Korean Cancer Prevention Study-II Research Articles

Abstract 2216: Population attributable fraction of tobacco smoking on cancer incidence in 2020 in the Republic of Korea

Abstract Backgrounds: Cancer is the most common cause of mortality in Korea. According to International Agency for Research on Cancer (IARC), tobacco smoking is the Group I carcinogen, and the National Cancer Center Korea reported in 2009 that 20.9% and 2.3% of total cancer incidence were attributable to tobacco smoking in men and women, respectively. As of 2020, we estimated population attributable fraction (PAF) of cancer incidence due to tobacco smoking. Methods: We organized the Consensus Committee to develop strategy and methodology for PAF estimation. From the consensus, cancer sites for PAF estimation were selected based on the IARC list of classification with sufficient evidence in human. PAF was calculated by using Levin’s formula which includes exposure prevalence and relative risk (RR). Exposure prevalence was collected from the Korea National Health and Nutrition Examination Survey (KNHANES) in 2005, assuming that latent period from risk exposure to cancer development was 15 years. Tobacco smoking was defined as a categorical variable including non-smokers, past smokers, and current smokers. Pooled RRs were estimated from meta-analysis of RRs obtained from Korean Genome and Epidemiology Study, National Health Examination data provided by National Health Insurance Services, Korean Cancer Prevention Study-II, and KNHANES, each of which was linked with Korea Cancer Registry. Cox proportional hazards model were used to estimate RRs, while adjusted by age groups and alcohol consumption. Results: For men, 17.4% of all cancer cases were attributed to smoking, compared to 1.7% for women. Specifically, in men, 57.9% of lung cancer, 36.4% of bladder cancer, 31.9% of esophageal cancer, 39.1% of laryngeal cancer, 25.4% of oral cavity/pharyngeal cancer, 19.7% of liver cancer, and 19.5% of stomach cancer were attributed to tobacco smoking. In women, 51.7% of laryngeal cancer, 15.0% of esophageal cancer, 11.6% of lung cancer, 6.0% of bladder cancer, 5.1% of oral cavity/pharyngeal cancer, 5.0% of cervix cancer, and 4.6% of liver cancer were due to smoking. Conclusion: Tobacco smoking is an important cause of esophageal, laryngeal, and lung cancer in men, and esophageal and laryngeal cancer in women, and comprises a substantial proportion of PAF in cancer incidence. Thus, intervention measures are needed to reduce smoking prevalence for cancer prevention in Korea. Citation Format: Su Jung Byoun, Yoon-Jung Choi, Ye Lin Min, Sue-Kyung Park, Kwang Pil Ko, So_Seul Sung, NaYoung Kim, Keum Ji Jung, Sun Ha Jee, Sung-II Cho, Min Kyung Lim, Sohee Park, Eun Young Park, Hae Dong Woo, Kyu-Won Jung, E Hwa Yun, Byungmi Kim, Jin-Kyoung Oh, Yoonjoo Choi, Bohyun Park, Hong Gwan Seo, Jeong-Soo Im. Population attributable fraction of tobacco smoking on cancer incidence in 2020 in the Republic of Korea [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2216.

Abstract 2201: Population attributable fraction of alcohol consumption on cancer incidence in 2020 in the Republic of Korea

