Joint identification of genetic variants for physical activity in Korean population.

There has been limited research on genome-wide association with physical activity (PA). This study ascertained genetic associations between PA and 344,893 single nucleotide polymorphism (SNP) markers in 8842 Korean samples. PA data were obtained from a validated questionnaire that included information on PA intensity and duration. Metabolic equivalent of tasks were calculated to estimate the total daily PA level for each individual. In addition to single- and multiple-SNP association tests, a pathway enrichment analysis was performed to identify the biological significance of SNP markers. Although no significant SNP was found at genome-wide significance level via single-SNP association tests, 59 genetic variants mapped to 76 genes were identified via a multiple SNP approach using a bootstrap selection stability measure. Pathway analysis for these 59 variants showed that maturity onset diabetes of the young (MODY) was enriched. Joint identification of SNPs could enable the identification of multiple SNPs with good predictive power for PA and a pathway enriched for PA.

A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study.

INTRODUCTION: Although approximately 25 common genetic susceptibility loci have been identified to be independently associated with breast cancer risk through genome-wide association studies (GWAS), the genetic risk variants reported to date only explain a small fraction of the heritability of breast cancer. Furthermore, GWAS-identified loci were primarily identified in women of European descent. METHODS: To evaluate previously identified loci in Korean women and to identify additional novel breast cancer susceptibility variants, we conducted a three-stage GWAS that included 6,322 cases and 5,897 controls. RESULTS: In the validation study using Stage I of the 2,273 cases and 2,052 controls, seven GWAS-identified loci [5q11.2/MAP3K1 (rs889312 and rs16886165), 5p15.2/ROPN1L (rs1092913), 5q12/MRPS30 (rs7716600), 6q25.1/ESR1 (rs2046210 and rs3734802), 8q24.21 (rs1562430), 10q26.13/FGFR2 (rs10736303), and 16q12.1/TOX3 (rs4784227 and rs3803662)] were significantly associated with breast cancer risk in Korean women (Ptrend < 0.05). To identify additional genetic risk variants, we selected the most promising 17 SNPs in Stage I and replicated these SNPs in 2,052 cases and 2,169 controls (Stage II). Four SNPs were further evaluated in 1,997 cases and 1,676 controls (Stage III). SNP rs13393577 at chromosome 2q34, located in the Epidermal Growth Factor Receptor 4 (ERBB4) gene, showed a consistent association with breast cancer risk with combined odds ratios (95% CI) of 1.53 (1.37-1.70) (combined P for trend = 8.8 × 10-14). CONCLUSIONS: This study shows that seven breast cancer susceptibility loci, which were previously identified in European and/or Chinese populations, could be directly replicated in Korean women. Furthermore, this study provides strong evidence implicating rs13393577 at 2q34 as a new risk variant for breast cancer.

Recapitulation of genome-wide association studies on pulse pressure and mean arterial pressure in the Korean population.

Increased pulse pressure (PP) and decreased mean arterial pressure (MAP) are strong prognostic predictors of adverse cardiovascular events. Recently, the International Consortium for Blood Pressure Genome-Wide Association Studies (ICBP-GWAS) reported eight loci that influenced PP and MAP. The ICBP-GWAS examined 51 cohorts--comprising 122 671 individuals of European ancestry--and identified eight SNPs: five that governed PP and three that controlled MAP. Six of these loci were novel. To replicate these newly identified loci and examine genetic architecture of PP and MAP between European and Asian populations, we conducted a meta-analysis of the eight SNPs combining data from ICBP and general population-based Korean cohorts. Two SNPs (rs13002573 (FIGN) and rs871606 (CHIC2)) for PP and two SNPs (rs1446468 (FIGN) and rs319690 (MAP4)) for MAP were replicated in Koreans. Although our GWAS only found moderate association, we believe that the findings promote us to propose that a similar genetic architecture governs PP and MAP in Asians and Europeans. However, further studies will be needed to confirm the possibility using other Asian population.

Prospective study of optimal obesity index cutoffs for predicting development of multiple metabolic risk factors: the Korean genome and epidemiology study.

