RESUMO
Transcriptome-wide association studies (TWAS) have identified many putative susceptibility genes for colorectal cancer (CRC) risk. However, susceptibility miRNAs, critical dysregulators of gene expression, remain unexplored. We genotyped DNA samples from 313 CRC East Asian patients and performed small RNA sequencing in their normal colon tissues distant from tumors to build genetic models for predicting miRNA expression. We applied these models and data from genome-wide association studies (GWAS) including 23 942 cases and 217 267 controls of East Asian ancestry to investigate associations of predicted miRNA expression with CRC risk. Perturbation experiments separately by promoting and inhibiting miRNAs expressions and further in vitro assays in both SW480 and HCT116 cells were conducted. At a Bonferroni-corrected threshold of P < 4.5 × 10-4, we identified two putative susceptibility miRNAs, miR-1307-5p and miR-192-3p, located in regions more than 500 kb away from any GWAS-identified risk variants in CRC. We observed that a high predicted expression of miR-1307-5p was associated with increased CRC risk, while a low predicted expression of miR-192-3p was associated with increased CRC risk. Our experimental results further provide strong evidence of their susceptible roles by showing that miR-1307-5p and miR-192-3p play a regulatory role, respectively, in promoting and inhibiting CRC cell proliferation, migration, and invasion, which was consistently observed in both SW480 and HCT116 cells. Our study provides additional insights into the biological mechanisms underlying CRC development.
Assuntos
Neoplasias Colorretais , MicroRNAs , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Transcriptoma/genética , Estudo de Associação Genômica Ampla , Neoplasias Colorretais/metabolismo , Células HCT116 , Regulação Neoplásica da Expressão Gênica/genética , Proliferação de Células/genéticaRESUMO
BACKGROUND: Pancreatic cancer is a lethal disease with a high mortality rate. The difficulty of early diagnosis is one of its primary causes. Therefore, we aimed to discover non-invasive biomarkers that facilitate the early diagnosis of pancreatic cancer risk. METHODS: The study subjects were randomly selected from the Korean Cancer Prevention Study-II and matched by age, sex, and blood collection point [pancreatic cancer incidence (n = 128) vs. control (n = 256)]. The baseline serum samples were analyzed by non-targeted metabolomics, and XGBoost was used to select significant metabolites related to pancreatic cancer incidence. Genomewide association study for the selected metabolites discovered valuable single nucleotide polymorphisms (SNPs). Moderation and mediation analysis were conducted to explore the variables related to pancreatic cancer risk. RESULTS: Eleven discriminant metabolites were selected by applying a cut-off of 4.0 in XGBoost. Five SNP presented significance in metabolite-GWAS (p ≤ 5 × 10-6) and logistic regression analysis. Among them, the pair metabolite of rs2370981, rs55870181, and rs72805402 displayed a different network pattern with clinical/biochemical indicators on comparison with allelic carrier and non-carrier. In addition, we demonstrated the indirect effect of rs59519100 on pancreatic cancer risk mediated by γ-glutamyl tyrosine, which affects the smoking status. The predictive ability for pancreatic cancer on the model using five SNPs and four pair metabolites with the conventional risk factors was the highest (AUC: 0.738 [0.661-0.815]). CONCLUSIONS: Signatures involving metabolites and SNPs discovered in the present research may be closely associated with the pathogenesis of pancreatic cancer and for use as predictive biomarkers allowing early pancreatic cancer diagnosis and therapy.
