Seung Ku Lee

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 Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci

Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10-12) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10-9; and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05); undersleeping and BMI (rG = 0.147, P = 1x10-5) and oversleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans.

Evening Chronotype Is Associated With Metabolic Disorders and Body Composition in Middle-Aged Adults

CONTEXT Chronotype is a trait determining individual circadian preference in behavioral and biological rhythm relative to external light-dark cycle. However, little is known about the relationship between chronotype and metabolic disorders. OBJECTIVE The aim of this study was to examine whether late chronotype is related to metabolic abnormalities and body composition in middle-aged adults, independent of sleep duration and lifestyle. DESIGN AND PARTICIPANTS A total of 1620 participants aged 47-59 years were recruited from the Korean Genome and Epidemiology Study. MAIN OUTCOME MEASURES Chronotype was assessed by the Morningness-Eveningness Questionnaire. Associations of chronotype with diabetes, metabolic syndrome, sarcopenia, and visceral obesity were analyzed. All participants underwent the oral glucose tolerance test, and body composition was measured with dual energy x-ray absorptiometry. Visceral obesity was designated as visceral fat area, measured by abdominal computed tomography, of >100 cm(2). RESULTS Chronotype was classified as morning in 29.6% of subjects, evening in 5.9%, neither morning nor evening in 64.5%. Evening type, when compared with morning type, was significantly associated with diabetes (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.01-2.95), metabolic syndrome (OR, 1.74; 95% CI, 1.05-2.87), and sarcopenia (OR, 3.16; 95% CI, 1.36-7.33) after adjusting for confounding factors. Gender differences in the associations were evident. In men, evening type was associated with diabetes (OR, 2.98; 95% CI, 1.39-6.39) and sarcopenia (OR, 3.89; 95% CI, 1.33-11.33). Only metabolic syndrome was associated with evening type in women (OR, 2.22; 95% CI, 1.11-4.43). CONCLUSIONS At the population level, evening chronotype was independently associated with diabetes, metabolic syndrome, and sarcopenia. These results support the importance of circadian rhythms in metabolic regulation.

Obesity phenotype and incident hypertension: a prospective community-based cohort study.

Objective: The relationship betweens the healthy obese phenotype and the risk of cardiovascular events remains unclear. We prospectively investigated the association between the obesity phenotype and the incidence of hypertension. Methods: We studied 2352 participants, aged 40–69 years at baseline, with normal blood pressure (BP) from the Ansan cohort and the Ansung cohort of the Korean Genome Epidemiology Study. Participants were divided into six groups based on BMI and the metabolic syndrome (MetS) components: healthy (none of the five MetS components) normal weight (BMI <23 kg/m2), unhealthy (one or more MetS component) normal weight, healthy overweight (BMI 23–24.9 kg/m2), unhealthy overweight, healthy obesity (BMI ≥25 kg/m2), and unhealthy obesity. The incidence of hypertension was identified by biennial health examinations during the 8-year follow-up. Results: After adjusting for age, sex, cohort, physical activity, smoking, alcohol consumption, and family history of hypertension and cardiovascular diseases, an increased risk for hypertension in combined cohort was observed in the healthy obesity [hazard ratio (HR): 2.20, 95% confidence interval (CI):1.34–3.60], unhealthy overweight (HR: 1.47, 95% CI: 1.00–2.14), and unhealthy obesity (HR: 2.45, 95% CI: 1.79–3.37), compared with the healthy normal weight group. In each cohort, the healthy obesity was still associated with a higher incidence of hypertension (HR 2.20, 95% CI 1.11–4.36 for the Ansan cohort and HR 2.21, 95% CI 1.01–4.83 for the Ansung cohort). Conclusion: These findings provide evidence that the metabolically healthy obese phenotype may not be a benign condition.

Longitudinal course of depression scores with and without insomnia in non-depressed individuals: a 6-year follow-up longitudinal study in a Korean cohort.