Abstract Backgrounds: Alcohol consumption is the Group I carcinogen according to International Agency for Research on Cancer (IARC). In 2009, National Cancer Center Korea reported that 3.0% and 0.5% of total cancer incidence were attributable to alcohol consumption in men and women, respectively. Herein, we estimated population attributable fraction (PAF) of cancer incidence due to alcohol consumption as of 2020. Methods: We organized the Consensus Committee to establish strategy and methodology of PAF estimation. Based on the consensus, cancer sites for PAF estimation were selected according to the IARC List of classification with sufficient evidence in human. PAF was calculated by using Levin’s formula which incorporates exposure prevalence and relative risk (RR). Exposure prevalence was obtained from the Korea National Health and Nutrition Examination Survey (KNHANES) in 2005, assuming that latent period between exposure to alcohol consumption and diagnosis of cancer would be 15 years. Alcohol consumption was defined as non-drinking (<0.1g/day), light (0.1~30g/day), moderate (30~60g/day), and heavy (60~588g/day) drinking according to the definition by World Health Organization. We estimated RRs from the cohort data established by Korean Genome and Epidemiology Study, National Health Examination data provided by National Health Insurance Services, Korean Cancer Prevention Study-II, and KNHANES, while each cohort was linked with Korea Cancer Registry. RRs were estimated by using Cox proportional hazards model adjusted by age group and smoking status. RRs were then meta-analyzed to yield pooled RR by using random-effects model. Results: A total of 4.1% and 1.2% of all cancer incidence were attributable to alcohol consumption in men and women. By cancer sites, 67.1% of esophageal cancer, 23.8% of oral cavity/pharyngeal cancer, 15.1% of laryngeal cancer, 12.0% of colorectal cancer, and 7.9% of liver cancer were attributable to alcohol consumption in men. In women, 54.1% of liver cancer, 10.3% of colorectal cancer, 7.8% of oral cavity/pharyngeal cancer, and 3.6% of breast cancer were due to alcohol consumption. Conclusion: PAF of cancer incidence due to alcohol consumption has increased in 2020 compared to PAF in 2009. As alcohol consumption is an important cause of oral cavity/pharyngeal, esophageal, and laryngeal cancer in men, and liver and breast cancer in women, prevention measures are required to reduce alcohol consumption for cancer prevention in Korea. Citation Format: Ye Lin Min, YounJu Park, Su Jung Byoun, Sue_Kyung Park, Kwang Pil Ko, So-Seul Sung, Na Young Kim, Keum Ji Jung, Sun Ha Jee, Sung-Il Cho, Min Kyung Lim, Sohee Park, Eun Young Park, Hae Dong Woo, Kyu-Won Jung, E Hwa Yun, Byungmi Kim, Jin-Kyoung Oh, Yoonjoo Choi, Bohyun Park, Hong Gwan Seo, Yoon-Jung Choi, Jeong-Soo Im. Population attributable fraction of alcohol consumption on cancer incidence in 2020 in the Republic of Korea [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2201.

Non-invasive biomarkers for early diagnosis of pancreatic cancer risk: metabolite genomewide association study based on the KCPS-II cohort

BackgroundPancreatic 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.MethodsThe 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.ResultsEleven 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]).ConclusionsSignatures 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.

Genetically determined alcohol consumption and cancer risk in Korea.

The purpose of this study was to determine the causal relationship between the genetically determined amount of alcohol consumption and the occurrence of major cancers. The data used in this study were from 129,324 people selected from the Korean Cancer Prevention Study-II, the participants of which visited 18 health examination centers between 2004 and 2013. Cancer incidence was confirmed as of 2020 using data from the National Cancer Center. A genome-wide association study (GWAS) on alcohol consumption was performed using PLINK 2.0, and sex, age, chip type, and principal components were adjusted. From the GWAS, a genetic risk score for alcohol consumption was calculated and genetically determined alcohol consumption (GDAC) was estimated. GDAC was divided into quintile groups and showed significant causal relationships with rectal cancer and liver cancer, but not with other cancers. For liver cancer, an association was shown in the hepatitis B surface antigen (HBsAg)-negative group, and a particularly strong association was found in the over-60-year-old HBsAg-negative group, in which, compared to the GDAC Q1 group, the Q4 group had a 2.35 times higher risk (95% confidence interval [CI], 1.05 to 5.23), and the Q5 group had a 2.40 times higher risk (95% CI, 1.09 to 5.30). The results of this study provided evidence that the amount of alcohol consumed is causally related to the occurrence of rectal cancer and liver cancer in HBsAg-negative individuals. Additional studies should be continued for other cancer types through long-term follow-up.

Associations of biomarkers for exposure to tobacco smoke with lung cancer risk in Korea.