Assuntos
Estudo de Associação Genômica Ampla , Neoplasias Pancreáticas , Humanos , Biomarcadores Tumorais/metabolismo , Detecção Precoce de Câncer , Metabolômica , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Fatores de Risco , Masculino , FemininoRESUMO
Several polygenic risk scores (PRSs) have been developed to predict the risk of colorectal cancer (CRC) in European descendants. We used genome-wide association study (GWAS) data from 22 702 cases and 212 486 controls of Asian ancestry to develop PRSs and validated them in two case-control studies (1454 Korean and 1736 Chinese). Eleven PRSs were derived using three approaches: GWAS-identified CRC risk SNPs, CRC risk variants identified through fine-mapping of known risk loci and genome-wide risk prediction algorithms. Logistic regression was used to estimate odds ratios (ORs) and area under the curve (AUC). PRS115-EAS , a PRS with 115 GWAS-reported risk variants derived from East-Asian data, validated significantly better than PRS115-EUR derived from European descendants. In the Korea validation set, OR per SD increase of PRS115-EAS was 1.63 (95% CI = 1.46-1.82; AUC = 0.63), compared with OR of 1.44 (95% CI = 1.29-1.60, AUC = 0.60) for PRS115-EUR . PRS115-EAS/EUR derived using meta-analysis results of both populations slightly improved the AUC to 0.64. Similar but weaker associations were found in the China validation set. Individuals among the highest 5% of PRS115-EAS/EUR have a 2.52-fold elevated CRC risk compared with the medium (41-60th) risk group and have a 12% to 20% risk of developing CRC by age 85. PRSs constructed using results from fine-mapping and genome-wide algorithms did not perform as well as PRS115-EAS and PRS115-EAS/EUR in risk prediction, possibly due to a small sample size. Our results indicate that CRC PRSs are promising in predicting CRC risk in East Asians and highlights the importance of using population-specific data to build CRC risk prediction models.
Assuntos
Neoplasias Colorretais , Estudo de Associação Genômica Ampla , Idoso de 80 Anos ou mais , Povo Asiático/genética , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
OBJECTIVE: A number of epidemiological studies have reported that decreased serum bilirubin, an endogenous antioxidant, is associated with cardiovascular disease. However, previous Mendelian randomization analyses conducted using a single sample have shown no evidence of association. Approach and Results: A 2-sample summary Mendelian randomization study was performed by obtaining exposure and outcome data from separate nonoverlapping samples. We utilized data from the KoGES (Korean Genome and Epidemiology Study; n=25 406) and KCPS-II (Korean Cancer Prevention Study-II; n=14 541) biobank for serum bilirubin and stroke, respectively. Using KoGES, a total of 1784 single nucleotide polymorphisms associated with serum bilirubin levels were discovered using a genome-wide significance threshold (P<5×10-8), of which 10 single nucleotide polymorphisms were identified as independent (R2<0.005) and adopted as genetic instruments. From KCPS-II, total and ischemic stroke cases were identified (n=1489 and n=686), with 12 366 acting as controls. Various 2-sample summary Mendelian randomization methods were employed, with Mendelian randomization estimates showing an inverse causal association between serum bilirubin levels and total stroke risk (odds ratio, 0.481 [95% CI, 0.234-0.988]; P=0.046). This association increased in magnitude when restricting the analysis to ischemic stroke cases (odds ratio, 0.302 [95% CI, 0.105-0.868]; P=0.026). CONCLUSIONS: Our findings provide evidence of significant causal relationship between high levels of bilirubin and decreased stroke risk in Korean population in agreement with observational approaches. This highlights the potential for bilirubin to serve as a therapeutic target for oxidative stress-related diseases such as stroke and suggests that previous findings were not a consequence of unmeasured confounding.
Assuntos
Bilirrubina/sangue , Isquemia Encefálica/sangue , Análise da Randomização Mendeliana/métodos , Adulto , Idoso , Biomarcadores/sangue , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prognóstico , República da Coreia/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND & AIMS: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations. METHODS: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels. RESULTS: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10-8. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci. CONCLUSIONS: We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to ß-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.
