Rapid decline in kidney function is associated with rapid deterioration of health-related quality of life in chronic kidney disease.

This study aimed to evaluate changes in health-related quality of life (HRQOL) in patients with chronic kidney disease (CKD) according to decline in kidney function. HRQOL was assessed using the Short Form-36 questionnaire composed of a physical component summary (PCS) and mental component summary (MCS). Rapid decline in kidney function was defined as a decline in the estimated glomerular filtration rate (eGFR) of > 3 mL/min/1.73 m2/year. Rapid deterioration of HRQOL was defined a change in the HRQOL value greater than the median. Among 970 patients, 360 (37.1%) were in the rapid kidney function decline group. In 720 patients who were 1:1 propensity score-matched, the baseline eGFR was not significantly different between the non-rapid and rapid kidney function decline groups. Compared with the baseline PCS score, the 5-year PCS score decreased in the non-rapid and rapid kidney function decline groups. The 5-year MCS score significantly decreased in the rapid kidney function decline group alone. Rapid decline in kidney function was significantly associated with rapid deterioration of the PCS (odds ratio [OR]: 1.48; 95% confidence interval [CI]: 1.07-2.05; P = 0.018) and MCS (OR: 1.89; 95% CI 1.36-2.62; P < 0.001) scores. Rapid decline in kidney function was associated with rapid deterioration of HRQOL in patients with CKD.

Serum creatinine to cystatin C ratio and clinical outcomes in adults with non-dialysis chronic kidney disease.

Background: Studies have suggested that the serum creatinine/cystatin C (Cr/CysC) ratio is a surrogate marker for muscle wasting is associated with adverse outcomes in several disease conditions. To clarify the utility of the Cr/CysC ratio as a prognostic marker in chronic kidney disease (CKD) we evaluated the association between the Cr/CysC ratio clinical outcomes in patients with non-dialysis CKD. Methods: This prospective observational cohort study included 1,966 participants of the KoreaN cohort study Outcomes in patients With CKD (KNOW-CKD). We evaluated associated factors with the serum Cr/CysC ratio and association between the serum Cr/CysC ratio and composite outcomes of all-cause death and cardiovascular events (CVEs). Results: The mean age was 54 ± 12 (SD) years and 61% were men. The mean serum Cr/CysC ratio was 10.97 ± 1.94 in men and 9.10 ± 1.77 in women. The Cr/CysC ratio correlated positively with urinary creatinine excretion, a marker of muscle mass. In the fully adjusted Cox proportional hazard model, the Cr/CysC ratio was associated with the occurrence of adverse outcomes through a median follow-up of 5.9 years [hazard ratio (HR) = 0.92, 95% confidence interval (CI) = 0.85-0.99 for the composite outcomes, HR = 0.87, 95% CI, 0.78 - 0.97 for all-cause death, and HR = 0.93; 95% CI, 0.84-1.04 for CVEs]. In subgroup analyses, there were interactions of the Cr/CysC ratio with age and sex for risk of the clinical outcomes, but not eGFR group. Conclusion: A higher Cr/CysC ratio is associated with a lower risk of the composite outcomes, especially all-cause mortality, even after adjusting for eGFR. These suggest that the Cr/CysC ratio is a useful prognostic marker in CKD.

Urine creatinine concentration influences the prognostic value of proteinuria for MACE prediction from the findings of the KNOW-CKD study.

Proteinuria is typically quantified according to the spot urine protein-creatinine ratio (UPCR) and an association with cardiovascular events has not been thoroughly investigated in chronic kidney disease (CKD) patients. We investigated whether the severity of proteinuria assessed by spot UPCR is associated with an increased risk for cardiovascular outcomes in the CKD population, and whether the relationship is influenced by urine creatinine concentration. We analyzed 1746 patients enrolled as part of The KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD). Multivariable Cox proportional hazard analysis was performed to evaluate models with proteinuria as a predictor of renal events and extended major adverse cardiovascular events (eMACEs). Risk for renal events was significantly associated with proteinuria across all eGFR and UPCR categories. By contrast, risk for eMACEs increased significantly with UPCR in patients with eGFR ≥ 60 mL/min/1.73 m2 (hazard ratio [HR] 2.109; 95% confidence interval [CI] 1.375-3.235; P = 0.001), but not in patients with eGFR < 60 mL/min/1.73 m2 (HR 1.086; 95% CI 0.910-1.296; P = 0.358). However, in those with the lower eGFR, risk for eMACEs increased significantly with UPCR in participants with urine creatinine concentration ≥ 95 mg/dL (HR 1.503; 95% CI 1.047-2.159; P = 0.027). In non-dialysis CKD patients, the prognostic value of UPCR for eMACEs is weakened in patients with reduced eGFR levels, for whom it has prognostic significance only in patients with high urine creatinine concentration.

