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Coronary artery disease (CAD) is one of the most common forms of heart disease. It has been demonstrated that chemokine-mediated inflammation is associated with the development of CAD. In this study, in order to determine the role of CCR2, a receptor for MCP-1, in the development of CAD, we initially sequenced and identified the genetic variants of CCR2 using 24 unrelated Korean individuals' DNA samples. A total of 13 genetic variants, including 1 deletion and 12 SNPs, were identified in the Korean population. Although we could not detect any association of CCR2 polymorphic markers with CAD, several SNP markers of CCR2 gene showed highly significant signals with the number of arteries with significant coronary artery stenosis in the CAD male patients. The most significant signal was detected at the SNP located at exon 2 (+780T>C, Asn260Asn) CI: 1.19-1.87, P=0.0005 (odds ratio: 1.49, 95% CI: 1.19-1.87, p=0.0005) (Table 3). This result indicates that CCR2 can play a role in the pathogenesis of CAD, especially to the number of vessels in CAD.

Hemoglobin A(1c) (HbA(1c)) is an indicator of long-term glycemic control. The purpose of this study was to determine whether habitual snoring is associated with increased HbA(1c) levels in non-obese and normoglycemic middle-aged men and women. A total of 6981 subjects (3362 men and 3619 women) aged 40-69 years from the Korean Health and Genome Study were examined for the study. Each participant received a comprehensive physical examination as well as a set of questions pertaining to demographic characteristics and snoring frequency. Habitual snoring was defined as a snoring frequency ofor = 4 days week(-1). After adjusting for age, abdominal obesity, and other confounding covariates, male habitual snorers showed a 1.69-fold excess [95% confidence interval (CI) 1.30-2.19] odds of having a high HbA(1c) level. Similarly, premenopausal women with habitual snoring had a 2.31 times (95% CI 1.22-4.39) significantly higher odds of having elevated HbA(1c)levels compared with non-snorers. This association was not found in postmenopausal women. Multivariate analysis revealed that male habitual snorers aged 40-50 had a 2.08-fold excess (95% CI 1.40-3.09) risk of having an elevated HbA(1c) level. In male habitual snores over 50, the strength of association was attenuated. Our findings based on cross-sectional data support a hypothesis that habitual snoring is associated with impaired glucose tolerance even in non-obese and normoglycemic men and premenopausal women. However, as waist circumference as an index of abdominal obesity (visceral adiposity) in the present study may only partially represent the effect of visceral fat, there may be a residual confounding from visceral obesity in our result. Longitudinal follow-up studies are necessary to confirm the association between sleep-disordered breathing and impaired glucose tolerance and to examine the causal relationship in a healthy population without obesity and diabetes.

Objectives Despite recent increasing trends in cardiovascular morbidities and mortality in Asia, studies on short-term changes in cardiovascular risks remain limited. This study estimated 2-year incidence rates of hypertension in middle-aged Korean adults aged 40-69 years, and investigated the impact of baseline levels of blood pressure, body mass index, and other conventional risk factors on the progression to hypertension. Methods Blood pressures of participants were evaluated twice with a 2-year interval, measured by mercury sphygmomanometer according to the standardized protocol. Hypertension was defined when either the systolic and diastolic blood pressures were greater than 140 and 90 mmHg, respectively, or when a participant was treated with antihypertensive medications. Results The crude 2-year incidence (calculated per 100) of hypertension was 12.2; 13.0 for men and 11.6 for women. For those who had higher blood pressure at baseline examination, incidence rates were two-fold or five-fold higher compared with those with optimal blood pressure. Older age and overweight were also major predictors for hypertension, even in Koreans with a low serum cholesterol level. Conclusion This is the first investigation of short-term incidence rates of hypertension in Asia. The results are consistent with the recently reported increasing trends in cardiovascular mortality and morbidity in Asia.

Both of prolonged QT interval and elevated C-reactive protein (CRP) levels are known to be risk factors of cardiovascular disease. To our knowledge, few studies have reported the direct relationship between CRP levels and the QT interval in middle-aged population. The objective of the present study was to examine the association of CRP level with QT interval.A total of 2471 men and 2287 women from the Korea n Health and Genome study underwent physical examination and completed a questionnaire. A 12-lead electrocardiogram (ECG) recording was obtained from each subject. Subjects who were taking statins, non-steroidal anti-inflammatory drugs (NSAID) and postmenopausal hormone replacement therapy, which are known to have an effect on CRP levels, were excluded. Geometric means of CRP levels were compared among three groups, which were classified by heart rate-corrected QT (QTc) interval: prolonged (or =440 msec in men andor =450 msec in women), borderline (420-439 msec in men and 430-449 msec in women) and normal (420 msec in men and430 msec in women) groups. The means of CRP level in women, though over normal range, increased significantly as QTc interval was longer, independent of confounding factors, while those of men were on the borderline of significance. However, compared to normal range of QTc interval, prolonged QTc interval was associated with elevated CRP level, defined as more than 95 percentile of CRP, in men and women, respectively.Prolonged QTc interval in middle-aged men and women is associated with the elevated CRP, independent of confounding factors.