Assuntos
Povo Asiático/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Loci Gênicos , Polimorfismo de Nucleotídeo Único , Ásia/epidemiologia , Estudos de Casos e Controles , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/imunologia , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Medição de Risco , Fatores de RiscoRESUMO
OBJECTIVES: The aim of this study was to examine the risk of bladder cancer according to the trajectory pattern of amount of smoking among Korean young adult men. METHODS: Smoking status was assessed with a standardized questionnaire in the Korean Life Course Health Study (KLCHS). Trajectory analyses were performed among young adult men using seven repeated surveys of cigarette per day (CPD) every two years from 1992 to 2005. The occurrence of bladder cancer was tracked from 2006 to 2016. The Cox proportional models were used to calculate the hazard ratio (HR) (95% confidence interval) of smoking patterns on bladder cancer. RESULTS: The mean (standard deviation) age of the 161,069 participants was 34.0 (3.9) years, and 2,280,143 person-years (PY) were examined during the follow-up period of 14.2 (median 14.3) years. During this period, 263 new cases of bladder cancer occurred (11.5/100,000 PY). Among the six trajectory groups (low steady, lowering, rise and fall, high steady, rise and sharp fall, and very high steady), there was a higher risk of developing bladder cancer in the all the other groups compared to the low steady group. The highest risk group was the very high steady group, with HR 2.83 (95% CI 1.79-4.49). In addition, the risk of bladder cancer was 2.61 (95% CI 1.50-4.54) in the rise and sharp fall group. CONCLUSION: The risk of bladder cancer did not show much difference according to trajectories, except for low steady group. Thus quitting smoking should be the priority to lower the risk of bladder cancer in smokers.
Assuntos
Fumar/epidemiologia , Neoplasias da Bexiga Urinária/epidemiologia , Adulto , Humanos , Incidência , Masculino , Modelos de Riscos Proporcionais , República da Coreia/epidemiologia , Fatores de Risco , Inquéritos e Questionários , Adulto JovemRESUMO
This study aimed to apply high-resolution metabolomics to detect compounds that may contribute significantly to prostate cancer (PCa) development. The test population's sera for evaluating the metabolic differences consisted of healthy control ( n = 96) and PCa ( n = 50) groups. PCa patients were further divided into two groups based on whether their PSA level was >4 ( n = 25) or <4 ( n = 25). Univariate analysis was performed with the false discovery rate (FDR) at q = 0.05 to determine significantly different metabolites. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) clearly distinguished healthy subjects from PCa groups, while no significant difference was observed in PCa patients with PSA level < 4 or > 4. Mummichog, in combination with the KEGG and MetaboAnalyst, showed that tryptophan metabolism along the kynurenine pathway was most significantly enriched, with -log ( p) < 0.05. l-Tryptophan, kynurenine, anthranilate, isophenoxazine, glutaryl-CoA, ( S)-3-hydroxybutanoyl-CoA, acetoacetyl-CoA, and acetyl-CoA were upregulated in correlation with the PSA level of PCa patients; in contrast, indoxyl, indolelactate, and indole-3-ethanol, involved in the alternative pathway, were downregulated in the PCa patients. Validation and quantification of potential metabolites by MS/MS further confirmed the disruption of tryptophan, kynurenine, and anthranilate, suggesting that the metabolites of this pathway are potential biomarkers in patients with PCa.
Assuntos
Cinurenina , Metaboloma/fisiologia , Neoplasias da Próstata , Idoso , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Humanos , Cinurenina/sangue , Cinurenina/metabolismo , Masculino , Metabolômica , Pessoa de Meia-Idade , Análise de Componente Principal , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/metabolismo , Reprodutibilidade dos Testes , Triptofano/sangue , ortoaminobenzoatos/sangueRESUMO
Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets.