BACKGROUND: In this prospective cohort study, we estimated the risk of developing more than 1 metabolic risk factor, using different obesity indices. In addition, we investigated the relative usefulness of the obesity indices for predicting development of such risk factors and calculated optimal cutoffs for the obesity indices. METHODS: The cohort comprised 10 038 representative residents of a small city and a rural county who were recruited in 2001-2002. Follow-up examinations were conducted every 2 years. Among the 3857 participants without metabolic syndrome at baseline, 1102 new cases occurred during the 6-year follow-up. Receiver operating characteristic (ROC) curves for the obesity indices were plotted to compare the usefulness of the obesity indices. RESULTS: The numbers of new cases of multiple metabolic risk factors among people in the highest quintiles of body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), and waist-height ratio at the baseline examination were 2 to 3 times those in the lowest quintiles. The area under the ROC curve for WHR was significantly higher than that for BMI. The optimal BMI cutoff was 24 kg/m(2) in men and women, and the optimal WC cutoffs were 80 cm and 78 cm in men and women, respectively. CONCLUSIONS: Both overall obesity and central obesity predicted risk of developing multiple metabolic risk factors, and WHR appeared to be a better discriminator than BMI. To prevent development of metabolic diseases among Koreans, it might be useful to lower the cutoff for abdominal obesity, as defined by WC.

Association of lipoprotein lipase (LPL) single nucleotide polymorphisms with type 2 diabetes mellitus.

The etiology and pathogenesis of type 2 diabetes mellitus (T2DM) are not completely understood although it is often associated with other conditions such as obesity, hypertension, and dyslipidemia. Lipoprotein lipase (LPL) is a key enzyme in human lipid metabolism that facilitates the removal of triglyceride-rich lipoproteins from the bloodstream. LPL hydrolyzes the core of triglyceride-rich lipoproteins (chylomicrons and very low density lipoprotein) into free fatty acids and monoacylglycerol. To gain insight into the possible role of LPL in T2DM, nine single nucleotide polymorphisms (SNPs) of LPL were analyzed for the association with T2DM using 944 unrelated Koreans, including 474 T2DM subjects and 470 normal healthy controls. Of the nine LPL SNPs we analyzed, a significant association with multiple tests by the false discovery rate (FDR) was observed between T2DM and SNP rs343 (+13836C>A in intron 3). SNP rs343 was also marginally associated with some of T2DM-related phenotypes including total cholesterol, high density lipoprotein cholesterol (HDLc), and log transformed glycosylated hemoglobin in 470 normal controls, although no significant association was detected by multiple tests. In total, our results suggest that the control of lipid level by LPL in the bloodstream might be an important factor in T2DM pathogenesis in the Korean population.

On the Estimation of Heritability with Family-Based and Population-Based Samples.

For a family-based sample, the phenotypic variance-covariance matrix can be parameterized to include the variance of a polygenic effect that has then been estimated using a variance component analysis. However, with the advent of large-scale genomic data, the genetic relationship matrix (GRM) can be estimated and can be utilized to parameterize the variance of a polygenic effect for population-based samples. Therefore narrow sense heritability, which is both population and trait specific, can be estimated with both population- and family-based samples. In this study we estimate heritability from both family-based and population-based samples, collected in Korea, and the heritability estimates from the pooled samples were, for height, 0.60; body mass index (BMI), 0.32; log-transformed triglycerides (log TG), 0.24; total cholesterol (TCHL), 0.30; high-density lipoprotein (HDL), 0.38; low-density lipoprotein (LDL), 0.29; systolic blood pressure (SBP), 0.23; and diastolic blood pressure (DBP), 0.24. Furthermore, we found differences in how heritability is estimated--in particular the amount of variance attributable to common environment in twins can be substantial--which indicates heritability estimates should be interpreted with caution.

Expression patterns of glucose transporter-1 gene and thyroid specific genes in human papillary thyroid carcinoma.