The rupture of an intracranial aneurysm (IA) results in subarachnoid hemorrhage, a catastrophic neurological condition with high morbidity and mortality. Following-up on our previous genome-wide linkage study in Japanese population, we extensively analyzed a 4.6 Mb linkage region around D7S2472 on 7q11 by genotyping 168 single nucleotide polymorphisms (SNPs). SNP association and window scan haplotype-based association studies revealed a susceptibility locus for IA on a single LD block covering the 3'-untranslated region (3'-UTR) of ELN and the entire region of LIMK1. An association study with 404 IA patients and 458 non-IA controls revealed that the ELN 3'-UTR G(+659)C SNP has the strongest association to IA (P=0.000002) and constitutes a tag-SNP for an at-risk haplotype, which contains two functional SNPs, the ELN 3'-UTR (+502) A insertion and the LIMK1 promoter C(-187)T SNP. These allelic and haplotype-based associations were confirmed in a Korean population. Ex vivo and in vitro analyses demonstrate that the functional impact of both SNPs is the decrease of transcript levels, either through accelerated ELN mRNA degradation or through decreased LIMK1 promoter activity. Elastin and LIMK1 protein are involved in the same actin depolymerization signaling pathway; therefore, these lines of evidence suggest a combined effect of the SNPs in the at-risk haplotype possibly by weakening the vascular wall and promoting the development of IA.

To examine the association between habitual snoring and components of the metabolic syndrome in Korean adults. Whether these associations are independent of obesity was also explored.Four thousand five hundred and six men and 5041 women aged 40-69 years from the Korean Health and Genome Study were examined. Information of snoring frequency was obtained by a questionnaire and components of the metabolic syndrome were measured.There was a clear dose-response relationship between the increasing frequency of snoring and the higher prevalence of each component of the metabolic syndrome (P0.001). After adjustment for age, abdominal obesity, and the other metabolic components, hypertension was significantly associated with a 1.2-fold excess of habitual snoring in both men (P0.05) and women (P0.05). The association of habitual snoring with hypertension was unaltered by obesity. Regardless of the presence or absence of abdominal obesity, there was an increase in the prevalence of habitual snoring as the number of metabolic abnormalities increased.Habitual snoring is associated with hypertension independent of obesity. While the relationship between habitual snoring and obesity is well recognized, characterization of the role of the other components of the metabolic syndrome as a cause or result of habitual snoring warrants a further study.

Aims Growing evidence supports the hypothesis that chronic low-grade inflammation related to innate immunity may play an important role in the pathophysiology of Type 2 diabetes mellitus (T2DM). The monocyte differentiation antigen CD14 gene (CD14) acts as the receptor for lipopolysaccharide (LPS) and augments monocyte/macrophage inflammatory responses. Methods We have sequenced the gene, including all exons, exon/intron boundaries, and the −1.5 kb of the 5′ flanking region. Two common loci (minor allele frequency > 0.05) were genotyped in 775 T2DM patients and 316 control subjects recruited in the Korean T2DM Study. Results Eight polymorphisms, including four non-synonymous forms, were identified in CD14. No polymorphisms were found in association with T2DM. However, one common promoter SNP (−260T>C) was significantly associated with both the serum triglyceride level (TG) and body mass index (BMI) in non-diabetic control subjects. Individuals who carried the minor allele (C) had higher TG levels (1.65 ± 0.81 vs. 1.46 ± 0.80 mmol/l; P = 0.0007) and BMI (23.96 ± 3.00 vs. 23.28 ± 3.22 kg/m2; P = 0.04) as compared with subjects carrying T/T genotypes. Conclusion Our data suggest that lipid metabolism and obesity, important pathophysiological elements of T2DM and the metabolic syndrome, are regulated by complex mechanisms that include the CD14 gene polymorphism-mediated genetic propensity to non-specific inflammatory responses.

To compare geographical difference in the prevalence of isolated systolic hypertension (ISH) in between urban (Ansan) and rural (Ansung) Korean adults aged 40-69 years, 4351 men and 4604 women enrolled in the Korean Health and Genome Study were analysed. Information was collected regarding gender, alcohol intake, smoking status, household income, occupation, and years of education by trained interviewers. Eligible subjects included untreated hypertensive and normotensive subjects. ISH was defined as a systolic blood pressure (SBP)or = 140 mmHg and diastolic BP90 mmHg. The overall age-adjusted prevalence of ISH was 4.1%. The prevalence of ISH in Ansung (5.7%) was higher than in Ansan (2.5%, P0.05). Also it increased with increments of age, from 1.0 to 12.8% in Ansung (P0.05) and from 0.3 to 13.0% in Ansan (P0.05). In those with body mass index (BMI)or = 30.0 kg/m2 in Ansung, the prevalence of ISH in women was twice as much as in men. The prevalence of ISH in obese men and women with a waist-hip ratioor =1.0 andor = 0.85, respectively, was more than that of nonobese men and women in both areas. In Korea, because of industrialization, the age distribution was skewed and the Korean population in rural areas is more aged. ISH will become a truly major health problem in rural area, because ISH is related to age, BMI and waist-hip ratio. Therefore, the Korean government will be required to institute different policies in the hypertension management to target populations in rural and urban areas.