Assuntos
Colesterol/genética , Triglicerídeos/genética , Adulto , Alelos , Povo Asiático/genética , Colesterol/metabolismo , Etnicidade , Feminino , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação/genética , Lipídeos/genética , Lipoproteínas HDL/genética , Lipoproteínas LDL/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas , Triglicerídeos/metabolismo , População Branca/genéticaRESUMO
BACKGROUND: To classify waist circumference (WC) trajectories and examine each trajectory's association with risk of incident type 2 diabetes mellitus (T2DM). METHODS: In Korean Genome and Epidemiology Study (KoGES 2001-2014), 4992 participants aged 40 years and above who received biennial health examinations from wave 1 to wave 4 (2001-2008) were selected. Five distinct trajectory groups were identified for WC using group-based trajectory modeling methods such as censored normal model. Cox proportional hazards model was used to examine the association of trajectories with risk of T2DM. RESULTS: During 31,118 person-years of follow-up (mean follow-up duration, 6.2 years), 276 incident cases of T2DM were identified. Through trajectory analysis, 5 distinct WC patterns were found during wave1 to wave 4, which were "Group A" was stable on very low levels, "Group B" was stable on low levels, "Group C" was stable on moderate levels, "Group D" had increasing pattern on elevated levels, "Group E" was shown increasing on high levels. Age-standardized incidences rates per 100,000 person-years were increased with WC expanding trajectory group (193.9 for Group A, 498.4 for Group B, 661.9 for Group C, 1845.9 for Group D, and 2045.0 for Group E). In multivariate analysis after adjusting for confounding variable at wave 4, Group B (Hazard ratio (HR), 2.2; 95% confidence interval (CI), and 1.1-4.6), Group C (HR: 2.5, 95% CI: 1.2-5.0), Group D (HR: 5.4, 95% CI: 2.7-10.9), Group E (HR: 7.3, 95% CI: 3.5-15.4) had a higher risk of T2DM than Group A. After further adjusting for body mass index strongly correlated with WC, the association was attenuated. CONCLUSIONS: WC trajectory was a significant predictor of T2DM risk in increasing trajectories on high level. This finding indicate the importance of WC management across prolong lifespan by assessing the prognosis and prevention strategies of high-risk populations for T2DM in middle-aged adults.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Circunferência da Cintura , Adulto , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Fatores de RiscoRESUMO
INTRODUCTION: Since blood is in contact with all tissues in the body and is considered to dynamically reflect the body's pathophysiological status, serum metabolomics changes are important and have diagnostic value in early cancer detection. OBJECTIVES: In this prospective study, we investigated the application of metabolomics to differentiate subjects with incident breast cancer (BC) from subjects who remained free of cancer during a mean follow-up period of 7 years with the aim of identifying valuable biomarkers for BC. METHODS: Baseline serum samples from 84 female subjects with incident BC (BC group) and 88 cancer-free female subjects (control group) were used. Metabolic alterations associated with BC were investigated via metabolomics analysis of the baseline serum samples using ultra-performance liquid chromatography-linear-trap quadrupole-Orbitrap mass spectrometry. RESULTS: A total of 57 metabolites were identified through the metabolic analysis. Among them, 20 metabolite levels were significantly higher and 22 metabolite levels were significantly lower in the BC group than in the control group at baseline. Ten metabolic pathways, including amino acid metabolism, arachidonic acid (AA) metabolism, fatty acid metabolism, linoleic acid metabolism, and retinol metabolism, showed significant differences between the BC group and the control group. Logistic regression revealed that the incidence of BC was affected by leucine, AA, prostaglandin (PG)J2, PGE2, and γ-linolenic acid (GLA). CONCLUSIONS: This prospective study showed the clinical relevance of dysregulation of various metabolisms on the incidence of BC. Additionally, leucine, AA, PGJ2, PGE2, and GLA were identified as independent variables affecting the incidence of BC.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/diagnóstico , Redes e Vias Metabólicas , Metaboloma , Adulto , Neoplasias da Mama/sangue , Neoplasias da Mama/prevenção & controle , Estudos de Casos e Controles , Cromatografia Líquida , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , República da Coreia , Espectrometria de Massas em TandemRESUMO
BACKGROUND AND PURPOSE: Circulating bilirubin, a natural antioxidant, is associated with decreased risk of stroke. However, the nature of the relationship between the two remains unknown. We used a Mendelian randomization analysis to assess the causal effect of serum bilirubin on stroke risk in Koreans. METHODS: The 14 single-nucleotide polymorphisms (SNPs) (<10-7) including rs6742078 of uridine diphosphoglucuronyl-transferase were selected from genome-wide association study of bilirubin level in the KCPS-II (Korean Cancer Prevention Study-II) Biobank subcohort consisting of 4793 healthy Korean and 806 stroke cases. Weighted genetic risk score was calculated using 14 SNPs selected from the top SNPs. RESULTS: Both rs6742078 (F statistics=138) and weighted genetic risk score with 14 SNPs (F statistics=187) were strongly associated with bilirubin levels. Simultaneously, serum bilirubin level was associated with decreased risk of stroke in an ordinary least-squares analysis. However, in 2-stage least-squares Mendelian randomization analysis, no causal relationship between serum bilirubin and stroke risk was found. CONCLUSIONS: There is no evidence that bilirubin level is causally associated with risk of stroke in Koreans. Therefore, bilirubin level is not a risk determinant of stroke.