Nicotine metabolite ratio (NMR) can be used to predict total nicotine clearance. However, it is unknown whether NMR could be used as a marker of lung cancer risk. To evaluate the blood metabolites of nicotine relating to the risk of developing lung cancer and investigate the combined effects of NMR and cigarette per day on the risk of lung cancer. Among the 1,054 eligible subjects from the Korean Cancer Prevention Study-II biobank cohort, those with cotinine values below 0 ng/ml were excluded. Slow and fast metabolizer groups were defined using the median value of the NMR, calculated with the control group data, as the cut-point. The multivariable Cox proportional hazard models demonstrated that, the fast metabolizer group had a significantly higher risk of lung cancer than the slow metabolizer group (Adjusted HR: 2.02, 95% CI: 1.32-3.10). Fast metabolizers who smoked more than 15 cigarettes per day had an even higher risk of lung cancer (Adjusted HR: 3.51, 95% CI: 1.96-6.29) than the slow metabolizers who smoked less than 15 cigarettes per day. In summary, the NMR may be an effective marker for estimating tobacco-related disease risks such as lung cancer.

High serum levels of L-carnitine and citric acid negatively correlated with alkaline phosphatase are detectable in Koreans before gastric cancer onset.

Monitoring metabolic biomarkers could be utilized as an effective tool for the early detection of gastric cancer (GC) risk. We aimed to discover predictive serum biomarkers for GC and investigate biomarker-related metabolism. Subjects were randomly selected from the Korean Cancer Prevention Study-II cohort and matched by age and sex. We analyzed baseline serum samples of 160 subjects (discovery set; control and GC occurrence group, 80 each) via nontargeted screening. Identifiedputative biomarkers were validated in baseline serum samples of 140 subjects (validation set; control and GC occurrence group, 70 each) using targeted metabolites analysis. The final analysis was conducted on the discovery set (control, n = 52 vs. GC occurrence, n = 50) and the validation set (control, n = 43 vs. GC occurrence, n = 44) applying exclusion conditions. Eighteen putative metabolite sets differed between two groups found on nontargeted metabolic screening. We focused on fatty acid-related energy metabolism. In targeted analysis, levels of decanoyl-L-carnitine (p = 0.019), L-carnitine (p = 0.033), and citric acid (p = 0.025) were significantly lower in the GC occurrence group, even after adjusting for age, sex, and smoking status. Additionally, L-carnitine and citric acid were confirmed to have an independently significant relationship to GC development. Notably, alkaline phosphatase showed a significant correlation with these two biomarkers. Changes in serum L-carnitine and citric acid levels that may result from alterations of fatty-acid-related energy metabolism are expected to be valuable biomarkers for the early diagnosis of GC risk.

The Association between Blood Concentrations of PCDD/DFs, DL-PCBs and the Risk of Type 2 Diabetes Mellitus and Thyroid Cancer in South Korea.

Background and Objectives: Epidemiological studies have inconsistently shown an association between dioxin and risk of type 2 diabetes mellitus (T2DM) and cancer. This study aims to examine the effects of blood concentration of dioxin-like polychlorinated biphenyls (DL-PCBs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/DFs) on T2DM and thyroid cancer. Methods: We conducted a nested case–control study within the Korean cancer prevention study-II (KCPS-II) consisting of 15 thyroid cancer cases, 30 T2DM cases, and 55 controls. A total of 500 samples were used in 100 pooling samples. An average value of a pooled sample was calculated weighted by the blood volume of each sample. Results: The study population included 100 participants from the KCPS-II (median (IQR) baseline age, 54.06 [21.04] years; 48 women). The toxic equivalents of PCDD/DFs showed a significant positive association with T2DM and thyroid cancer, after adjustments for potential confounders (T2DM ORs = 1.23; 95% CI = 1.05–1.43; thyroid cancer ORs = 1.34; 95% CI = 1.12–1.61). Conclusion: In this study, both T2DM and thyroid cancer were associated with the blood concentrations of PCDD/DFs. The association between PCDD/DFs and T2D was found among women but not among men. Our findings suggest that further biochemical in vivo research and epidemiologic studies are needed to clarify the association between dioxins concentrations and diseases.