The Association between Plasma Concentration of Phytoestrogens and Hypertension within the Korean Multicenter Cancer Cohort.

In order to examine the association between plasma phytoestrogen concentration (genistein, daidzein, equol and enterolactone) and hypertension, we conducted a nested case-control study for 229 hypertension cases including 112 prehypertension and 159 healthy controls derived from the Korean Multi-center Cancer Cohort (KMCC). The concentration of plasma phytoestrogens was measured using time-resolved fluoroimmunoassay. We assessed the association between plasma phytoestrogens and hypertension using logistic regression models using odds ratio (OR) and 95% confidence interval (95%CI). The highest tertile of plasma equol and enterolactone concentration exhibited a significantly decreased risk of hypertension (equol, OR = 0.34, 95%CI 0.20-0.57; enterolactone, OR = 0.32, 95%CI 0.18-0.57), compared with the lowest tertile. Equol and enterolactone showed reduced ORs for prehypertension (the highest tertile relative to the lowest tertile, OR = 0.50, 95%CI 0.26-0.96; OR = 0.38, 95%CI 0.19-0.75, respectively) and hypertension (OR = 0.42, 95%CI 0.22-0.81; OR = 0.28, 95%CI 0.14-0.54, respectively). There was a stronger association in hypertension (the highest tertile relative to the lowest tertile in obesity vs. non-obesity; equol, OR = 0.06 vs. 0.63; enterolactone, OR = 0.07 vs. 0.46; both p-heterogeneity < 0.01). This study suggests that equol and enterolactone may contribute to prevent primarily prehypertension and hypertension, and control cardiovascular disease (CVD) based on the continuum of hypertension and CVD. Further study to assess hypertension risk based on useful biomarkers, including phytoestrogens, may contribute to primary prevention of hypertension.

Smoking Cessation and Coronary Artery Calcification in CKD.

BACKGROUND AND OBJECTIVES: Smoking is associated with vascular calcification and a higher risk of cardiovascular disease. In this study, we investigated the association of smoking dose and cessation with coronary artery calcification (CAC) in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From a nationwide, prospective cohort of Korean patients with CKD, 1914 participants were included. Prevalent CAC was defined as an Agatston score >0, using computed tomography. CAC progression was defined as ≥30%/yr increase in Agatston score at the 4-year follow-up examination in patients with baseline CAC. RESULTS: Prevalent CAC was observed in 952 (50%) patients. Compared with never smokers, former smokers had a similar prevalence ratio for CAC, but current smokers had a 1.25-fold higher prevalence ratio (95% confidence interval [95% CI], 1.10 to 1.42). Among former smokers, a lower smoking load of <10 pack-years (prevalence ratio, 0.77; 95% CI, 0.65 to 0.90) and longer duration of smoking cessation (prevalence ratio for 10 to <20 years, 0.85; 95% CI, 0.73 to 0.98: prevalence ratio for ≥20 years, 0.83; 95% CI, 0.73 to 0.96) were associated with lower risk of prevalent CAC compared with current smoking. The prevalence ratios did not differ between never smoking and long-term cessation. However, short-term cessation with heavy smoking load was associated with a higher risk of prevalent CAC (prevalence ratio, 1.21; 95% CI, 1.03 to 1.40) compared with never smoking. CAC progression was observed in 111 (33%) patients with baseline CAC. Compared with never smokers, former smokers showed a similar risk of CAC progression, but current smokers had a higher risk (relative risk, 1.92; 95% CI, 1.30 to 2.86). CONCLUSIONS: In CKD, former smoking with a lower smoking load and long-term cessation were associated with a lower risk of prevalent CAC than current smoking. CAC progression was more pronounced in current smokers.

Discrepant glomerular filtration rate trends from creatinine and cystatin C in patients with chronic kidney disease: results from the KNOW-CKD cohort.