Assuntos
Bilirrubina/sangue , Glucuronosiltransferase/genética , Acidente Vascular Cerebral/sangue , Bancos de Tecidos , Adulto , Idoso , Bilirrubina/genética , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , República da Coreia , Risco , Acidente Vascular Cerebral/genéticaRESUMO
BACKGROUND: Overweight and obesity are increasing worldwide. To help assess their relevance to mortality in different populations we conducted individual-participant data meta-analyses of prospective studies of body-mass index (BMI), limiting confounding and reverse causality by restricting analyses to never-smokers and excluding pre-existing disease and the first 5 years of follow-up. METHODS: Of 10â625â411 participants in Asia, Australia and New Zealand, Europe, and North America from 239 prospective studies (median follow-up 13·7 years, IQR 11·4-14·7), 3â951â455 people in 189 studies were never-smokers without chronic diseases at recruitment who survived 5 years, of whom 385â879 died. The primary analyses are of these deaths, and study, age, and sex adjusted hazard ratios (HRs), relative to BMI 22·5-<25·0 kg/m(2). FINDINGS: All-cause mortality was minimal at 20·0-25·0 kg/m(2) (HR 1·00, 95% CI 0·98-1·02 for BMI 20·0-<22·5 kg/m(2); 1·00, 0·99-1·01 for BMI 22·5-<25·0 kg/m(2)), and increased significantly both just below this range (1·13, 1·09-1·17 for BMI 18·5-<20·0 kg/m(2); 1·51, 1·43-1·59 for BMI 15·0-<18·5) and throughout the overweight range (1·07, 1·07-1·08 for BMI 25·0-<27·5 kg/m(2); 1·20, 1·18-1·22 for BMI 27·5-<30·0 kg/m(2)). The HR for obesity grade 1 (BMI 30·0-<35·0 kg/m(2)) was 1·45, 95% CI 1·41-1·48; the HR for obesity grade 2 (35·0-<40·0 kg/m(2)) was 1·94, 1·87-2·01; and the HR for obesity grade 3 (40·0-<60·0 kg/m(2)) was 2·76, 2·60-2·92. For BMI over 25·0 kg/m(2), mortality increased approximately log-linearly with BMI; the HR per 5 kg/m(2) units higher BMI was 1·39 (1·34-1·43) in Europe, 1·29 (1·26-1·32) in North America, 1·39 (1·34-1·44) in east Asia, and 1·31 (1·27-1·35) in Australia and New Zealand. This HR per 5 kg/m(2) units higher BMI (for BMI over 25 kg/m(2)) was greater in younger than older people (1·52, 95% CI 1·47-1·56, for BMI measured at 35-49 years vs 1·21, 1·17-1·25, for BMI measured at 70-89 years; pheterogeneity<0·0001), greater in men than women (1·51, 1·46-1·56, vs 1·30, 1·26-1·33; pheterogeneity<0·0001), but similar in studies with self-reported and measured BMI. INTERPRETATION: The associations of both overweight and obesity with higher all-cause mortality were broadly consistent in four continents. This finding supports strategies to combat the entire spectrum of excess adiposity in many populations. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, US National Institutes of Health.
Assuntos
Índice de Massa Corporal , Causas de Morte , Mortalidade/tendências , Adulto , Idoso , Ásia/epidemiologia , Austrália/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , América do Norte/epidemiologia , Sobrepeso/mortalidade , Estudos ProspectivosRESUMO
BACKGROUND & AIMS: Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC. METHODS: This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases. RESULTS: We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10(-8) to 1.24 × 10(-12): 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P < .05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2. CONCLUSIONS: We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.