Abstract 5903: Polygenic risk scores for prediction of breast cancer in Korean women

Abstract Background: Polygenic risk scores (PRS) developed in large European GWAS have been shown to perform well in Asian women relative to PRS developed in smaller Asian studies. However, prospective validation of absolute risk prediction models combining lifestyle and PRS in Asian women is limited. We evaluate the calibration of four PRS developed using Asian or European training samples; two PRS were restricted to genome-wide significant SNPs (GRS-11ASN, GRS-136EUR) and two included sub-genome-wide significant SNPs (PRS-42ASN, PRS-209EUR). Methods: For each PRS, we compared discrimination (area under the curve [AUC]) and calibration (expected-to-observed ratio [E/O]) of three absolute risk models among 41,031 women from the Korean Cancer Prevention Study-II Biobank: (i) a model using incidence, mortality, and risk factor distributions (reference inputs) among U.S. women and European relative risks; (ii) a recalibrated model, using Korean reference but European relative risks; and (iii) a fully Korean-based model using Korean reference and relative risk estimates from KCPS. Results: All Asian and European PRS improved risk prediction for breast cancer in Korean women (Qx: AUC=0.65, Qx+PRS-42ASN: AUC=0.68, Qx+PRS-209EUR: AUC=0.69 in Korean-based model for age less than 50). We found that the U.S.-based absolute risk models overestimated the risks for women age ≥50 years (PRS-42ASN: E/O=1.93, 95% CI=1.69, 2.19, PRS-209EUR: E/O = 1.92, 95% CI=1.69, 2.19). Our absolute risk projections suggest that risk-reducing lifestyle changes would lead to larger absolute risk reductions among women at higher PRS. Conclusions: Incorporation of PRS previously developed in Asian and European-ancestry populations can improve discrimination in Korean women. Our finding suggests that PRS may be useful for prioritizing individuals for targeted intervention on their lifestyle such as alcohol intake and obesity. Larger Asian training samples should improve PRS discrimination among Korean women. Further studies are needed to evaluate the value of incorporating additional information on factors into a model in ancestrally diverse populations. Citation Format: Yon Ho Jee, Weang-Kee Ho, Sohee Park, Douglas Easton, Soo-Hwang Teo, Keum Ji Jung, Peter Kraft. Polygenic risk scores for prediction of breast cancer in Korean women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5903.

Abstract 2321: Validating breast cancer risk prediction models in the Korean Cancer Prevention Study-II Biobank

Abstract Background: Informative and well-calibrated risk prediction models may be useful for precision breast-cancer screening. However, these models often have not been validated across diverse populations. Validation in East Asian populations is particularly lacking. Objective: To evaluate the performance of breast cancer risk models developed in European-ancestry studies in a Korean population, both directly and after recalibration. Methods: We compared discrimination and calibration of three multivariable risk models in a cohort of 77,457 women from the Korean Cancer Prevention Study-II. The first incorporated US breast-cancer incidence and mortality rates, US risk-factor distributions, and relative risk (RR) estimates from European-ancestry studies. The second recalibrated the first by using Korean incidence and mortality rates and Korean risk factor distributions, while retaining the European-ancestry RR estimates. Finally, we derived a Korea-specific model incorporating the RR estimates from Korean Cancer Prevention Study. The Individualized Coherent Absolute Risk Estimation (iCARE) software package was used to calculate 5 year predicted absolute risks of breast cancer and assess model performance. Results: The US European-ancestry breast cancer risk model was well calibrated among Korean women <50 years (E/O=1.124 (0.989, 1.278)) but markedly overestimated the risk for those ≥50 years (E/O=2.472 (2.005, 3.049)). Recalibrating absolute risk estimates using Korean breast cancer rates and risk distributions markedly improved the calibration in women ≥50 (E/O=1.018 (0.825, 1.255)). The model incorporating Korean-based RRs had similar but not clearly improved performance relative to the recalibrated model; this may reflect at most modest differences in the RRs between European and Korean populations and the relatively small sample used to estimate RRs among Korean women. Conclusions: The poor performance of the US European-ancestry breast cancer risk model among older Korean women highlights the importance of tailoring absolute risk models to specific populations. Recalibrating the model using Korean incidence and mortality rates and risk factor distributions greatly improved performance; we anticipate the performance could be further improved by incorporating multivariable risk-factor RRs from large Korea-based studies. Citation Format: Yon Ho Jee, Chi Gao, Jihye Kim, Seho Park, Sun Ha Jee, Peter Kraft. Validating breast cancer risk prediction models in the Korean Cancer Prevention Study-II Biobank [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2321.