BACKGROUND: Serum creatinine (Cr) and cystatin C (CysC) can both be used to estimate glomerular filtration rate (eGFRCr and eGFRCysC). However, certain conditions may cause discrepancies between eGFR trends from Cr and CysC, and these remain undetermined in patients with chronic kidney disease (CKD). METHODS: A total of 1069 patients from the Korean CKD cohort (KNOW-CKD), which enrolls pre-dialytic CKD patients, whose Cr and CysC had been followed for more than 4 years were included in the sample. We performed trajectory analysis using latent class mixed modeling and identified members of the discrepancy group when patient trends between eGFRCr and eGFRCysC differed. Multivariate logistic analyses with Firth's penalized likelihood regression models were performed to identify conditions related to the discrepancy. RESULTS: Trajectory patterns of eGFRCr were classified into three groups: two groups with stable eGFRCr (stable with high eGFRCr and stable with low eGFRCr) and one group with decreasing eGFRCr. Trajectory analysis of eGFRCysC also showed similar patterns, comprising two groups with stable eGFRCysC and one group with decreasing eGFRCysC. Patients in the discrepancy group (decreasing eGFRCr but stable & low eGFRCysC; n = 55) were younger and had greater proteinuria values than the agreement group (stable & low eGFRCr and eGFRCysC; n = 706), differences that remained consistent irrespective of the measurement period (4 or 5 years). CONCLUSIONS: In the present study, we identify conditions related to discrepant trends of eGFRCr and eGFRCysC. Clinicians should remain aware of such potential discrepancies when tracing both Cr and CysC.

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

BACKGROUND: We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genome-wide association studies (GWAS) have accumulated data for hundreds of thousands of subjects. It's necessary to re-evaluate these variants in large GWAS datasets. METHODS: Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets. FINDINGS: Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P < 2·19 × 10-4. The associations for four variants reached P < 5 × 10-8 and have been reported by previous GWAS, including rs6435074 and rs6723097 (CASP8), rs17879961 (CHEK2) and rs2853669 (TERT). The remaining eight variants were rs676387 (HSD17B1), rs762551 (CYP1A2), rs1045485 (CASP8), rs9340799 (ESR1), rs7931342 (CHR11), rs1050450 (GPX1), rs13010627 (CASP10) and rs9344 (CCND1). Further investigating these 10 genes identified associations for two additional variants at P < 5 × 10-8, including rs4793090 (near HSD17B1), and rs9210 (near CYP1A2), which have not been identified by previous GWAS. INTERPRETATION: Though most candidate gene variants were not associated with breast cancer risk, we found 14 variants showing an association. Our findings warrant further functional investigation of these variants. FUND: National Institutes of Health.

Weight change after smoking cessation and incident metabolic syndrome in middle-aged Korean men: an observational study.

We aimed to examine the effect of weight change attributable to cessation of cigarette smoking on newly diagnosed metabolic syndrome (MetS). We prospectively followed 5,809 men aged between 40 to 69 years without MetS at baseline in the Health Examinees-Gem (HEXA-G) study up to 4 years. The participants were grouped into continual smokers, quitters with weight gain, quitters without weight change, quitters with weight loss, and never smokers. We constructed multivariable logistic regression models adjusted for sociodemographic factors, health status, and health conditions to estimate the odds of newly diagnosed MetS. During the follow-up, there were 609 cases of newly diagnosed MetS in 5,809 men of the HEXA-G study. After adjustment for potential confounders, the odd ratios (OR) and 95% confidence intervals (95% CI) for MetS were 1.90 (95% CI: 1.43-2.52) in quitters with weight gain, 0.77 (95% CI: 0.60-1.00) in quitters without weight change, and 0.40 (95% CI: 0.28-0.57) in quitters with weight loss compared with continual smokers. Never smokers also had lower odds of MetS (OR = 0.54; 95% CI: 0.42-0.71) compared to continual smokers. Weight management program following smoking cessation may be necessary in clinical practice to reduce worsening of cardiometabolic risk factors related to post-cessation weight gain.

Reclassification of BRCA1 and BRCA2 variants of uncertain significance: a multifactorial analysis of multicentre prospective cohort.