STUDY OBJECTIVE This is a population-based longitudinal study that followed insomnia symptoms over a 6-year period in non-depressed individuals. The purpose of the study was to (1) investigate the longitudinal course of depression based on number of insomnia episodes; and (2) describe longitudinal associations between insomnia and depression, and insomnia and suicidal ideation. DESIGN Population-based longitudinal study. SETTING Community-based sample from the Korean Genome and Epidemiology Study (KoGES). PARTICIPANTS 1,282 non-depressed individuals (44% male, mean age 52.3 ± 7.14 years). MEASUREMENTS AND RESULTS This study prospectively assessed insomnia, depression, and suicidal ideation with 4 time points. Individuals were classified into no insomnia (NI), single episode insomnia (SEI), and persistent insomnia (PI; ≥ insomnia at 2+ time points) groups based on number of times insomnia was indicated. Mixed effects modeling indicated that depression scores increased significantly faster in the PI group compared to the NI (P < 0.001) and SEI (P = 0.02) groups. Additionally, the PI group had significantly increased odds of depression as compared to NI or SEI (OR 2.44, P = 0.001) groups, with 18.7% meeting criteria for depression compared to the NI (5.3%) and SEI (11.6%) groups at end point. The PI group also had significantly increased odds of suicidal ideation as compared to NI or SEI (OR 1.86, P = 0.002) groups. CONCLUSIONS Persistent insomnia significantly increases the rate in which depression occurs over time in non-depressed individuals, which ultimately leads to higher risk for depression. Additionally, having persistent insomnia also increased the risk of suicidal ideation. CITATION Suh S; Kim H; Yang HC; Cho ER; Lee SK; Shin C. Longitudinal course of depression scores with and without insomnia in non-depressed individuals: a 6-year follow-up longitudinal study in a Korean cohort. SLEEP 2013;36(3):369-376.

Non-alcoholic fatty liver disease, metabolic syndrome and subclinical cardiovascular changes in the general population

Objective The effect of non-alcoholic fatty liver disease (NAFLD) on cardiovascular system remains controversial. We investigated the independent contribution of NAFLD to cardiovascular structure and function in the general population. Methods A total of 1886 participants without known cardiovascular disease were enrolled from the Korean Genome Epidemiology Study. The participants were divided into four groups, based on the presence of NAFLD, metabolic syndrome (MetS), neither or both. NAFLD was diagnosed by CT. Changes in cardiovascular structure and function were assessed by tissue Doppler imaging (TDI) echocardiography, carotid ultrasound and brachial-ankle pulse wave velocity (baPWV). Results In multivariate analyses, subjects with both NAFLD and MetS had a higher E/Ea ratio and baPWV, as well as a lower TDI Ea velocity (all p<0.001) than those with neither NAFLD nor MetS. Subjects with either NAFLD or MetS also showed significant differences in TDI Ea velocity and baPWV (all p<0.05). However, no significant differences of carotid intima-media thickness (CIMT) values were seen among the four groups. Multivariate linear regression revealed that both NAFLD and MetS were independent predictors of TDI Ea velocity and baPWV (all p<0.001). Both MetS and NAFLD were not a determinant of CIMT. Conclusions NAFLD was associated with early alterations of cardiovascular system, independent of established cardiovascular risk factors and MetS.

Obstructive sleep apnea as a risk factor for silent cerebral infarction

Previous studies have suggested that obstructive sleep apnea (OSA) may be a risk factor for stroke. In this study, we assessed that OSA is an independent risk factor of silent cerebral infarction (SCI) in the general population, and in a non‐obese population. This study recruited a total of 746 participants (252 men and 494 women) aged 50–79 years as part of the Korean Genome and Epidemiology Study (KoGES); they underwent polysomnography, brain magnetic resonance imaging and health screening examinations. SCI was assessed by subtypes and brain regions, and lacunar infarction represented lesions <15 mm in size in the penetrating arteries. Moderate–severe OSA was determined by apnea–hypopnea index ≥15. The results indicated that 12.06% had moderate–severe OSA, 7.64% of participants had SCI and 4.96% had lacunar infarction. Moderate–severe OSA was associated positively with SCI [odds ratio (OR): 2.44, 95% confidence interval (CI): 1.03–5.80] and lacunar infarction (OR: 3.48, 95% CI: 1.31–9.23) in the age ≥65‐year group compared with those with non‐OSA. Additionally, in the basal ganglia, OSA was associated with an increase in the odds for SCI and lacunar infarction in all age groups, and especially in the ≥65‐year age group. In the non‐obese participants, OSA was also associated positively with SCI in the ≥65‐year age group, lacunar infarction in all age groups, and especially in the ≥65‐year age group. There was also a positive association with the basal ganglia. Moderate–severe OSA was associated positively with SCI and lacunar infarction in elderly participants. Treatment of OSA may reduce new first‐time cerebrovascular events and recurrences.

Low vitamin D status is associated with nonalcoholic Fatty liver disease independent of visceral obesity in Korean adults.