Assuntos
Povo Asiático/genética , Neoplasias Colorretais/genética , Loci Gênicos , Predisposição Genética para Doença , Adulto , Idoso , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Estudos de Casos e Controles , Fator de Iniciação 3 em Eucariotos/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteínas Qb-SNARE/genética , Proteínas Ribossômicas/genética , Fatores de Risco , Esteroide 17-alfa-Hidroxilase/genética , Proteínas Supressoras da Sinalização de Citocina/genética , Adulto JovemRESUMO
BACKGROUND: Reported associations of estimated glomerular filtration rate (eGFR) with cancer risk are inconsistent, and data for the proteinuria-cancer relationship are sparse. We sought to quantify the associations of cancer incidence with eGFR and with proteinuria in a large population-based cohort. STUDY DESIGN: A prospective cohort study. SETTING & PARTICIPANTS: 242,583 adults (30-74 years old) without a diagnosis of cancer at baseline in the Korean Heart Study, based on health checkups in 1996 to 2004 with follow-up until 2012. PREDICTORS: Creatinine-based eGFR (≥90, 60-89, 45-59, and <45mL/min/1.73m2) and dipstick proteinuria (undetectable/trace, 1+, 2+, and ≥3+). OUTCOMES: Overall and site-specific cancer incidence based on ICD-10 codes. RESULTS: 15,165 cases of cancer were detected. The relationship between eGFR and incidence of any cancer was J shaped, with the lowest risk at 45 to 59mL/min/1.73m2. There was 44% higher risk for any cancer among those with eGFRs<45mL/min/1.73m2 compared with those with eGFRs≥90mL/min/1.73m2 (HR, 1.44; 95% CI, 1.11-1.87). High proteinuria was also associated with cancer risk, showing a dose-response relationship (HRs of 1.24 [95% CI, 1.13-1.35], 1.38 [95% CI, 1.17-1.63], and 1.66 [95% CI, 1.30-2.12] for 1+, 2+, and ≥3+ vs undetectable/trace). Examining site-specific cancer, eGFR<45 (vs ≥45) mL/min/1.73m2 was significantly associated with kidney and ureteral cancer, multiple myeloma, and leukemia, whereas proteinuria ≥ 1+ (vs undetectable/trace) was related to a broader set of cancers (ie, stomach, rectal, liver, lung, ovarian, kidney, bladder, and multiple myeloma). After excluding study participants with follow-up less than 3 years, the associations remained consistent for kidney cancer and myeloma with eGFR and for rectal, liver, lung, and ovarian cancer with proteinuria. LIMITATIONS: Relatively small number of participants with severely reduced eGFR or 70 years or older. CONCLUSIONS: Kidney measures, particularly proteinuria, were associated with increased incidence of cancer. Future studies are needed to better understand the pathophysiologic mechanisms underlying these associations.
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Taxa de Filtração Glomerular , Neoplasias/complicações , Neoplasias/epidemiologia , Proteinúria/complicações , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Adulto , Idoso , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: Adiponectin levels have been shown to be associated with colorectal cancer (CRC). Furthermore, a newly identified adiponectin receptor, T-cadherin, has been associated with plasma adiponectin levels. Therefore, we investigated the potential for a genetic association between T-cadherin and CRC risk. RESULT: We conducted a case-control study using the Korean Cancer Prevention study-II cohort, which is composed of 325 CRC patients and 977 normal individuals. Study results revealed that rs3865188 in the 5' flanking region of the T-cadherin gene (CDH13) was significantly associated with CRC (p = 0.0474). The odds ratio (OR) for the TT genotype as compared to the TA + AA genotype was 1.577 (p = 0.0144). In addition, the interaction between CDH13 and the adiponectin gene (APN) for CRC risk was investigated using a logistic regression analysis. Among six APN single nucleotide polymorphisms (rs182052, rs17366568, rs2241767, rs3821799, rs3774261, and rs6773957), an interaction with the rs3865188 was found for four (rs2241767, rs3821799, rs3774261, and rs6773957). The group with combined genotypes of TT for rs3865188 and GG for rs377426 displayed the highest risk for CRC development as compared to those with the other genotype combinations. The OR for the TT/GG genotype as compared to the AA/AA genotype was 4.108 (p = 0.004). Furthermore, the plasma adiponectin level showed a correlation with the gene-gene interaction, and the group with the highest risk for CRC had the lowest adiponectin level (median, 4.8 µg/mL for the TT/GG genotype vs.7.835 µg/mL for the AA/AA genotype, p = 0.0017). CONCLUSIONS: The present study identified a new genetic factor for CRC risk and an interaction between CDH13 and APN in CRC risk. These genetic factors may be useful for predicting CRC risk.
