromic end motifs and specific repeats. Conclusions In conclusion, our results highlight the utility of in vitro organoid models as a valuable tool for studying cfDNA biology and its associated fragmentation patterns. This, in turn, will pave the way for further enhancements in noninvasive cancer detection methodologies based on fragmentomics.

Epigenetic influence plays a role in the association between exposure to air pollution and attention deficit hyperactivity disorder (ADHD); however, research regarding sulfur dioxide (SO 2 ) is scarce. Herein, we investigate the associations between prenatal SO 2 exposure and ADHD rating scale (ARS) at ages 4, 6 and 8 years repeatedly in a mother–child cohort (n = 329). Whole blood samples were obtained at ages 2 and 6 years, and genome-wide DNA methylation (DNAm) was analyzed for 51 children using the Illumina Infinium HumanMethylation BeadChip. We analyzed the associations between prenatal SO 2 exposure and DNAm levels at ages 2 and 6, and further investigated the association between the DNAm and ARS at ages 4, 6 and 8. Prenatal SO 2 exposure was associated with ADHD symptoms. From candidate gene analysis, DNAm levels at the 6 CpGs at age 2 were associated with prenatal SO 2 exposure levels. Of the 6 CpGs, cg07583420 ( INS-IGF2 ) was persistently linked with ARS at ages 4, 6 and 8. Epigenome-wide analysis showed that DNAm at 6733 CpG sites were associated with prenatal SO 2 exposure, of which 58 CpGs involved in Notch signalling pathway were further associated with ARS at age 4, 6 and 8 years, persistently. DNAm at age 6 was not associated with prenatal SO 2 exposure. Changes in DNAm levels associated with prenatal SO 2 exposure during early childhood are associated with increases in ARS in later childhood.

Background and purpose Genome-wide association studies (GWAS) of metabolic syndrome (MetS) have predominantly focused on non-Asian populations, with limited representation from East Asian cohorts. Moreover, previous GWAS analyses have primarily emphasized the significance of top single nucleotide polymorphisms (SNPs), poorly explaining other SNP signals in linkage disequilibrium. This study aimed to reveal the interaction between rs651821 and rs2266788, the principal variants of apolipoprotein A5 ( APOA5 ), within the most significant loci identified through GWAS on MetS. Methods GWAS on MetS and its components was conducted using the data from the Korean Genome and Epidemiology Study (KoGES) city cohort comprising 58,600 individuals with available biochemical, demographic, lifestyle factors, and the most significant APOA5 locus was analyzed further in depth. Results According to GWAS of MetS and its diagnostic components, a significant association between the APOA5 SNPs rs651821/rs2266788 and MetS/triglycerides/high-density lipoprotein phenotypes was revealed. However, a conditional analysis employing rs651821 unveiled a reversal in the odds ratio for rs2266788. Therefore, rs651821 and rs2266788 emerged as independent and opposing signals in the extended GWAS analysis, i.e., the multilayered effects. Further gene-environment interaction analyses regarding lifestyle factors such as smoking, alcohol consumption, and physical activity underscored these multilayered effects. Conclusion This study unveils the intricate interplay between rs651821 and rs2266788 derived from MetS GWAS. Removing the influence of lead SNP reveals an independent protective signal associated with rs2266788, suggesting a multilayered effect between these SNPs. These findings underline the need for novel perspectives in future MetS GWAS.

We present an in-depth single-cell atlas of in vitro multiculture systems on human primary airway epithelium derived from normal and diseased lungs of 27 individual donors. Our large-scale single-cell profiling identified new cell states and differentiation trajectories of rare airway epithelial cell types in human distal lungs. By integrating single-cell datasets of human lung tissues, we discovered immune-primed subsets enriched in lungs and organoids derived from patients with chronic respiratory disease. To demonstrate the full potential of our platform, we further illustrate transcriptomic responses to various respiratory virus infections in vitro airway models. Our work constitutes a single-cell roadmap for the cellular and molecular characteristics of human primary lung cells in vitro and their relevance to human tissues in vivo. Organ models: Checking a match with human lung tissue A new atlas of single cell profiles from human lungs provides a powerful platform for comparing immune responses in vitro and in vivo. The COVID-19 pandemic highlighted the usefulness of growing mini human organ cultures, called organoids, to understand the pathogenesis of diseases, especially in the epithelial cells that line the lungs. However, it is vital to confirm that these model systems accurately replicate the gene expression of real tissues. Jong-Il Kim at Seoul National University and co-workers established a biobank of 83 organoid lines derived from 27 healthy and diseased donor lungs, and verified that their transcriptomes—single cell mRNA expression profiles – were similar to those of real human lung tissues. This enabled them to map the differentiation of resident stem cells into rare airway types, and discover distinct subsets of cells primed for immunity.