BACKGROUND: BRCA1 and BRCA2 (BRCA1/2) variants classified ambiguously as variants of uncertain significance (VUS) are a major challenge for clinical genetic testing in breast cancer; their relevance to the cancer risk is unclear and the association with the response to specific BRCA1/2-targeted agents is uncertain. To minimise the proportion of VUS in BRCA1/2, we performed the multifactorial likelihood analysis and validated this method using an independent cohort of patients with breast cancer. METHODS: We used a data set of 2115 patients with breast cancer from the nationwide multicentre prospective Korean Hereditary Breast Cancer study. In total, 83 BRCA1/2 VUSs (BRCA1, n=26; BRCA2, n=57) were analysed. The multifactorial probability was estimated by combining the prior probability with the overall likelihood ratio derived from co-occurrence of each VUS with pathogenic variants, personal and family history, and tumour characteristics. The classification was compared with the interpretation according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG/AMP) guidelines. An external validation was conducted using independent data set of 810 patients. RESULTS: We were able to redefine 38 VUSs (BRCA1, n=10; BRCA2, n=28). The revised classification was highly correlated with the ACMG/AMP guideline-based interpretation (BRCA1, p for trend=0.015; BRCA2, p=0.001). Our approach reduced the proportion of VUS from 19% (154/810) to 8.9% (72/810) in the retrospective validation data set. CONCLUSION: The classification in this study would minimise the 'uncertainty' in clinical interpretation, and this validated multifactorial model can be used for the reliable annotation of BRCA1/2 VUSs.

Health and Prevention Enhancement (H-PEACE): a retrospective, population-based cohort study conducted at the Seoul National University Hospital Gangnam Center, Korea.

PURPOSE: The Health and Prevention Enhancement (H-PEACE) study was designed to investigate the association of diagnostic imaging results, biomarkers and the predisease stage of non-communicable diseases (NCDs), such as malignancies and metabolic diseases, in an average-risk population in Korea. PARTICIPANTS: This study enrolled a large-scale retrospective cohort at the Healthcare System Gangnam Center, Seoul National University Hospital, from October 2003 to December 2014. FINDINGS TO DATE: The baseline and follow-up information collected in the predisease stage of NCDs allows for evaluation of an individual's potential NCD risk, which is necessary for establishing personalised prevention strategies. A total of 91 336 health examinees were included in the cohort, and we repeatedly measured and collected information for 50.9% (n=46 484) of the cohort members. All participants completed structured questionnaires (lifestyle, medical history, mini-dietary assessment index, sex-specific variables and psychiatric assessment), doctors' physical examinations, laboratory blood and urine tests and digital chest X-ray imaging. For participants with available data, we also obtained information on specific diagnostic variables using advanced diagnostic tests, including coronary CT for coronary calcium scores, colonoscopy and brain MRI. Furthermore, 17 455 of the participants who provided informed consent and donated blood samples were enrolled into the Gene-environmental interaction and phenotype study, a subcohort of the H-PEACE, from October 2013, and we analysed genome-wide single-nucleotide polymorphism array data for 6579 of these blood samples. FUTURE PLANS: The data obtained from this cohort will be used to facilitate advanced and accurate diagnostic techniques related to NCDs while considering various phenotypes. Potential collaborators can access the dataset after receiving approval from our institutional review board. Applications can be submitted on the study homepage (http://en-healthcare.snuh.org/HPEACEstudy).

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

Attributable fraction of alcohol consumption on cancer using population-based nationwide cancer incidence and mortality data in the Republic of Korea.

BACKGROUND: In the Republic of Korea, cancer is the most common cause of death, and cancer incidence and mortality rates are the highest in East Asia. As alcoholic beverages are carcinogenic to humans, we estimated the burden of cancer related to alcohol consumption in the Korean population. METHODS: The cancer sites studied were those for which there is convincing evidence of a positive association with alcohol consumption: oral cavity, pharynx, esophagus, colon, rectum, liver, larynx and female breast. Sex- and cancer-specific population attributable fractions (PAF) were calculated based on: 1) the prevalence of alcohol drinkers among adults ≥ 20 years of age in 1989; 2) the average daily alcohol consumption (g/day) among drinkers in 1998; 3) relative risk (RR) estimates for the association between alcohol consumption and site-specific cancer incidence obtained either from a large Korean cohort study or, when more than one Korean study was available for a specific cancer site, meta-analyses were performed and the resulting meta-RRs were used; 4) national cancer incidence and mortality data from 2009. RESULTS: Among men, 3% (2,866 cases) of incident cancer cases and 2.8% (1,234 deaths) of cancer deaths were attributable to alcohol consumption. Among women, 0.5% (464 cancer cases) of incident cancers and 0.1% (32 deaths) of cancer deaths were attributable to alcohol consumption. In particular, the PAF for alcohol consumption in relation to oral cavity cancer incidence among Korean men was 29.3%, and the PAFs for pharyngeal and laryngeal cancer incidence were 43.3% and 25.8%, respectively. Among Korean women, the PAF for colorectal cancer incidence was the highest (4.2%) and that for breast cancer incidence was only 0.2%. Avoiding alcohol consumption, or reducing it from the median of the highest 4th quartile of consumption (56.0 g/day for men, 28.0 g/day for women) to the median of the lowest quartile (2.80 g/day for men, 0.80 g/day for women), would reduce the burden of alcohol-related cancers in Korea. CONCLUSIONS: A reduction in alcohol consumption would decrease the cancer burden and a significant impact is anticipated specifically for the cancers oral cavity, pharynx, and larynx among men in the Republic of Korea.

