A genome-wide by PM10 exposure interaction study for blood pressure in Korean adults.

Blood pressure (BP) is a typical complex trait, and the genetic susceptibility of individuals to changes in BP induced by air pollution exposure is different. Although interactions of exposure to air pollutants with several candidate genes have been identified, genome-wide interaction studies (GWISs) are needed to understand the association between them with BP. Therefore, we aimed to discover the unique genetic loci for BP that interact with exposure to air pollutants in Korean adults. We ultimately included 1868 participants in the discovery step and classified them into groups of those with low-to-moderate exposure and high exposure to average annual concentration of particulate matter with an aerodynamic diameter ≤ 10 µm (PM10). Because none of the single nucleotide polymorphisms (SNPs) achieved a genome-wide level of significance of pint < 5 × 10-8 for either systolic BP (SBP) or diastolic BP (DBP), we considered the top 10 ranking SNPs for each BP trait. To validate these suggestive SNPs, we finally selected six genetic variants for SBP and five variants for DBP, respectively. In a replication result for SBP, only one SNP (rs12914147) located in an intergenic region of the NR2F2 showed a significant interaction. We also identified several genetic susceptibility loci (e.g., CHST11, TEK, and ITGA1) implicated in candidate mechanisms such as inflammation and oxidative stress in the discovery step, although their interaction effects were not replicated. Our study reports the first GWIS finding to our knowledge, and the association between exposure to PM10 and BP levels may be determined in part by several newly discovered genetic suggestive loci, including NR2F2.

A whole-genome reference panel of 14,393 individuals for East Asian populations accelerates discovery of rare functional variants.

Underrepresentation of non-European (EUR) populations hinders growth of global precision medicine. Resources such as imputation reference panels that match the study population are necessary to find low-frequency variants with substantial effects. We created a reference panel consisting of 14,393 whole-genome sequences including more than 11,000 Asian individuals. Genome-wide association studies were conducted using the reference panel and a population-specific genotype array of 72,298 subjects for eight phenotypes. This panel yields improved imputation accuracy of rare and low-frequency variants within East Asian populations compared with the largest reference panel. Thirty-nine previously unidentified associations were found, and more than half of the variants were East Asian specific. We discovered genes with rare protein-altering variants, including LTBP1 for height and GPR75 for body mass index, as well as putative regulatory mechanisms for rare noncoding variants with cell type-specific effects. We suggest that this dataset will add to the potential value of Asian precision medicine.

A Genome-Wide Association Study on Abdominal Adiposity-Related Traits in Adult Korean Men.

INTRODUCTION: Although previous genome-wide association studies (GWASs) have identified genetic susceptibility loci for abdominal adiposity, GWASs on Asian samples remain scarce. Therefore, we performed a GWAS for abdominal adipose tissue depots in a Korean population. METHODS: A total of 1,937 Korean men were included in the study. Areas of abdominal fat were quantified by computed tomography. We performed a GWAS analysis under an additive model, and a replication study was conducted on 480 additional Korean adult men. RESULTS: In the discovery step, we identified a total of 10 single-nucleotide polymorphisms (SNPs) associated with adiposity indicators (p < 1 × 10-5). The top SNP, rs1028014, for visceral adipose tissue (VAT) was located in the ZMAT4 gene and remained significant after adjustment for body mass index (BMI). Three additional SNPs were also associated with VAT-adj-BMI and located within the SLC26A10, FAM155A, and COL4A1-COL4A2 genes, respectively. In addition, we identified a SNP (rs4668224) of the MYO3B gene for visceral-to-subcutaneous fat ratio. For subcutaneous adipose tissue and total adipose tissue, two (rs6585735 and rs363527) and three SNPs (rs1487892, rs9357565, and rs1985358) were found, respectively. Overall, eight SNPs were used in the replication study; however, none of the SNPs reached our level of significance for replication (p < 0.0063). Nevertheless, rs4773144 of COL4A1-COL4A2 for VAT-adj-BMI was the most interesting SNP identified in previous GWASs for coronary artery disease (based on the same risk allele "G"), along with functional effects. CONCLUSION: This study suggests for the first time that an SNP (rs4773144) of COL4A1-COL4A2 may contribute to the increase in VAT level, especially in adult Korean men.

Early onset female pattern hair loss: A case-control study for analyzing clinical features and genetic variants.