Validating Breast Cancer Risk Prediction Models in the Korean Cancer Prevention Study-II Biobank.

Risk prediction models may be useful for precision breast cancer screening. We aimed to evaluate the performance of breast cancer risk models developed in European-ancestry studies in a Korean population. We compared discrimination and calibration of three multivariable risk models in a cohort of 77,457 women from the Korean Cancer Prevention Study (KCPS)-II. The first incorporated U.S. breast cancer incidence and mortality rates, U.S. risk factor distributions, and RR estimates from European-ancestry studies. The second recalibrated the first by using Korean incidence and mortality rates and Korean risk factor distributions, while retaining the European-ancestry RR estimates. Finally, we derived a Korea-specific model incorporating the RR estimates from KCPS. The U.S. European-ancestry breast cancer risk model was well calibrated among Korean women <50 years [expected/observed = 1.124 (0.989, 1.278)] but markedly overestimated the risk for those ≥50 years [E/O = 2.472 (2.005, 3.049)]. Recalibrating absolute risk estimates using Korean breast cancer rates and risk distributions markedly improved the calibration in women ≥50 [E/O = 1.018 (0.825, 1.255)]. The model incorporating Korean-based RRs had similar but not clearly improved performance relative to the recalibrated model. The poor performance of the U.S. European-ancestry breast cancer risk model among older Korean women highlights the importance of tailoring absolute risk models to specific populations. Recalibrating the model using Korean incidence and mortality rates and risk factor distributions greatly improved performance. The data will provide valuable information to plan and evaluate actions against breast cancer focused on primary prevention and early detection in Korean women.

Two-Sample Mendelian Randomization Study of Lipid levels and Ischemic Heart Disease.

Background and ObjectivesAssociations between blood lipids and risk of ischemic heart disease (IHD) have been reported in observational studies. However, due to confounding and reverse causation, observational studies are influenced by bias, thus their results show inconsistency in the effects of lipid levels on IHD. In this study, we evaluate whether lipid levels have an effect on the risk of IHD in a Korean population.MethodsA 2-sample Mendelian randomization (MR) study, using the genetic variants associated with lipid levels as the instrumental variables was performed. Genetic variants significantly associated with lipid concentrations were obtained from the Korean Genome and Epidemiology Study (n=35,000), and the same variants on IHD were obtained from the Korean Cancer Prevention Study-II (n=13,855). Inverse variance weighting (IVW), weighted median, and MR-Egger approaches were used to assess the causal association between lipid levels and IHD. Radial MR methods were applied to remove outliers subject to pleiotropic bias.ResultsCausal association between low-density lipoprotein-cholesterol (LDL-C) and IHD was observed in the IVW method (odds ratio, 1.013; 95% confidence interval, 1.007–1.109). However, high-density lipoprotein-cholesterol (HDL-C) and triglyceride (TG) did not show causal association with IHD. In the Radial MR analysis of the relationship between HDL-C, TG and IHD, outliers were detected. Interestingly, after removing the outliers, a causal association between TG and IHD was found.ConclusionsHigh levels LDL-C and TG were causally associated with increased IHD risk in a Korean population, these results are potentially useful as evidence of a significant causal relationship.

Causal Associations Between Serum Bilirubin Levels and Decreased Stroke Risk: A Two-Sample Mendelian Randomization Study.

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). 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.

Liver Cirrhosis Patients Who Had Normal Liver Function Before Liver Cirrhosis Development Have the Altered Metabolic Profiles Before the Disease Occurrence Compared to Healthy Controls.