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Adiponectina/genética , Caderinas/genética , Neoplasias Colorretais/genética , Epistasia Genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Adulto , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Genome-wide association studies have identified numerous single nucleotide polymorphisms (SNPs) as associated with colorectal cancer (CRC) risk in populations of European descent. However, their utility for predicting risk to CRC in Asians remains unknown. A case-cohort study (random sub-cohort N=1,685) from the Korean Cancer Prevention Study-II (KCPS-II) (N=145,842) was used. Twenty-three SNPs identified in previous 47 studies were genotyped on the KCPS-II sub-cohort members. A genetic risk score (GRS) was calculated by summing the number of risk alleles over all SNPs. Prediction models with or without GRS were evaluated in terms of the area under the receiver operating characteristic curve (AUROC) and the continuous net reclassification index (NRI). RESULTS: Seven of 23 SNPs showed significant association with CRC and rectal cancer in Koreans, but not with colon cancer alone. AUROCs (95% CI) for traditional risk score (TRS) alone and TRS plus GRS were 0.73 (0.69-0.78) and 0.74 (0.70-0.78) for CRC, and 0.71 (0.65-0.77) and 0.74 (0.68-0.79) for rectal cancer, respectively. The NRI (95% CI) for a prediction model with GRS compared to the model with TRS alone was 0.17 (-0.05-0.37) for CRC and 0.41 (0.10-0.68) for rectal cancer alone. CONCLUSION: Our results indicate genetic variants may be useful for predicting risk to CRC in the Koreans, especially risk for rectal cancer alone. Moreover, this study suggests effective prediction models for colon and rectal cancer should be developed separately.
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Povo Asiático/genética , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Modelos Teóricos , Risco , Adulto , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Curva ROC , Sistema de Registros , República da Coreia/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND: It is unclear whether an 'obesity survival paradox' exists for pneumonia. Therefore, we conducted a meta-analysis to assess the associations between increased body mass index (BMI), pneumonia risk, and mortality risk. METHODS: Cohort studies were identified from the PubMed and Embase databases. Summary relative risks (RRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random effects model. RESULTS: Thirteen cohort studies on pneumonia risk (n = 1,536,623), and ten cohort studies on mortality (n = 1,375,482) were included. Overweight and obese individuals were significantly associated with an increased risk of pneumonia (RR = 1.33, 95% CI 1.04 to 1.71, P = 0.02, I(2) = 87%). In the dose-response analysis, the estimated summary RR of pneumonia per 5 kg/m(2) increase in BMI was 1.04 (95% CI 1.01 to 1.07, P = 0.01, I(2) = 84%). Inversely, overweight and obese subjects were significantly associated with reduced risk of pneumonia mortality (RR = 0.83, 95% CI 0.77 to 0.91, P < 0.01, I(2) = 34%). The estimated summary RR of mortality per 5 kg/m(2) increase in BMI was 0.95 (95% CI 0.93 to 0.98, P < 0.01, I(2) = 77%). CONCLUSIONS: This meta-analysis suggests that an 'obesity survival paradox' exists for pneumonia. Because this meta-analysis is based on observational studies, more studies are required to confirm the results.