BACKGROUND: Female pattern hair loss (FPHL), the most common cause of alopecia in adult women, is classified into two subtypes: early onset and late onset (or postmenopausal). Little is known about the clinical features and genetic characteristics of early onset female pattern hair loss (eFPHL). OBJECTIVES: To investigate the clinical features and genetic characteristics of eFPHL. METHODS: Patients with eFPHL and controls without eFPHL were prospectively recruited. The demographic and clinical features were collected. Single nucleotide polymorphisms (SNPs) located around the selected 30 candidate genes potentially associated with eFPHL were evaluated. RESULTS: eFPHL patients (n = 63) manifested a decreased hair shaft density and cross-sectional area of the hair shaft compared to the control group (n = 341). eFPHL is associated with androgen-related features, including scalp greasiness, folliculitis, hirsutism, and polycystic ovary syndrome. Scalp pain and itching have been reported more frequently in patients with eFPHL. Forty-nine SNPs located around PPARGC1A, ABCC4, CYP11B2, FSHB, and CYP19A1 were found to be significant for eFPHL, including two PPARGC1A-associated SNPs: rs186530605 and rs192713767 (p = 3.94 × 10-11). CONCLUSIONS: This study provided clinical features and genetic variants for eFPHL, which could provide insight into the underlying pathologic etiology. Considering the limited number of patients, a large-scale study is required in the future.

A population-specific low-frequency variant of SLC22A12 (p.W258*) explains nearby genome-wide association signals for serum uric acid concentrations among Koreans.

Prolonged hyperuricemia is a cause of gout and an independent risk factor for chronic health conditions including diabetes and chronic kidney diseases. Genome-wide association studies (GWASs) for serum uric acid (SUA) concentrations have repeatedly confirmed genetic loci including those encoding uric acid transporters such as ABCG2 and SLC9A2. However, many single nucleotide polymorphisms (SNPs) found in GWASs have been common variants with small effects and unknown functions. In addition, there is still much heritability to be explained. To identify the causative genetic variants for SUA concentrations in Korean subjects, we conducted a GWAS (1902 males) and validation study (2912 males and females) and found four genetic loci reaching genome-wide significance on chromosomes 4 (ABCG2) and 11 (FRMD8, EIF1AD and SLC22A12-NRXN2). Three loci on chromosome 11 were distributed within a distance of 1.3 megabases and they were in weak or moderate linkage disequilibrium (LD) states (r2 = 0.02-0.68). In a subsequent association analysis on the GWAS loci of chromosome 11 using closely positioned markers derived from whole genome sequencing data, the most significant variant to be linked with the nearby GWAS signal was rs121907892 (c.774G>A, p.W258*) of the SLC22A12 gene. This variant, and each of the three GWAS SNPs, were in LD (r2 = 0.06-0.32). The strength of association of SNPs with SUA concentration (negative logarithm of P-values) and the genetic distance (r2 of LD) between rs121907892 and the surrounding SNPs showed a quantitative correlation. This variant has been found only in Korean and Japanese subjects and is known to lower the SUA concentration in the general population. Thus, this low-frequency variant, rs121907892, known to regulate SUA concentrations in previous studies, is responsible for the nearby GWAS signals.

Genetic variations associated with response to dutasteride in the treatment of male subjects with androgenetic alopecia.

Dutasteride, a dual inhibitor of both type I and II 5α-reductases, is used to treat male pattern hair loss (MPHL). However, patient response to dutasteride varies in each individual, the cause of which is yet to be identified. To identify genetic variants associated with response to dutasteride treatment for MPHL, a total of 42 men with moderate MPHL who had been treated with dutasteride for 6 months were genotyped and analysed by quantitative linear regression, case-control association tests, and Fisher's exact test. The synonymous single nucleotide polymorphism (SNP) rs72623193 in DHRS9 was most significantly associated with response to dutasteride, followed by the non-synonymous SNP rs2241057 in CYP26B1. Additionally, variants in ESR1, SRD5A1, CYP19A1, and RXRG are suggested to be associated with response to dutasteride. Cumulative effect and interaction among these SNPs were presented in both additive and non-additive models.

Interactions of CDH13 gene polymorphisms and ambient PM10 air pollution exposure with blood pressure and hypertension in Korean men.