Attributable fraction of tobacco smoking on cancer using population-based nationwide cancer incidence and mortality data in Korea.

BACKGROUND: Smoking is by far the most important cause of cancer that can be modified at the individual level. Cancer incidence and mortality rates in Korea are the highest among all Asian countries, and smoking prevalence in Korean men is one of the highest in developed countries. The purpose of the current study was to perform a systematic review and provide an evidence-based assessment of the burden of tobacco smoking-related cancers in the Korean population. METHODS: Sex- and cancer-specific population-attributable fractions (PAF) were estimated using the prevalence of ever-smoking and second-hand smoking in 1989 among Korean adults, respectively, and the relative risks were estimated from the meta-analysis of studies performed in the Korean population for ever-smoking and in the Asian population for passive smoking. National cancer incidence data from the Korea Central Cancer Registry and national cancer mortality data from Statistics Korea for the year 2009 were used to estimate the cancer cases and deaths attributable to tobacco smoking. RESULTS: Tobacco smoking was responsible for 20,239 (20.9%) cancer incident cases and 14,377 (32.9%) cancer deaths among adult men and 1,930 (2.1%) cancer incident cases and 1,351 (5.2%) cancer deaths among adult women in 2009 in Korea. In men, 71% of lung cancer deaths, 55%-72% of upper aerodigestive tract (oral cavity, pharynx, esophagus and larynx) cancer deaths, 23% of liver, 32% of stomach, 27% of pancreas, 7% of kidney and 45% of bladder cancer deaths were attributable to tobacco smoking. In women the proportion of ever-smoking-attributable lung cancer was 8.1%, while that attributable to second-hand smoking among non-smoking women was 20.5%. CONCLUSIONS: Approximately one in three cancer deaths would be potentially preventable through appropriate control of tobacco smoking in Korean men at the population level and individual level. For Korean women, more lung cancer cases and deaths were attributable to second-hand than ever-smoking. Effective control programs against tobacco smoking should be further developed and implemented in Korea to reduce the smoking-related cancer burden.

Population-attributable causes of cancer in Korea: obesity and physical inactivity.

BACKGROUND: Changes in lifestyle including obesity epidemic and reduced physical activity influenced greatly to increase the cancer burden in Korea. The purpose of the current study was to perform a systematic assessment of cancers attributable to obesity and physical inactivity in Korea. METHODOLOGY/PRINCIPAL FINDINGS: Gender- and cancer site-specific population-attributable fractions (PAF) were estimated using the prevalence of overweight and obesity in 1992-1995 from a large-scale prospective cohort study, the prevalence of low physical activity in 1989 from a Korean National Health Examination Survey, and pooled relative risk estimates from Korean epidemiological studies. The overall PAF was then estimated using 2009 national cancer incidence data from the Korea Central Cancer Registry. Excess body weight was responsible for 1,444 (1.5%) and 2,004 (2.2%) cancer cases among men and women, respectively, in 2009 in Korea. Among men, 6.8% of colorectal, 2.9% of pancreatic, and 16.0% of kidney cancer was attributable to excess body weight. In women, 6.6% of colorectal, 3.9% of pancreatic, 18.7% of kidney, 8.2% of postmenopausal breast, and 32.7% of endometrial cancer was attributable to excess body weight. Low leisure-time physical activity accounted for 8.8% of breast cancer, whereas the PAF for overall cancer was low (0.1% in men, 1.4% in women). Projections suggest that cancers attributable to obesity will increase by 40% in men and 16% in women by 2020. CONCLUSIONS/SIGNIFICANCE: With a significantly increasing overweight and physically inactive population, and increasing incidence of breast and colorectal cancers, Korea faces a large cancer burden attributable to these risk factors. Had the obese population of Korea remained stable, a large portion of obesity-related cancers could have been avoided. Efficient cancer prevention programs that aim to reduce obesity- and physical inactivity-related health problems are essential in Korea.