Objective To investigate the association between serum 25-hydroxyvitamin D [25(OH)D] levels and nonalcoholic fatty liver disease (NAFLD) independent of visceral obesity in Koreans and to examine whether the associations differ according to the presence of diabetes or insulin resistance. Research Design and Methods A total of 1081 adults were enrolled from a population-based cohort in Ansan city. Serum 25(OH)D concentrations were measured in all subjects. Insulin resistance was measured by homeostasis model assessment of insulin resistance (HOMA-IR). Using computed tomography, NAFLD was diagnosed if the liver attenuation index (LAI, the difference between the mean hepatic and splenic attenuation) was <5 Hounsfield Units. Results In subjects with diabetes (n = 282), 25(OH)D levels were negatively associated with waist circumference, fasting insulin, HOMA-IR, triglyceride levels, and visceral abdominal fat, and were positively associated with LAI after adjusting for age, sex, season, exercise, and vitamin supplementation. In subjects without diabetes, only triglyceride level was negatively associated with 25(OH)D. The adjusted odds ratio (OR) for NAFLD increased sequentially across decreasing quartiles of 25(OH)D in subjects with diabetes even after adjusting for visceral fat [Q1 vs. Q4; OR for NAFLD 2.5 (95% CI:1.0–6.2)]. In contrast, no significant difference in OR was observed in subjects without diabetes. When we classified non-diabetic subjects by HOMA-IR, an increase in the OR for NAFLD across decreasing quartiles of 25(OH)D was observed in the high HOMA-IR (≥2.5) group [n = 207, Q1 vs. Q4; OR 3.8(1.4–10.3)], but not in the low HOMA-IR (<2.5) group [n = 592, OR 0.8 (0.3–1.9)]. Conclusions Low vitamin D status is closely associated with NAFLD, independent of visceral obesity in subjects with diabetes or insulin resistance.

Association of Obstructive Sleep Apnea and Glucose Metabolism in Subjects With or Without Obesity

OBJECTIVE The purpose of this study was to investigate whether the impact of obstructive sleep apnea (OSA) on glucose metabolism was different according to the presence or absence of obesity. RESEARCH DESIGN AND METHODS A total of 1,344 subjects >40 years old from the Korean Genome and Epidemiology Study were included. OSA was detected by home portable sleep monitoring. Plasma glucose, HbA1c, and insulin resistance were compared according to OSA and obesity status. The associations between OSA and impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG + IGT, and diabetes were evaluated in subjects with and without obesity after adjusting for several confounding variables. The effect of visceral obesity on this association was evaluated in 820 subjects who underwent abdominal computed tomography scanning. RESULTS In subjects without obesity, fasting glucose, 2-h glucose after 75-g glucose loading, and HbA1c were higher in those with OSA than in those without after controlling for age, sex, and BMI. In addition, the presence of OSA in nonobese subjects was associated with a higher prevalence of IFG + IGT and diabetes after adjusting for several confounding variables (odds ratio 3.15 [95% CI 1.44–6.90] and 2.24 [1.43–3.50] for IFG + IGT and diabetes, respectively). Further adjustment for visceral fat area did not modify this association. In contrast, in those with obesity, none of the abnormal glucose tolerance categories were associated with OSA. CONCLUSIONS The presence of OSA in nonobese individuals is significantly associated with impaired glucose metabolism, which can be responsible for future risk for diabetes and cardiovascular disease.

Association of VEGF and KDR Single Nucleotide Polymorphisms With Colorectal Cancer Susceptibility in Koreans

Vascular endothelial growth factor (VEGF) and its receptor kinase insert domain‐containing receptor (KDR) play crucial roles in angiogenesis, which contributes to the development and progression of solid tumors. The aim of this study was to investigate the associations of VEGF (−2578C > A, −1154G > A, −634G > C, and 936C > T) and KDR (−604T > C and 1192G > A) polymorphisms with the development of colorectal cancer (CRC). A total of 882 participants (390 CRC patients and 492 controls) were enrolled in the study. The genotyping of VEGF and KDR polymorphisms was performed by polymerase chain reaction–restriction fragment length polymorphism assay. We found that the CT and TT genotype of the 936C > T was associated with an increased risk of CRC compared with the CC genotype as the dominant model for the T allele. In addition, we also found a increased CRC risk with TC + CC genotype of KDR −604T > C compared with TT genotype in CRC patients and control subjects. Similarly, KDR 1192G > A also showed significant association between 1192G > A variants and risk of CRC. In the haplotype analyses, haplotype −2578A/−1154A/−634G/936T of VEGF polymorphisms and haplotype −604C/1192G and −604C/1192A of KDR polymorphisms were associated with an increased susceptibility of CRC. Our results suggest that the VEGF 936C > T, KDR −604T > C, and KDR 1192G > A polymorphisms may be contribute to CRC risk in the Korean population.