Identifying the predisposing factors to chronic or end-stage kidney disease is essential to preventing or slowing kidney function decline. Therefore, here, we investigated the genetic variants related to a rapid decline in the estimated glomerular filtration rate (eGFR) (i.e., a loss of >5 mL/min/1.73 m2 per year) and verified the relationships between variant-related diseases and metabolic pathway signaling in patients with chronic kidney disease. We conducted a genome-wide association study that included participants with diabetes, hypertension, and rapid eGFR decline from two Korean data sources (N = 115 and 69 for the discovery and the validation cohorts, respectively). We identified a novel susceptibility locus: 4q32.3 (rs10009742 in the MARCHF1 gene, beta = −3.540, P = 4.11 × 10−8). Fine-mapping revealed 19 credible, causal single-nucleotide polymorphisms, including rs10009742. The pimelylcarnitine and octadecenoyl carnitine serum concentrations were associated with rs10009742 (beta = 0.030, P = 7.10 × 10−5, false discovery rate (FDR) = 0.01; beta = 0.167, P = 8.11 × 10−4, FDR = 0.08). Our results suggest that MARCHF1 is associated with a rapid eGFR decline in patients with hypertension and diabetes. Furthermore, MARCHF1 affects the pimelylcarnitine metabolite concentration, which may mediate chronic kidney disease progression by inducing oxidative stress in the endoplasmic reticulum.

The aim of this study was to examine the association between indoor tanning use and the risk of overall and early-onset (age < 50) melanoma and non-melanoma skin cancer (NMSC). To evaluate the association between indoor tanning and skin cancer, a systematic review of the literature published until July 2021 was performed using PubMed, EMBASE, and MEDLINE. Summary relative risk (RR) from 18 studies with 10,406 NMSC cases and 36 studies with 14,583 melanoma cases showed significant association between skin cancer and indoor tanning (melanoma, RR= 1.27, 95% CI 1.16–1.39; NMSC, RR = 1.40, 95% CI 1.18–1.65; squamous cell carcinoma (SCC), RR = 1.58, 95% CI 1.38–1.81; basal cell carcinoma (BCC), RR = 1.24, 95% CI 1.00–1.55). The risk was more pronounced in early-onset skin cancer (melanoma, RR = 1.75, 95% CI 1.14–2.69; NMSC, RR = 1.99, 95% CI 1.48–2.68; SCC, RR = 1.81, 95% CI 1.38–2.37; BCC, RR = 1.75, 95% CI 1.15–2.77). Moreover, first exposure at an early age (age ≤ 20 years) and higher exposure (annual frequency ≥ 10 times) to indoor tanning showed increasing risk for melanoma (RR = 1.47, 95% CI 1.16–1.85; RR = 1.52, 1.22–1.89) and NMSC (RR = 2.02, 95% CI 1.44–2.83; RR = 1.56, 95% CI 1.31–1.86). These findings provide evidence supporting primary prevention policies regulating modifiable behaviors to reduce the additional risk of skin cancer among younger adults.

Chronological age (CA) predicts health status but its impact on health varies with anthropometry, socioeconomic status (SES), and lifestyle behaviors. Biological age (BA) is, therefore, considered a more precise predictor of health status. We aimed to develop a BA prediction model from self-assessed risk factors and validate it as an indicator for predicting the risk of chronic disease. A total of 101,980 healthy participants from the Korean Genome and Epidemiology Study were included in this study. BA was computed based on body measurements, SES, lifestyle behaviors, and presence of comorbidities using elastic net regression analysis. The effects of BA on diabetes mellitus (DM), hypertension (HT), combination of DM and HT, and chronic kidney disease were analyzed using Cox proportional hazards regression. A younger BA was associated with a lower risk of DM (HR = 0.63, 95% CI: 0.55–0.72), hypertension (HR = 0.74, 95% CI: 0.68–0.81), and combination of DM and HT (HR = 0.65, 95% CI: 0.47–0.91). The largest risk of disease was seen in those with a BA higher than their CA. A consistent association was also observed within the 5-year follow-up. BA, therefore, is an effective tool for detecting high-risk groups and preventing further risk of chronic diseases through individual and population-level interventions.