Chol Shin

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 × 10−9) and 6q22 (rs12110693, P = 1.6 × 10−9), with the latter ∼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 × 10−7). For waist-hip ratio, variants on chromosome 12q24 (rs2074356, P = 7.8 × 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 × 10−11), tibia (P = 1.6 × 10−6) and heel (P = 1.9 × 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 × 10−3, P = 1.4 × 10−7 and P = 6.0 × 10−4, respectively). This large-scale GWA analysis of well-characterized Korean population-based samples highlights previously unknown biological pathways.

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.

Prevalence, awareness, treatment, control and risk factors of hypertension in Korea: the Ansan study

Objectives To determine prevalence, awareness, treatment, and control of hypertension, and its risk factors in an urban Korean population. Design and setting A cross-sectional survey in Ansan-city, Korea. Subjects and methods Population-based samples of people aged 18–92 years in Ansan-city, Korea, were selected, yielding 2278 men and 1948 women, and their blood pressures were measured using a highly standardized protocol. Hypertension was defined as a systolic BP ⩾ 140 mmHg or diastolic BP ⩾ 90 mmHg or reported treatment with antihypertensive medications, and subclassified according to 1999 WHO-ISH guidelines. Isolated systolic hypertension (ISH) defined as a systolic BP ⩾140 mmHg and diastolic BP < 90 mmHg was also examined. Data were stratified by age and sex. Results The overall prevalence of hypertension in this study was 33.7%. Among these, 64.9% had Grade 1 hypertension, 22.5% Grade 2, and 12.5% Grade 3. Age-specific prevalence of hypertension increased progressively with age, from 14.19% in 18 to 24 year-olds to 71.39% in those 75 years or older. Hypertension prevalence was significantly higher in men (41.5%) than in women (24.5%) (P < 0.001). Isolated systolic hypertension had significantly lower prevalence (4.33%) within the population, although in the elderly aged 55 years or more it rose by 11.13%. Overall, 24.6% of hypertensive individuals were aware that they had high blood pressure, as much as 78.6% were being treated with antihypertensive medications, and 24.3% were under control. Hypertension awareness as well as treatment and control rates varied by sex, with women higher in all three rates. Multivariate analysis revealed that age, body mass index and abdomen circumference were significantly associated with prevalence of hypertension both in men and women. Conclusions Hypertension is highly prevalent in Korea. Despite the high rate of treatment, the rates of awareness and control are relatively low, suggesting the nationwide demand for preventing and controlling high blood pressure in Korea in order to avert an epidemic of cardiovascular disease.

Adiponectin concentrations: a genome-wide association study.

Adiponectin is associated with obesity and insulin resistance. To date, there has been no genome-wide association study (GWAS) of adiponectin levels in Asians. Here we present a GWAS of a cohort of Korean volunteers. A total of 4,001 subjects were genotyped by using a genome-wide marker panel in a two-stage design (979 subjects initially and 3,022 in a second stage). Another 2,304 subjects were used for follow-up replication studies with selected markers. In the discovery phase, the top SNP associated with mean log adiponectin was rs3865188 in CDH13 on chromosome 16 (p = 1.69 × 10(-15) in the initial sample, p = 6.58 × 10(-39) in the second genome-wide sample, and p = 2.12 × 10(-32) in the replication sample). The meta-analysis p value for rs3865188 in all 6,305 individuals was 2.82 × 10(-83). The association of rs3865188 with high-molecular-weight adiponectin (p = 7.36 × 10(-58)) was even stronger in the third sample. A reporter assay that evaluated the effects of a CDH13 promoter SNP in complete linkage disequilibrium with rs3865188 revealed that the major allele increased expression 2.2-fold. This study clearly shows that genetic variants in CDH13 influence adiponectin levels in Korean adults.

Prevalence and correlates of orthostatic hypotension in middle-aged men and women in Korea: the Korean Health and Genome Study.