Associations between air pollution and blood pressure (BP) traits can be modified by several candidate genes, which might explain differences in individual genetic susceptibility. Based on recent evidence hypothesized to link air pollution and BP traits, we examined whether the polymorphisms of CDH13-a candidate gene-would modify the relationship between them in adult Korean men. A total of 1816 subjects were included. We divided them into two groups of high or low to moderate exposure using the annual average concentration of particulate matter with an aerodynamic diameter ≤10 µm (PM10). We conducted an interaction analysis of PM10 exposure using 200 single-nucleotide polymorphisms (SNPs), located within CDH13, in subjects with regard to BP traits and hypertension. The rs7500599 intronic SNP of CDH13 had the strongest signals for all BP traits including systolic blood pressure (SBP), diastolic blood pressure, and hypertension, by interacting with PM10 exposure. An additional stratified analysis showed that the effects of PM10 exposure on elevated BP and hypertension increased gradually in proportion to the number of minor alleles in this SNP. In addition, PM10 exposure in the TT or GT genotype groups did not show significant associations with BP traits, whereas in a homozygous risk allele (GG) group, PM10 exposure was significantly associated with BP traits and hypertension. For SBP, these patterns were reproducible at two independent sampling sites. This CDH13 polymorphism amplifies the negative associations of PM10 exposure and elevated BP or hypertension in Korean men.

Genome-Wide Association Study Reveals Distinct Genetic Susceptibility of Thyroid Nodules From Thyroid Cancer.

Context: Thyroid nodules are very common, and 7% to 15% of them are diagnosed as thyroid cancer. However, the inherited genetic risk factors for thyroid nodules and their associations with thyroid cancer remain unknown. Objective: To identify the genetic variants associated with susceptibility to thyroid nodules in comparison with thyroid cancer. Design and Setting: We performed a three-stage genome-wide association study for thyroid nodules. The discovery stage involved a genome-wide scan of 811 subjects with thyroid nodules and 691 subjects with a normal thyroid from a population-based cohort. Replication studies were conducted in an additional 1981 cases and 3100 controls from the participants of a health checkup. We also performed expression quantitative trait loci analysis of public data. Results: The most robust association was observed in TRPM3 (rs4745021) in the joint analysis (OR, 1.26; P = 6.12 × 10-8) and meta-analysis (OR, 1.28; P = 2.11 × 10-8). Signals at MBIP/NKX2-1 were replicated but did not reach genome-wide significance in the joint analysis (rs2415317, P = 4.62 × 10-5; rs944289, P = 8.68 × 10-5). The expression quantitative trait loci analysis showed that TRPM3 expression was associated with the rs4745021 genotype in thyroid tissues. Conclusions: To the best of our knowledge, we have performed the first genome-wide association study of thyroid nodules and identified a susceptibility locus associated with thyroid nodules, suggesting that thyroid nodules have a genetic predisposition distinct from that of thyroid cancer.

CYP1A1 gene polymorphisms modify the association between PM10 exposure and lung function.

Genetic epidemiological studies have provided evidence that several genes modify the link between air pollution and lung function. We assessed whether the adverse impacts of particulate matter with an aerodynamic diameter ≤10 µm (PM10) on lung function are modified by CYP1A1 gene polymorphisms in Korean adults. We used health check-up data from 1817 men, and the annual mean concentrations of ambient PM10 estimated from the ambient data. Three single nucleotide polymorphisms (SNPs) of CYP1A1 were selected for our study. We identified significant CYP1A1 SNPs-by-PM10 interactions for forced expiratory volume 1 s (FEV1) and forced vital capacity (FVC) (all pint < 0.05). Minor allele carriers of the SNPs were more susceptible to PM10-induced FEV1 and FVC reduction. The subgroup analysis of SNP genotypes showed that no significant association between PM10 and FEV1 or FVC was observed in homozygous reference genotype groups of all SNPs (all passoc > 0.05), whereas in heterozygous or homozygous alternate genotype groups, PM10 was significantly associated with decreased FEV1 (all passoc for FEV1 < 0.05). The association between persistent exposure to PM10 and lung function decline in Korean men may be determined in part by several functional variants of the CYP1A1 gene.

Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer.