Liver cirrhosis (LC) is the final usual outcome of liver damage induced by various chronic liver diseases. Because of asymptomatic nature of LC, it is usually diagnosed at late and advanced stages, and patients are easy to miss the best timing for treatment. Thus, the early detection of LC is needed. In the prospective Korean Cancer Prevention Study-II (K-II), we aimed to identify valuable biomarkers for LC using metabolomics to distinguish subjects with incident LC (LC group) from subjects free from LC (control group) during a mean 7-year follow-up period. Metabolic alterations were investigated using baseline serum specimens acquired from 94 subjects with incident LC and 180 age- and sex-matched LC-free subjects via ultra-performance liquid chromatography (UPLC)-linear-trap quardrupole (LTQ)-Orbitrap mass spectrometry (MS). As a result of the metabolic analysis, 46 metabolites were identified. Among them, 11 and 18 metabolite level showed a significant increase and decrease, respectively, in the LC group compared to the control group. Nine metabolic pathways, including glyoxylate and dicarboxylate metabolism, amino acid metabolism, fatty acid metabolism, linoleic acid metabolism, α-linolenic acid metabolism, and arachidonic acid metabolism, were significantly different between the two groups. Logistic regression demonstrated that the LC emergence was independently affected by serum levels of myristic acid, palmitic acid, linoleic acid, eicosapentaenoic acid (EPA), lysophosphatidic acid (LPA) (18:1), glycolic acid, lysophosphatidylcholine (lysoPC) (22:6), and succinylacetone (R2 = 0.837, P < 0.001). This prospective study revealed that dysregulation of various metabolism had the clinical relevance on the LC development. Moreover, myristic acid, palmitic acid, linoleic acid, EPA, LPA (18:1), glycolic acid, lysoPC (22:6), and succinylacetone were emerged as independent variables influencing the incidence of LC. The results support that the early biomarkers found in this study may useful for predicting and remedying the risk of LC.

Causal effect of alcohol consumption on hyperuricemia using a Mendelian randomization design.

We used a Mendelian randomization analysis to assess the causal effect of alcohol consumption on hyperuricemia in Koreans. The Korean Cancer Prevention Study-II (KCPS-II) Biobank cohort consisted of 156701 healthy Korean aged 20years or older. Clinical data including serum uric acid, alcohol consumption, and other related confounding variables were collected at baseline. The 27 single nucleotide polymorphisms (SNP) including rs671 in aldehyde dehydrogenase 2 (ALDH2) were obtained from a genome-wide association study of alcohol consumption in the KCPS-II Biobank among 11678 men and women in 2017. Both unweighted and weighted genetic risk score (wGRS) were calculated using 10 SNPs selected based on linkage disequilibrium. As strong instrumental variables, both rs671 and wGRS were associated with an increased amount of alcohol drinking in men and women. Alcohol consumption was also positively associated with hyperuricemia risk in men (P<.001) and women (P=.014). Both rs671 major G allele and wGRS were not associated with hyperuricemia. In Mendelian randomization analysis, the causal relationship between any alcohol consumption and hyperuricemia was found only in men, albeit non-significant after correction for multiple testing. The associations did not change after excluding heavy drinkers or the elderly. These results provide evidence that alcohol consumption is causally associated with risk of hyperuricemia in Korean men and support its role as a risk determinant.

Bilirubin and risk of ischemic heart disease in Korea: a two-sample Mendelian randomization study

OBJECTIVESBilirubin is an endogenous antioxidant that protects cells against oxidative stress. Increased plasma levels of bilirubin have been associated with a reduced risk of ischemic heart disease (IHD) in previous studies. Nonetheless, whether those associations reflect a true protective effect of bilirubin on IHD, rather than confounding or reverse causation, remains unknown. Therefore, we applied two-sample Mendelian randomization to evaluate the causal association between bilirubin levels and IHD risk in a Korean population.METHODSA total of 5 genetic variants—TRPM8 (rs10490012), USP40 (rs12993249), ATG16L1 (rs2119503), SLCO1B1 (rs4149014), and SLCO1B3 (rs73233620)—were selected as genetic instruments for serum bilirubin levels using a communitybased cohort, the Korean Genome and Epidemiology Study, comprising 33,598 subjects. We then evaluated their impact on IHD using the Korean Cancer Prevention Study-II cohort.RESULTSAmong the 5 instrumental variables that showed significant associations with serum bilirubin levels, rs12993249 (USP40) showed the most significant association (p<2.36×10-105). However, we found no significant association between serum bilirubin levels and IHD. Sensitivity analyses demonstrated a consistent association, suggesting that our observations were robust.CONCLUSIONSUsing two-sample Mendelian randomization, we found no association between serum bilirubin levels and IHD. Further studies that confirm the observed interactions among other ethnicities are warranted.