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Índice de Massa Corporal , Obesidade/mortalidade , Pneumonia/mortalidade , Estudos de Coortes , Intervalos de Confiança , Bases de Dados Factuais , Feminino , Humanos , Obesidade/complicações , Estudos Observacionais como Assunto , Sobrepeso/complicações , Sobrepeso/mortalidade , Pneumonia/complicações , Risco , Comportamento de Redução do RiscoRESUMO
Objectives: Previous research has predominantly focused on total bilirubin levels without clearly distinguishing between direct and indirect bilirubin. In this study, the differences between these forms were examined, and their potential causal relationships with ischemic stroke were investigated. Methods: Two-sample multivariable Mendelian randomization (MVMR) analysis was employed, extracting summary data on bilirubin from the Korean Cancer Prevention Study-II (KCPS-II; n=159,844) and the Korean Genome and Epidemiology Study (KoGES; n=72,299). Data on ischemic stroke were obtained from BioBank Japan (BBJ; n=201,800). Colocalization analysis was performed, focusing on the UGT1A1, SLCO1B1, and SLCO1B3 genes, which are the primary loci associated with serum bilirubin levels. Results: Crude 2-sample Mendelian randomization analysis revealed a significant negative association between total bilirubin levels and ischemic stroke. However, in MVMR analyses, only indirect bilirubin demonstrated a significant negative association with ischemic stroke (odds ratio, 0.76; 95% confidence interval, 0.59 to 0.98). Colocalization analysis did not identify a shared causal variant between the 3 genetic loci related to indirect bilirubin and the risk of ischemic stroke. Conclusion: Our study establishes a causal association between higher genetically determined levels of serum indirect bilirubin and reduced risk of ischemic stroke in an Asian population. Future research should include more in-depth analysis of shared genetic variants between indirect bilirubin and ischemic stroke.
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OBJECTIVES: Tobacco use ranks among the leading preventable causes of death worldwide. This study was conducted to calculate the mortality rate attributable to smoking in Korea for 2019 and to highlight the importance of tracking and monitoring smoking-related deaths for public health purposes. METHODS: Population attributable risk (PAR) was used to estimate the number of deaths related to smoking in 2019. PAR percentages were applied to the estimated mortality figures for various diseases, with PAR determined based on relative risk (RR). Levin's formula was used to calculate PAR, and RR was adjusted for age and alcohol consumption using Cox proportional hazards regression model to derive disease-specific regression coefficients. The analysis incorporated previously determined smoking rates from 1985, and use rates of novel tobacco products were not considered. RESULTS: The findings revealed a total of 67,982 smoking-attributable deaths in Korea in 2019, 56,993 of which occurred in men and 11,049 in women. The PAR of smoking for various causes of death in adult men was highest for lung cancer at 74.9%, followed by pneumonia (29.4%), ischemic heart disease (42.3%), and stroke (30.2%). For women, the PAR for smoking-related death was highest for lung cancer (19.9%), followed by stroke (7.6%), pneumonia (5.7%), and ischemic heart disease (9.1%). CONCLUSIONS: In countries experiencing rapid fluctuations in smoking rates, including Korea, regular studies on smoking-related mortality is imperative. Furthermore, it is necessary to investigate smoking-related deaths, including the prevalence of novel tobacco product use, to accurately gauge the risks associated with emerging tobacco products.
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Causas de Morte , Fumar , Humanos , República da Coreia/epidemiologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Fumar/epidemiologia , Idoso , Adulto JovemRESUMO
Genome-wide association studies (GWAS) have been predominantly conducted in populations of European ancestry, limiting opportunities for biological discovery in diverse populations. We report GWAS findings from 153,950 individuals across 36 quantitative traits in the Korean Cancer Prevention Study-II (KCPS2) Biobank. We discovered 616 novel genetic loci in KCPS2, including an association between thyroid-stimulating hormone and CD36. Meta-analysis with the Korean Genome and Epidemiology Study, Biobank Japan, Taiwan Biobank, and UK Biobank identified 3,524 loci that were not significant in any contributing GWAS. We describe differences in genetic architectures across these East Asian and European samples. We also highlight East Asian specific associations, including a known pleiotropic missense variant in ALDH2, which fine-mapping identified as a likely causal variant for a diverse set of traits. Our findings provide insights into the genetic architecture of complex traits in East Asian populations and highlight how broadening the population diversity of GWAS samples can aid discovery.