Association of selected medical conditions with breast cancer risk in Korea.

OBJECTIVES: To estimate the effect of medical conditions in the population of Korea on breast cancer risk in a case-control study. METHODS: The cases were 3242 women with incident, histologically confirmed breast cancer in two major hospitals interviewed between 2001 and 2007. The controls were 1818 women each admitted to either of those two hospitals for a variety of non-neoplastic conditions. Information on each disease was obtained from a standardized questionnaire by trained personnel. Odds ratios (ORs) for each disease were derived from multiple logistic regression adjusted for age, age of menarche, pregnancy, age of first pregnancy, and family history of breast cancer. RESULTS: Among all of the incident breast cancer patients, pre-existing diabetes (OR, 1.33; 95% confidence interval [CI], 0.99 to 1.78), hypertension (OR, 1.46; 95% CI, 1.18 to 1.83), thyroid diseases (OR, 1.26; 95% CI, 1.00 to 1.58), and ovarian diseases (OR, 1.70; 95% CI, 1.23 to 2.35) were associated with an increased risk of breast cancer when other factors were adjusted for. In a stratified analysis by menopausal status, pre-existing hypertension (pre-menopause OR, 0.80; 95% CI, 0.48 to 1.34 vs. post-menopause OR, 1.87; 95% CI, 1.44 to 2.43; p-heterogeneity <0.01) and ovarian disease (pre-menopause OR, 4.20; 95% CI, 1.91 to 9.24 vs. post-menopause OR, 1.39; 95% CI, 1.02 to 1.91; p-heterogeneity 0.01) showed significantly different risks of breast cancer. CONCLUSIONS: Our results suggest the possibility that medical conditions such as hypertension affect breast cancer development, and that this can differ by menopausal status. Our study also indicates a possible correlation between ovarian diseases and breast cancer risk.

A prospective cohort study on the relationship of sleep duration with all-cause and disease-specific mortality in the Korean Multi-center Cancer Cohort study.

OBJECTIVES: Emerging evidence indicates that sleep duration is associated with health outcomes. However, the relationship of sleep duration with long-term health is unclear. This study was designed to determine the relationship of sleep duration with mortality as a parameter for long-term health in a large prospective cohort study in Korea. METHODS: The study population included 13 164 participants aged over 20 years from the Korean Multi-center Cancer Cohort study. Information on sleep duration was obtained through a structured questionnaire interview. The hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality were estimated using a Cox regression model. The non-linear relationship between sleep duration and mortality was examined non-parametrically using restricted cubic splines. RESULTS: The HRs for all-cause mortality showed a U-shape, with the lowest point at sleep duration of 7 to 8 hours. There was an increased risk of death among persons with sleep duration of ≤5 hours (HR, 1.21; 95% CI, 1.03 to 1.41) and of ≥10 hours (HR, 1.36; 95% CI, 1.07 to 1.72). In stratified analysis, this relationship of HR was seen in women and in participants aged ≥60 years. Risk of cardiovascular disease-specific mortality was associated with a sleep duration of ≤5 hours (HR, 1.40; 95% CI, 1.02 to 1.93). Risk of death from respiratory disease was associated with sleep duration at both extremes (≤5 and ≥10 hours). CONCLUSIONS: Sleep durations of 7 to 8 hours may be recommended to the public for a general healthy lifestyle in Korea.

Interaction of body mass index and diabetes as modifiers of cardiovascular mortality in a cohort study.