To examine the prevalence and correlates of orthostatic hypotension (OH) in middle-aged adults enrolled in the Korean Health and Genome Study. Participants were 8908 individuals aged 40–69 years. Supine blood pressure (BP) was measured three times at 30-s intervals after at least 5 min of rest in the supine position and single standing BP was measured at 0 and 2 min after standing, respectively. OH was defined as a reduction in systolic BP or diastolic BP⩾20 and 10 mmHg, respectively. The prevalence of OH at 0 and 2 min after standing was 12.3 and 2.9%, respectively. At 0 min of standing, OH frequency increased significantly with age from 6.4% in those aged 40–44 years to 23.1% in those aged 65–69 (P<0.001). After adjustment for age and other characteristics, hypertension was associated with a 1.7-fold excess in the odds of OH in men and a 1.6-fold excess in women (P<0.001). In contrast, an increase in body mass index (BMI) on the order of 5 kg/m2 was associated with a 20–30% reduction in the odds of OH (P<0.001). Diabetes in women was also associated with a 1.4-fold excess in the odds of OH (P<0.05). An increase in triglyceride by 136 mg/dl in men was associated with an increase in the odds of OH (P<0.05). In conclusion, the prevalence and correlates of OH other than diabetes and triglycerides were notably similar in men and women. While the association between hypertension and OH has been observed elsewhere, low BMI in Korean adults with OH may be an important marker for subclinical morbidity or coexisting risk factors that need to be identified.

Secular trend in age at menarche for South Korean women born between 1920 and 1986: the Ansan Study

BACKGROUND There is strong evidence of a downward secular trend in age at menarche in Europe and the USA during the last century and in Japan and China during the past few decades. However, no study on this trend in age at menarche has been reported in South Korea. AIM To measure the trend in age at menarche in South Korea during the past few decades and the association of height with this trend. SUBJECTS AND METHODS A total of 1061 South Korean women born between 1920 and 1986 were randomly recruited from Ansan Cohort Study samples and separate school girl samples, and subjected to this analysis. The data on age at menarche were collected by the retrospective method. Height was measured at time studied and assumed to be relatively constant since age at menarche. Women were grouped with respect to decade of birth and mean age at menarche was determined. The secular trends in annual age at menarche and in height were analysed by the 3-year moving average. RESULTS Mean menarcheal age decreased from 16.8 to 12.7 years during the past 67 years, corresponding to -0.64 years per decade. Height increased from 149.23 to 161.75 cm during the same period, showing an inverse relationship in the change of trend between height and mean age at menarche. CONCLUSION Our data suggest that the downward secular trend in age at menarche may reflect the secular change in physical growth in South Korean women during the past 67 years.

A genome-wide association study of a coronary artery disease risk variant

Although over 30 common genetic susceptibility loci have been identified to be independently associated with coronary artery disease (CAD) risk through genome-wide association studies (GWAS), genetic risk variants reported to date explain only a small fraction of heritability. To identify novel susceptibility variants for CAD and confirm those previously identified in European population, GWAS and a replication study were performed in the Koreans and Japanese. In the discovery stage, we genotyped 2123 cases and 3591 controls with 521 786 SNPs using the Affymetrix SNP Array 6.0 chips in Korean. In the replication, direct genotyping was performed using 3052 cases and 4976 controls from the KItaNagoya Genome study of Japan with 14 selected SNPs. To maximize the coverage of the genome, imputation was performed based on 1000 Genome JPT+CHB and 5.1 million SNPs were retained. CAD association was replicated for three GWAS-identified loci (1p13.3/SORT1 (rs599839), 9p21.3/CDKN2A/2B (rs4977574), and 11q22.3/ PDGFD (rs974819)) in Koreans. From GWAS and a replication, SNP rs3782889 showed a strong association (combined P=3.95 × 10−14), although the association of SNP rs3782889 doesn’t remain statistically significant after adjusting for SNP rs11066015 (proxy SNP with BRAP (r2=1)). But new possible CAD-associated variant was observed for rs9508025 (FLT1), even though its statistical significance did marginally reach at the genome-wide a significance level (combined P=6.07 × 10−7). This study shows that three CAD susceptibility loci, which were previously identified in European can be directly replicated in Koreans and also provides additional evidences implicating suggestive loci as risk variants for CAD in East Asian.