PURPOSE: The expression of glucose transporter-1 (Glut-1) gene and those of major thyroid-specific genes were examined in papillary carcinoma tissues, and the expressions of these genes were compared with cancer differentiation grades. MATERIALS AND METHODS: Twenty-four human papillary carcinoma tissues were included in this study. The expressions of Glut-1- and thyroid-specific genes [sodium/iodide symporter (NIS), thyroid peroxidase, thyroglobulin, TSH receptor and pendrin] were analyzed by RT-PCR. Expression levels were expressed as ratios versus the expression of beta-actin. Pathologic differentiation of papillary carcinoma was classified into a relatively well-differentiated group (n = 13) and relatively less differentiated group (n = 11). RESULTS: Glut-1 gene expression was significantly higher in the less differentiated group (0.66 ± 0.04) than in the well-differentiated group (0.59 ± 0.07). The expression levels of the NIS, PD and TG genes were significantly higher in the well-differentiated group (NIS: 0.67 ± 0.20, PD: 0.65 ± 0.21, TG: 0.74 ± 0.16) than in the less differentiated group (NIS: 0.36 ± 0.05, PD: 0.49 ± 0.08, TG: 0.60 ± 0.11), respectively. A significant negative correlation was found between Glut-1 and NIS expression, and positive correlations were found between NIS and TG, and between NIS and PD. CONCLUSION: The NIS, PD and TG genes were highly expressed in well-differentiated thyroid carcinomas, whereas the Glut-1 gene was highly expressed in less differentiated thyroid carcinomas. These findings provide a molecular rationale for the management of papillary carcinoma, especially in the selection of FDG PET or radioiodine whole-body scan and I-131-based therapy.

Current status, challenges, policies, and bioethics of biobanks.

Many biobanks were established as biorepositories for biomedical research, and a number of biobanks were founded in the 1990s. The main aim of the biobank is to store and to maintain biomaterials for studying chronic disease, identifying risk factors of specific diseases, and applying personalized drug therapies. This report provides a review of biobanks, including Korean biobanks and an analysis of sample volumes, regulations, policies, and ethical issues of the biobank. Until now, the top 6 countries according to the number of large-scale biobanks are the United Kingdom, United States, Sweden, France, the Netherlands, and Italy, and there is one major National Biobank of Korea (NBK) and 17 regional biobanks in Korea. Many countries have regulations and guidelines for the biobanks, and the importance of good management of biobanks is increasing. Meanwhile, according to a first survey of 456 biobank managers in the United States, biobankers are concerned with the underuse of the samples in their repositories, which need to be advertised for researchers. Korea Biobank Network (KBN) project phase II (2013-2015) was also planned for the promotion to use biospecimens in the KBN. The KBN is continuously introducing for researchers to use biospecimens in the biobank. An accreditation process can also be introduced for biobanks to harmonize collections and encourage use of biospecimens in the biobanks. KBN is preparing an on-line application system for the distribution of biospecimens and a biobank accreditation program and is trying to harmonize the biobanks.

Dietary patterns and osteoporosis risk in postmenopausal korean women.

OBJECTIVES: The prevalence of osteoporosis and related fractures has increased rapidly in Korean women. Proper nutrition intake is associated with the prevention of osteoporosis. We analyzed the association between dietary patterns and the risk of osteoporosis during a 4-year follow-up in postmenopausal Korean women. METHODS: Postmenopausal women (n = 1,725) who participated in the Korean Genome and Epidemiology Study were enrolled. Food intake was assessed using a validated semiquantitative food frequency questionnaire, and a quantitative ultrasound device was used to measure the speed of sound at the radius and tibia. RESULTS: THREE MAJOR DIETARY PATTERNS WERE IDENTIFIED USING FACTOR ANALYSIS BASED ON BASELINE INTAKE DATA: traditional (high intake of rice, kimchi, and vegetables), dairy (high intake of milk, dairy products, and green tea), and western (high intake of sugar, fat, and bread). Multivariate Cox proportional hazards models were used to estimate relative risk for osteoporosis. An inverse association was detected between the dairy dietary pattern and the osteoporosis incidence [relative risk (RR): 0.63, 95% confidence interval (CI): 0.42-0.93, p-trend=0.055 in radius; RR: 0.56, 95% CI: 0.35-0.90, p-trend=0.048 in tibia]. Individuals in the highest quintile for the traditional dietary pattern (p-trend = 0.009 in tibia) and western dietary pattern (p-trend = 0.043 in radius) demonstrated a higher risk of osteoporosis incidence than those in the lowest quintile. CONCLUSION: These results suggested that high consumption of milk, dairy products, and green tea may reduce the risk of osteoporosis in postmenopausal Korean women.

Practical issues in genome-wide association studies for physical activity.