Thyroid cancer is the most common cancer in Korea. Several susceptibility loci of differentiated thyroid cancer (DTC) were identified by previous genome-wide association studies (GWASs) in Europeans only. Here we conducted a GWAS and a replication study in Koreans using a total of 1,085 DTC cases and 8,884 controls, and validated these results using expression quantitative trait loci (eQTL) analysis and clinical phenotypes. The most robust associations were observed in the NRG1 gene (rs6996585, P=1.08 × 10-10) and this SNP was also associated with NRG1 expression in thyroid tissues. In addition, we confirmed three previously reported loci (FOXE1, NKX2-1 and DIRC3) and identified seven novel susceptibility loci (VAV3, PCNXL2, INSR, MRSB3, FHIT, SEPT11 and SLC24A6) associated with DTC. Furthermore, we identified specific variants of DTC that have different effects according to cancer type or ethnicity. Our findings provide deeper insight into the genetic contribution to thyroid cancer in different populations.

Low muscle mass and risk of type 2 diabetes in middle-aged and older adults: findings from the KoGES.

AIMS/HYPOTHESIS: Asians have a propensity to develop type 2 diabetes with a lower BMI than Western populations. This discrepancy may be due to differences in body fat and muscle mass for a given BMI. However, unlike adiposity, it is unclear whether muscle mass affects the risk of type 2 diabetes in Asian populations. METHODS: We conducted a 2-yearly prospective assessment of 6895 participants who were free of diabetes at the baseline examination as part of the Korean Genome Epidemiology Study. The muscle mass index (MMI) was defined as the weight-adjusted appendicular skeletal muscle mass. Using Cox regression models, we evaluated the association between MMI and the risk of developing type 2 diabetes across sex-specific tertiles of MMI. Low muscle mass was defined as the sex-specific lowest tertile of MMI. Main covariates included age, sex, urban or rural residence, family history of diabetes, hypertension, smoking status, education level, monthly income, physical activity, alcohol consumption and diet. In addition, body fat mass, waist circumference and BMI were controlled as categorical variables. Obesity was defined as a BMI of ≥25 kg/m2 or a waist circumference of ≥90 cm for men and ≥85 cm for women. RESULTS: During a median follow-up of 9.06 years, 1336 participants developed type 2 diabetes. At baseline, the mean age was 52.1 years and the mean BMI was 24.4 kg/m2. The mean MMI for men and women was 32.1% and 26.0%, respectively. There was an inverse association between MMI and the risk of type 2 diabetes. Multivariate-adjusted HRs for the risk of developing type 2 diabetes were 2.05 (95% CI 1.73, 2.43), 1.39 (95% CI 1.17, 1.66) and 1.0 from the lowest to highest sex-specific MMI tertile, with an HR of 1.35 (95% CI 1.26, 1.45) per SD decline in MMI. Further adjustments for fat mass, waist circumference and BMI as categorical variables did not modify the relationship (each p < 0.01). In BMI-stratified analyses, the population-attributable fraction of the lowest tertile of MMI for developing type 2 diabetes was increased by 11.9% in the non-obese group and 19.7% in the obese group. CONCLUSIONS/INTERPRETATION: Low muscle mass as defined by MMI was associated with an increased risk of type 2 diabetes, independent of general obesity, in middle-aged and older Korean adults.

Genome-Wide Association Study of Bone Mineral Density in Korean Men.

Osteoporosis is a medical condition of global concern, with increasing incidence in both sexes. Bone mineral density (BMD), a highly heritable trait, has been proven a useful diagnostic factor in predicting fracture. Because medical information is lacking about male osteoporotic genetics, we conducted a genome-wide association study of BMD in Korean men. With 1,176 participants, we analyzed 4,414,664 single nucleotide polymorphisms (SNPs) after genomic imputation, and identified five SNPs and three loci correlated with bone density and strength. Multivariate linear regression models were applied to adjust for age and body mass index interference. Rs17124500 (p = 6.42 × 10(-7)), rs34594869 (p = 6.53 × 10(-7)) and rs17124504 (p = 6.53 × 10(-7)) in 14q31.3 and rs140155614 (p = 8.64 × 10(-7)) in 15q25.1 were significantly associated with lumbar spine BMD (LS-BMD), while rs111822233 (p = 6.35 × 10(-7)) was linked with the femur total BMD (FT-BMD). Additionally, we analyzed the relationship between BMD and five genes previously identified in Korean men. Rs61382873 (p = 0.0009) in LRP5, rs9567003 (p = 0.0033) in TNFSF11 and rs9935828 (p = 0.0248) in FOXL1 were observed for LS-BMD. Furthermore, rs33997547 (p = 0.0057) in ZBTB and rs1664496 (p = 0.0012) in MEF2C were found to influence FT-BMD and rs61769193 (p = 0.0114) in ZBTB to influence femur neck BMD. We identified five SNPs and three genomic regions, associated with BMD. The significance of our results lies in the discovery of new loci, while also affirming a previously significant locus, as potential osteoporotic factors in the Korean male population.