286-LB: The Difference in Metabolic Profiles between Liver Cirrhosis Patients and Healthy Control before Liver Cirrhosis Development: A Prospective, Korean Cancer Prevention Study-II Cohort Study

Objectives: In the prospective Korean Cancer Prevention Study-II (KCPS-II), we investigated the application of metabolomics to differentiate subjects with incident liver cirrhosis (LC group) from subjects who remained free of LC (control group) during a mean follow-up period of 7 years, with the aim of identifying valuable biomarkers for LC. Methods: Metabolic alterations were investigated using baseline serum samples from 94 subjects with incident LC and 180 age- and sex-matched LC-free subjects via ultra-performance liquid chromatography (UPLC)-linear-trap quardrupole (LTQ)-Orbitrap mass spectrometry (MS). Results: A total of 46 metabolites were identified through the metabolic analysis. Among them, 11 metabolite levels were significantly higher, and 18 metabolite levels were significantly lower in the LC group than in the control group. 9 metabolic pathways, including glyoxylate and dicarboxylate metabolism, amino acid metabolism, fatty acid metabolism, linoleic acid metabolism, α-linolenic acid metabolism, and arachidonic acid metabolism, showed significant differences between the two groups. Logistic regression revealed that the incidence of LC was independently affected by serum levels of myristic acid, palmitic acid, linoleic acid, eicosapentaenoic acid (EPA), lysophosphatidic acid (LPA) (18:1), glycolic acid, lysophosphatidylcholine (lysoPC) (22:6), and succinylacetone (R2=0.837, P&amp;lt;0.001). Conclusions: This prospective study showed the clinical relevance of dysregulation of various metabolisms on the incidence of LC. Additionally, myristic acid, palmitic acid, linoleic acid, EPA, LPA (18:1), glycolic acid, lysoPC (22:6), and succinylacetone were identified as independent variables affecting the incidence of LC. Disclosure H. Yoo: None. M. Kim: None. Y. Han: None. C. Yoonjeong: None. J. Lee: None. Funding Korean Ministry of Health and Welfare (HI14C2686); Korean National Research Foundation (NRF-2012M3A9C4048762, NRF-2017R1C1B2007195)

Analysis of metabolites and metabolic pathways in breast cancer in a Korean prospective cohort: the Korean Cancer Prevention Study-II.

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. 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 7years with the aim of identifying valuable biomarkers for BC. 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. 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). 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.

Metabolomics Profiles of Hepatocellular Carcinoma in a Korean Prospective Cohort: The Korean Cancer Prevention Study-II.