Genome-wide association studies (GWAS) have successfully identified many genetic variants that are associated with many complex traits. For example, GWAS can be useful for understanding the genetic basis of physical activity (PA). To date, however, there have been only a few GWAS regarding PA. In this article, we overview some practical issues for more efficient GWAS for PA: phenotype definition of PA, the analysis method, population stratification, replication, and sample size. We discuss these issues within a large-scale GWA data set from the Korea Association REsource (KARE) project, including 8,842 samples and 352,228 single nucleotide polymorphism (SNP) markers. Information on PA was obtained from questionnaires, and GWA analysis was performed to find genetic associations between PA and SNP markers in the Korean population.

A prospective study investigating the association between environmental tobacco smoke exposure and the incidence of type 2 diabetes in never smokers.

PURPOSE: We studied a cohort of individuals to assess whether intensity of environmental tobacco smoke (ETS) exposure is associated with the incidence of type 2 diabetes. METHODS: Study subjects were selected from an ongoing population-based cohort of Korea Genome and Epidemiology Study. Participants of the baseline study 10,038 persons within the age range of 40 to 69 years old. Among 4,442 never smokers without prevalent diabetes, 465 type 2 diabetes cases were identified through biennial active follow-ups for a 6-year period. Cox proportional hazard models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) after adjustment for covariates. RESULTS: The risk of type 2 diabetes was higher in subjects exposed to ETS compared with the nonexposure group (HR = 1.41, 95% CI: 1.1-1.70). Daily exposure to ETS at home increased the risk of type 2 diabetes when compared with the risk level of nonexposure (HR = 1.46, 95% CI: 1.16-1.83). Over 4 hours exposure to ETS at home and in the workplace was associated with increased the risk of type 2 diabetes (HR = 1.96, 95% CI: 1.21-3.19). CONCLUSIONS: Our study suggests that ETS exposure is a significant risk factor for the development of type 2 diabetes with dose-response relationship.

Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits.

To identify the genetic bases for nine metabolic traits, we conducted a meta-analysis combining Korean genome-wide association results from the KARE project (n = 8,842) and the HEXA shared control study (n = 3,703). We verified the associations of the loci selected from the discovery meta-analysis in the replication stage (30,395 individuals from the BioBank Japan genome-wide association study and individuals comprising the Health2 and Shanghai Jiao Tong University Diabetes cohorts). We identified ten genome-wide significant signals newly associated with traits from an overall meta-analysis. The most compelling associations involved 12q24.11 (near MYL2) and 12q24.13 (in C12orf51) for high-density lipoprotein cholesterol, 2p21 (near SIX2-SIX3) for fasting plasma glucose, 19q13.33 (in RPS11) and 6q22.33 (in RSPO3) for renal traits, and 12q24.11 (near MYL2), 12q24.13 (in C12orf51 and near OAS1), 4q31.22 (in ZNF827) and 7q11.23 (near TBL2-BCL7B) for hepatic traits. These findings highlight previously unknown biological pathways for metabolic traits investigated in this study.

A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits.

To identify genetic factors influencing quantitative traits of biomedical importance, we conducted a genome-wide association study in 8,842 samples from population-based cohorts recruited in Korea. For height and body mass index, most variants detected overlapped those reported in European samples. For the other traits examined, replication of promising GWAS signals in 7,861 independent Korean samples identified six previously unknown loci. For pulse rate, signals reaching genome-wide significance mapped to chromosomes 1q32 (rs12731740, P = 2.9 x 10(-9)) and 6q22 (rs12110693, P = 1.6 x 10(-9)), with the latter approximately 400 kb from the coding sequence of GJA1. For systolic blood pressure, the most compelling association involved chromosome 12q21 and variants near the ATP2B1 gene (rs17249754, P = 1.3 x 10(-7)). For waist-hip ratio, variants on chromosome 12q24 (rs2074356, P = 7.8 x 10(-12)) showed convincing associations, although no regional transcript has strong biological candidacy. Finally, we identified two loci influencing bone mineral density at multiple sites. On chromosome 7q31, rs7776725 (within the FAM3C gene) was associated with bone density at the radius (P = 1.0 x 10(-11)), tibia (P = 1.6 x 10(-6)) and heel (P = 1.9 x 10(-10)). On chromosome 7p14, rs1721400 (mapping close to SFRP4, a frizzled protein gene) showed consistent associations at the same three sites (P = 2.2 x 10(-3), P = 1.4 x 10(-7) and P = 6.0 x 10(-4), respectively). This large-scale GWA analysis of well-characterized Korean population-based samples highlights previously unknown biological pathways.