Predictive Value of Glucose Parameters Obtained From Oral Glucose Tolerance Tests in Identifying Individuals at High Risk for the Development of Diabetes in Korean Population.

Previous studies suggest that the future risk for type 2 diabetes is not similar among subjects in the same glucose tolerance category. In this study, we aimed to evaluate simple intuitive indices to identify subjects at high risk for future diabetes development by using 0, 30, 120 minute glucose levels obtained during 75 g OGTTs from participants of a prospective community-based cohort in Korea.Among subjects enrolled at the Chungju Metabolic disease Cohort, those who performed an OGTT between 2007 and 2010 and repeated the test between 2011 and 2014 were recruited after excluding subjects with diabetes at baseline. Subjects were categorized according to their 30 minute glucose (G30) and the difference between 120 and 0 minute glucose (G(120-0)) levels with cutoffs of 9.75 and 2.50 mmol/L, respectively.Among 1126 subjects, 117 (10.39%) developed type 2 diabetes after 4 years. In diabetes nonconverters, increased insulin resistance was accompanied by compensatory insulin secretion, but this was not observed in converters during 4 years of follow-up. Subjects with G(120-0) ≥ 2.50 mmol/L or G30 ≥ 9.75 mmol/L demonstrated lower degrees of insulin secretion, higher degrees of insulin resistance, and ∼6-fold higher risk of developing future diabetes compared to their lower counterparts after adjustment for possible confounding factors. Moreover, subjects with high G(120-0) and high G30 demonstrated 22-fold higher risk for diabetes development compared to subjects with low G(120-0) and low G30.By using the G(120-0) and G30 values obtained during the OGTT, which are less complicated measurements than previously reported methods, we were able to select individuals at risk for future diabetes development. Further studies in different ethnicities are required to validate our results.

Gender- and age-group-specific associations between physical performance and bone mineral density, falls, and osteoporotic fractures in Koreans: the Chungju Metabolic Disease Cohort study.

Several factors increase the risk of fragility fracture, including low bone mineral density, falls, and poor physical performance. The associations among these factors have been investigated; however, most of the subjects of previous studies were either elderly men or elderly women, and the associations were controversial. The aim of this study was to evaluate the associations between physical performance and bone mineral density, and the history of falls and fractures, stratified by gender and age group. We analyzed 5368 subjects who were aged 50 years or older, including 1288 younger men (younger than 70 years), 1615 younger women (younger than 70 years), 1087 older men (70 years or older), and 1378 older women (70 years or older). We used the one-leg standing time (OLST) for assessing static balance and the timed up-and-go test (TUGT) for assessing dynamic balance. The subjects in the worst performance quartile for the OLST were more likely to have osteoporosis than those in the best performance quartile. Additionally, women who had experienced a fracture during the past 2 years were 1.68 times more likely to be in the worst performance quartile for the OLST than women without a previous fracture. Although the TUGT time was not associated with either the incidence of osteoporosis or the fracture history, the odds ratios for falling were 1.51 and 1.28 as the TUGT time increased by one standard deviation in younger men and younger women, respectively. The findings of the present study show that the OLST was associated with the incidence of osteoporosis and previous fracture and that the TUGT time was associated with the incidence of falling.

Insulin Initiation in Insulin-Naïve Korean Type 2 Diabetic Patients Inadequately Controlled on Oral Antidiabetic Drugs in Real-World Practice: The Modality of Insulin Treatment Evaluation Study.