OBJECTIVES: Diabetes and obesity each increases mortality, but recent papers have shown that lean Asian persons were at greater risk for mortality than were obese persons. The objective of this study is to determine whether an interaction exists between body mass index (BMI) and diabetes, which can modify the risk of death by cardiovascular disease (CVD). METHODS: Subjects who were over 20 years of age, and who had information regarding BMI, past history of diabetes, and fasting blood glucose levels (n=16 048), were selected from the Korea Multi-center Cancer Cohort study participants. By 2008, a total of 1290 participants had died; 251 and 155 had died of CVD and stroke, respectively. The hazard for deaths was calculated with hazard ratio (HR) and 95% confidence interval (95% CI) by Cox proportional hazard model. RESULTS: Compared with the normal population, patients with diabetes were at higher risk for CVD and stroke deaths (HR, 1.84; 95% CI, 1.33 to 2.56; HR, 1.82; 95% CI, 1.20 to 2.76; respectively). Relative to subjects with no diabetes and normal BMI (21 to 22.9 kg/m(2)), lean subjects with diabetes (BMI <21 kg/m(2)) had a greater risk for CVD and stroke deaths (HR, 2.83; 95% CI, 1.57 to 5.09; HR, 3.27; 95% CI, 1.58 to 6.76; respectively), while obese subjects with diabetes (BMI ≥25 kg/m(2)) had no increased death risk (p-interaction <0.05). This pattern was consistent in sub-populations with no incidence of hypertension. CONCLUSIONS: This study suggests that diabetes in lean people is more critical to CVD deaths than it is in obese people.

Antioxidant vitamins intake, ataxia telangiectasia mutated (ATM) genetic polymorphisms, and breast cancer risk.

Ataxia telangiectasia mutated (ATM) cells exist under a constant state of oxidative stress with high levels of reactive oxygen species, which are removed by cellular antioxidant vitamins. We investigated the independent and combined effect of antioxidant vitamins intake and the ATM genotype or diplotype on the breast cancer risk. Analyses included 323 cases and age-matched controls who participated in the Korean Breast Cancer Study during 2001-2003 with complete dietary information. The vitamin A (P < 0.01) and α-tocopherol (P < 0.01) were associated with lower breast cancer risk as well as some water-soluble vitamins including vitamin B(2) (P = 0.01), vitamin C (P < 0.01), and folic acid (P = 0.02) intake. No five single nucleotide polymorphisms (ATM-5144A > T (rs228589), IVS21 + 1049T > C (rs664677), IVS33-55T > C (rs664982), IVS34+60G > A (rs664143), and 3393T > G (rs4585)) studied showed significant differences in their allele frequencies between the cases and controls. On the other hand, compared with the diploid of ATTGT/ATTGT, as the number of ATTGT haplotype decreased, the risk of breast cancer increased (P = 0.04). The association between ATM diplotype and the breast cancer risk was predominantly among women with low intake of antioxidant vitamins including vitamin A, vitamin C, and folic acid. This study suggested that some antioxidant vitamins intake may modify the effect of ATM diplotype on the breast cancer risk among Korean women.

Estrogen and progesterone receptor status affect genome-wide DNA methylation profile in breast cancer.

DNA methylation is the main epigenetic modification that occurs at the early stages of carcinogenesis. We performed a genome-wide DNA methylation profiling to evaluate whether the DNA methylation state is different in the estrogen receptor (ER) and progesterone receptor (PR) status of breast cancer. Twelve ER+/PR+ and 12 ER-/PR- breast cancer tissues were selected from the biorepository of the Seoul Breast Cancer Study for Infinium Methylation Assay. The difference of the DNA methylation state of 27 578 methylation sites in 14 000 genes between two groups was evaluated by Student's t-test. False discovery rate (FDR) was estimated to evaluate the probability of false positive associations. Of the 27 578 sites, 148 sites (0.54%) were significantly different between ER+/PR+ and ER-/PR- breast cancers (P < 0.001); 93 hypermethylated and 55 hypomethylated. Five genes, FAM124B (P = 7.26 × 10(-7)), MANEAL (P = 3.38 × 10(-7)), ST6GALNAC1 (P = 2.85 × 10(-6)), NAV1 (P = 5.94 × 10(-6)) and PER1 (P = 6.45 × 10(-6)) remained significant after correction for multiple tests (FDR < 0.05). In a subsequent replication study for five genes, four of the five genes were validated; FAM124B and ST6GALNAC1 were significantly hypermethylated, and NAV1 and PER1 were significantly hypomethylated in ER+/PR+ breast cancers (P < 0.05). In the first genome-wide DNA methylation profiling according to the receptor status of breast cancer, we found that ER/PR status affects the DNA methylation state of FAM124B, ST6GALNAC1, NAV1 and PER1 in breast cancer.