Prevalence of restless legs syndrome and associated factors in the Korean adult population: The Korean Health and Genome Study

Abstract  The present study was purposed to identify the prevalence of restless legs syndrome (RLS) and its associated factors in the Korean adult population. Among a total of 9939 participants derived from the Korean Health and Genome Study, 12.1% of subjects (men, 8.5%; women, 15.4%) suffered from RLS. Factors independently related with RLS were older age and frequent fatigue in both men and women.

Obstructive sleep apnea as a risk factor for cerebral white matter change in a middle-aged and older general population

STUDY OBJECTIVE Obstructive sleep apnea (OSA) contributes to the development of systemic hypertension, and hypertension strongly predicts the development of white matter change (WMC). Thus, it is plausible that OSA mediates WMC. The goal of the current study is to determine whether a contextual relationship exists between OSA and cerebral WMC. DESIGN Cross-sectional analyses conducted in a population-based study. SETTING Korean community-based sample from the Korean Genome and Epidemiology Study (KoGES) who attended examinations in 2011 at a medical center. PARTICIPANTS There were 503 individuals (mean ± SD, age 59.63 ± 7.48 y) who were free of previously diagnosed cardiovascular and neurologic diseases. MEASUREMENTS AND RESULTS Participants underwent 1-night polysomnography and were classified as no OSA (obstructive apnea-hypopnea index [AHI] < 5, n = 289), mild OSA (AHI 5-15, n = 161), and moderate to severe OSA (AHI ≥ 15, n = 53). WMC was identified with brain magnetic resonance imaging (MRI) and was found in 199 individuals (39.56%). Multivariate logistic regression analyses adjusted for covariates revealed that moderate to severe OSA was significantly associated with the presence of WMC (odds ratio [OR] 2.08, 95%, confidence interval [CI] 1.05-4.13) compared with no OSA. Additional adjustment of hypertension to the model did not alter the significance of the association (OR 2.03, 95% CI 1.02-4.05). CONCLUSIONS Moderate to severe OSA is an independent risk factor for WMC in middle-aged and older individuals. Thus, early recognition and treatment of OSA could reduce the risk of stroke and vascular dementia.

Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men

BACKGROUND Genome-wide association (GWA) studies regarding the quantitative trait of alcohol consumption are limited. OBJECTIVE The objective of the study was to explore genetic loci associated with the amount of alcohol consumed. DESIGN We conducted a GWA study with discovery data on single nucleotide polymorphisms (SNPs) for 1721 Korean male drinkers aged 40-69 y who were included in an urban population-based cohort. Another sample that comprised 1113 male drinkers who were from an independent cohort enrolled in a rural area served as a resource for replication. At baseline (18 June 2001 through 29 January 2003), members of both cohorts provided information on average daily alcohol consumptions, and their DNA samples were collected for genotyping. RESULTS We tested 315,914 SNPs of discovery data by using multivariate linear regression analysis adjusted for age and smoking, and 12 SNPs on chromosome 12q24 had genome-wide significant associations with alcohol consumption; adjusted P values by using Bonferroni correction were 1.6 × 10(-5) through 5.8 × 10(-46). We observed most SNPs in intronic regions and showed that the genes that harbor SNPs were C12orf51, CCDC63, MYL2, OAS3, CUX2, and RPH3A. In particular, signals in or near C12orf51, CCDC63, and MYL2 were successfully replicated in the test for 317,951 SNPs; rs2074356 in C12orf51 was in high linkage disequilibrium with SNPs in ALDH2, but other SNPs were not. CONCLUSIONS In a GWA study, we identified loci and alleles highly associated with alcohol consumption. The findings suggest the need for further investigations on the genetic propensity for drinking excessive amounts of alcohol.