BACKGROUND: The Modality of Insulin Treatment Evaluation (MOTIV) study was performed to provide real-world data concerning insulin initiation in Korean type 2 diabetes mellitus (T2DM) patients with inadequate glycemic control with oral hypoglycemic agents (OHAs). METHODS: This multicenter, non-interventional, prospective, observational study enrolled T2DM patients with inadequate glycemic control (glycosylated hemoglobin [HbA1c] ≥7.0%) who had been on OHAs for ≥3 months and were already decided to introduce basal insulin by their physician prior to the start of the study. All treatment decisions were at the physician's discretion to reflect real-world practice. RESULTS: A total of 9,196 patients were enrolled, and 8,636 patients were included in the analysis (mean duration of diabetes, 8.9 years; mean HbA1c, 9.2%). Basal insulin plus one OHA was the most frequently (51.0%) used regimen. After 6 months of basal insulin treatment, HbA1c decreased to 7.4% and 44.5% of patients reached HbA1c <7%. Body weight increased from 65.2 kg to 65.5 kg, which was not significant. Meanwhile, there was significant increase in the mean daily insulin dose from 16.9 IU at baseline to 24.5 IU at month 6 (P<0.001). Overall, 17.6% of patients experienced at least one hypoglycemic event. CONCLUSION: In a real-world setting, the initiation of basal insulin is an effective and well-tolerated treatment option in Korean patients with T2DM who are failing to meet targets with OHA therapy.

Family-Based Association Study of Pulmonary Function in a Population in Northeast Asia.

The spirometric measurement of pulmonary function by measuring the forced expiratory volume in one second (FEV1) is a heritable trait that reflects the physiological condition of the lung and airways. Genome-wide linkage and association studies have identified a number of genes and genetic loci associated with pulmonary function. However, limited numbers of studies have been reported for Asian populations. In this study, we aimed to investigate genetic evidence of pulmonary function in a population in northeast Asia. We conducted a family-based association test with 706 GENDISCAN study participants from 72 Mongolian families to determine candidate genetic determinants of pulmonary function. For the replication, we chose seven candidate single nucleotide polymorphisms (SNPs) from the 5 loci, and tested 1062 SNPs for association with FEV1 from 2,729 subjects of the Korea Healthy Twin study. We identified TMEM132C as a potential candidate gene at 12q24.3, which is a previously reported locus of asthma and spirometric indices. We also found two adjacent candidate genes (UNC93A and TTLL2) in the 6q27 region, which has been previously identified as a pulmonary function locus in the Framingham cohort study. Our findings suggest that novel candidate genes (TMEM132C, UNC93A and TTLL2) in two different regions are associated with pulmonary function in a population in northeast Asia.

Changes in Metabolic Health Status Over Time and Risk of Developing Type 2 Diabetes: A Prospective Cohort Study.

Metabolic health and obesity are not stable conditions, and changes in the status of these conditions might lead to different clinical outcomes. We aimed to determine whether changes in metabolic health status or obesity over time have any effect on the risk of future diabetes. Nondiabetic individuals (n = 2692) from a population-based prospective cohort study with baseline and 2 follow-up examinations at 4-year intervals were included. Being "metabolically obese" (MO) was defined as being in the highest quartile of the TyG index (ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]), whereas falling into the lower 3 quartiles was regarded as being "metabolically healthy" (MH). Individuals were classified as "obese" (O) or "nonobese" (NO) using a body mass index of 25 kg/m2 as a cut-off. The risk of diabetes at year 8 was assessed according to changes of metabolic health status between year 0 and 4. Multivariate-adjusted relative risks (RRs) (95% confidence interval [CI]) of diabetes were significantly higher in individuals who retained the MONO phenotype (RR 3.72, 95% CI 2.10, 6.60) or who had progressed to MONO from the MHNO phenotype (RR 1.96, 95% CI 1.06, 3.61), whereas it was not significant in individuals who had improved to MHNO from the MONO phenotype (RR 0.67, 95% CI 0.26, 1.74) compared with individuals who retained the MHNO phenotype. In contrast, obese individuals had significantly higher RRs for diabetes, independent of changes in metabolic health status, whereas weight reduction resulted in a decreased risk of diabetes. Sensitivity analysis using the presence or absence of the metabolic syndrome as a definition of metabolic health revealed similar results. Changes in metabolic health status were an independent risk factor for future diabetes in nonobese individuals, whereas general obesity had a greater contribution to the risk of obese individuals developing diabetes. These observations might imply a different intervention strategy for diabetes prevention according to obesity status.

A Common Variant of NGEF Is Associated with Abdominal Visceral Fat in Korean Men.