In the prospective Korean Cancer Prevention Study-II (KCPS-II), we investigated the application of metabolomics to differentiate subjects with incident hepatocellular carcinoma (HCC group) from subjects who remained free of cancer (control group) during a mean follow-up period of 7 years with the aim of identifying valuable metabolic biomarkers for HCC. We used baseline serum samples from 75 subjects with incident HCC and 134 age- and gender-matched cancer-free subjects. Serum metabolic profiles associated with HCC incidence were investigated via metabolomics analysis. Compared with the control group, the HCC group showed significantly higher serum levels of aspartate aminotransferase (AST), alanine aminotransferase, and γ-glutamyl transpeptidase. At baseline, compared with the control group, the HCC group showed significantly higher levels of 9 metabolites, including leucine, 5-hydroxyhexanoic acid, phenylalanine, tyrosine, arachidonic acid, and tauroursodeoxycholic acid (TUDCA), but lower levels of 28 metabolites, including oleamide, androsterone sulfate, L-palmitoylcarnitine, lysophosphatidic acid (LPA) 16:0, LPA 18:1, and lysophosphatidylcholines (lysoPC). Multiple linear regression revealed that the incidence of HCC was associated with the levels of tyrosine, AST, lysoPCs (16:1, 20:3), oleamide, 5-hydroxyhexanoic acid, androsterone sulfate, and TUDCA (adjusted R2 = 0.514, P = 0.036). This study showed the clinical relevance of the dysregulation of not only branched amino acids, aromatic amino acids, and lysoPCs but also bile acid biosynthesis and linoleic acid, arachidonic acid, and fatty acid metabolism. In addition, tyrosine, AST, lysoPCs (16:1, 20:3), oleamide, 5-hydroxyhexanoic acid, androsterone sulfate, and TUDCA were identified as independent variables associated with the incidence of HCC. Cancer Prev Res; 11(5); 303-12. ©2018 AACR.

Traditional and Genetic Risk Score and Stroke Risk Prediction in Korea.

Background and ObjectivesWhether using both traditional risk factors and genetic variants for stroke as opposed to using either of the 2 alone improves the prediction of stroke risk remains unclear. The purpose of this study was to compare the predictability of stroke risk between models using traditional risk score (TRS) and genetic risk score (GRS).MethodsWe used a case-cohort study from the Korean Cancer Prevention Study-II (KCPS-II) Biobank (n=156,701). We genotyped 72 single nucleotide polymorphisms (SNPs) identified in genome-wide association study (GWAS) on the KCPS-II sub-cohort members and stroke cases. We calculated GRS by summing the number of risk alleles. Prediction models with or without GRS were evaluated in terms of the area under the receiver operating characteristic curve (AUROC).ResultsSixteen out of 72 SNPs identified in GWAS showed significant associations with stroke, with an odds ratio greater than 2.0. For participants aged <40 years, AUROCs for incident stroke were 0.58, 0.65, and 0.67 in models using modifiable TRS only, GRS only, and TRS plus GRS, respectively, showing that GRS only model had better prediction than TRS only. For participants aged ≥40 years, however, TRS only model had better prediction than GRS only model. Favorable levels of traditional risk were associated with significantly lower stroke risks within each genetic risk category.ConclusionsTRS and GRS were both independently associated with stroke risk. Using genetic variants in addition to traditional risk factors may be the most accurate way of predicting stroke risk, particularly in relatively younger individuals.

Serum persistent organic pollutants levels and stroke risk.

Knowledge of environmental risk factors for stroke and their role are limited. We performed a case-cohort study to evaluate the association between serum persistent organic pollutants (POPs) level and stroke risk. 526 subcohort members and 111 stroke incidence cases were identified from the Korean Cancer Prevention Study-II. Serum levels of POPs were measured using gas chromatography/high-resolution mass spectrometry. The hazard ratios (HRs) for stroke (ischemic, hemorrhagic, and all stroke types) were estimated using the weighted Cox regression model. Age, sex, body mass index, smoking status, physical activity, family history of cardiovascular disease, and hypertension were adjusted in the weighted Cox regression model. After adjusting for potential confounding factors, increased risk for stroke was observed among participants with serum concentration of p,p'-DDE in the highest tertile compared to those in the lowest tertile (HR=4.10, 95% CI: 1.58, 10.59). A similar association was estimated for PCB118 (HR=2.33, 95% CI: 1.04, 5.22), PCB156 (HR=3.42, 95% CI: 1.42, 8.23), and PCB138 (HR=3.80, 95% CI: 1.48, 9.76). For TEQ, stroke was three times as likely to occur among subjects with TEQ in the highest tertile compared to those in the lowest tertile (HR=3.12, 95% CI: 1.27, 7.65). PCBs were positively associated with ischemic stroke, but not with hemorrhagic stroke. Elevated serum POPs levels were associated with an increased risk of stroke, especially ischemic stroke.