Central adiposity, rather than body mass index (BMI), is a key pathophysiological feature of the development of obesity-related diseases. Although genetic studies by anthropometric measures such as waist circumference have been widely conducted, genetic studies for abdominal fat deposition measured by computed tomography (CT) have been rarely performed. A total of 1,243 participants who were recruited from two health check-up centers were included in this study. We selected four and three single-nucleotide polymorphisms (SNPs) in NGEF and RGS6, respectively, and analyzed the associations between the seven SNPs and central adiposity measured by CT using an additive, dominant, or recessive model. The participants were generally healthy middle-aged men (50.7 ± 5.3 years). In the additive model, the rs11678490 A allele of NGEF was significantly associated with total adipose tissue, visceral adipose tissue (VAT), and subcutaneous adipose tissue (all P < 0.05). The AA genotype of this SNP in the recessive model showed a more significant association with all adiposity traits, and its association with VAT remained significant even after adjustment for BMI (P = 0.005). In the overall or visceral obesity group analysis, the AA genotype of rs11678490 showed no association with overall obesity (P = 0.148), whereas it was significantly associated with visceral obesity both before (P = 0.010) and after (P = 0.029) adjustment for BMI. In particular, an AA genotype effect was conspicuous between lower and upper groups with 5% extreme VAT phenotypes (OR = 9.59, 95% CI = 1.50-61.31). However, we found no significant association between SNPs of RGS6 and central adiposity. We identified a visceral-fat-associated SNP, rs11678490 of NGEF, in Korean men. This study suggests that the genetic background of central adiposity and BMI is different, and that additional efforts should be made to find the unique genetic architecture of intra-abdominal fat accumulation.

Genetic association of APOA5 and APOE with metabolic syndrome and their interaction with health-related behavior in Korean men.

BACKGROUND: Genome-wide association studies have been used extensively to identify genetic variants linked to metabolic syndrome (MetS), but most of them have been conducted in non-Asian populations. This study aimed to evaluate the association between MetS and previously studied single nucleotide polymorphisms (SNPs), and their interaction with health-related behavior in Korean men. METHODS: Seventeen SNPs were genotyped and their association with MetS and its components was tested in 1193 men who enrolled in the study at Seoul National University Hospital. RESULTS: We found that rs662799 near APOA5 and rs769450 in APOE had significant association with MetS and its components. The SNP rs662799 was associated with increased risk of MetS, elevated triglyceride (TG) and low levels of high-density lipoprotein, while rs769450 was associated with a decreased risk of TG. The SNPs showed interactions between alcohol drinking and physical activity, and TG levels in Korean men. CONCLUSIONS: We have identified the genetic association and environmental interaction for MetS in Korean men. These results suggest that a strategy of prevention and treatment should be tailored to personal genotype and the population.

The Insulin Resistance but Not the Insulin Secretion Parameters Have Changed in the Korean Population during the Last Decade.

BACKGROUND: This study aimed to compare the patterns of insulin secretion and resistance between Korean subjects in the 1990s and 2000s. METHODS: Insulin secretion and resistance indices were calculated from subjects who underwent 75-g oral glucose tolerance tests in the year 1997 to 1999 and 2007 to 2011 at the Seoul St. Mary's Hospital, Korea. RESULTS: A total of 578 subjects from the 1990s (mean age, 48.5 years) and 504 subjects from the 2000s (mean age, 50.2 years) were enrolled. Compared with the subjects from the 1990s, those from the 2000s exhibited increased insulin resistance (increased homeostatic model assessment for insulin resistance), and reduced insulin sensitivity (reduced Matsuda index and quantitative insulin sensitivity check index), regardless of their glucose tolerance status. However, insulinogenic index did not reveal significant differences between the 2 decades in subjects with or without diabetes. A distinct relationship was confirmed between Matsuda index and total area under the curve (insulin/glucose) in each glucose tolerance group. The mean product of the Matsuda index and the total area under the curve (insulin/glucose) as well as the oral disposition index, was lower in subjects with normal glucose tolerance from the 2000s than in those from the 1990s. CONCLUSION: After rapid economic growth and changes in lifestyle patterns, insulin resistance has worsened across the glucose tolerance status; however, the insulin secretory function remained unchanged, which resulted in an increase in the susceptibility to the development of type 2 diabetes mellitus among Korean subjects without diabetes. We could not rule out the potential selection bias and therefore, further studies in general Korean population are needed.