Single nucleotide polymorphisms (SNPs) are considered as very promising genetic markers for complex disease gene hunting. However, it has been demonstrated that there are significant ethnic differences in genetic variations. In order to investigate the genetic variations in the Korean population and their ethnic differences, a large number of SNPs of 161 disease candidate genes were collected from a publicly available SNP database and then tested for the distribution of allele frequency in the Korean population. Of all 458 SNPs tested, approximately 43.9% were polymorphic in the Korean population, whereas 44.5% were monomorphic. The remaining 11.6% were failed in the test. Significant differences have been observed when SNP allele frequency pattern of Koreans was compared with those of Caucasians and Africans, whereas this pattern was highly similar between Korean and Japanese populations. Our data indicate that although many of the SNPs available in publicly available database, especially coding-region SNPs (cSNPs), can be used as informative genetic markers for disease association studies, an extensive verification of public SNPs in a particular population studied should be undertaken prior to their association studies.

Asthma manifests as TH2-dominant airway inflammation regulated by inducible T-cell kinase (ITK). To investigate associations between genetic variants of the ITK gene and asthma, 31 single-nucleotide polymorphisms (SNPs) were genotyped in 303 normal controls and 498 asthmatics and the two groups were compared using logistic regression models. The functional effects of the ITK promoter SNP were assessed using pGL3 luciferase reporter systems and gel-shift assays. The minor allele-196CT in the promoter region of the ITK gene was significantly more frequent in asthmatics than in controls. The luciferase activity of the PGL3-ITK-196T allele construct was higher than that of the -196C allele. In the gel-shift assay, -196T double-stranded oligonucleotides bound more strongly to Jurkat cell nuclear protein compared to the -196C double-stranded oligonucleotides. People with the -rare allele 196CT may be more susceptible to asthma via transcriptional regulation of the ITK gene.

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.

Purpose To determine the spectrum and frequency of rhodopsin gene (RHO) mutations in Korean patients with retinitis pigmentosa (RP) and to characterize genotype–phenotype correlations in patients with mutations. Methods The RHO mutations were screened by direct sequencing, and mutation prevalence was measured in patients and controls. The impact of missense mutations to RP was predicted by segregation analysis, peptide sequence alignment, and in silico analysis. The severity of disease in patients with the missense mutations was compared by visual acuity, electroretinography, optical coherence tomography, and kinetic visual field testing. Results Five heterozygous mutations were identified in six of 302 probands with RP, including a novel mutation (c.893C>A, p.A298D) and four known mutations (c.50C>T, p.T17M; c.533A>G, p.Y178C; c.888G>T, p.K296N; and c.1040C>T, p.P347L). The allele frequency of missense mutations was measured in 114 ethnically matched controls. p.A298D, newly identified in a sporadic patient, had never been found in controls and was predicted to be pathogenic. Among the patients with the missense mutations, we observed the most severe phenotype in patients with p.P347L, less severe phenotypes in patients with p.Y178C or p.A298D, and a relatively moderate phenotype in a patient with p.T17M. Conclusions The results reveal the spectrum of RHO mutations in Korean RP patients and clinical features that vary according to mutations. Our findings will be useful for understanding these genetic spectra and the genotype–phenotype correlations and will therefore help with predicting disease prognosis and facilitating the development of gene therapy.

The natural course of hepatitis B virus (HBV) infection is likely related to host immune factors. Interleukin-18 (IL-18) plays a significant role in immune defense. This study was undertaken to determine the association between the presence of hepatocellular carcinoma (HCC) and single-nucleotide polymorphisms (SNPs) in the IL-18 gene in HBV-infected patients. Between March 2002 and December 2004, 730 Korean subjects were enrolled in two different groups: (1) chronic carrier without HCC (n = 637) and (2) HCC (n = 93). We analyzed SNPs at four polymorphic sites in the IL-18 gene at positions −667G>T, −148G>C, +8925C>G, and +13925A>C in the study subjects. To evaluate the functional significance of SNPs in the IL-18 gene promoter region, we performed a reporter gene assay in HepG2 and Hep3B cells transfected with different alleles. The IL-18 −148C allele, +8925G allele, +13925C allele, and haplotype 3 (TCGC) were associated with the presence of HCC in codominant and dominant models. Furthermore, functional analyses using the reporter gene assay revealed that the −148C allele conferred significantly lower promoter activity. This study indicates that the −148C, +8925G, and +13925C alleles of the IL-18 gene are associated with the presence of HCC and the 148G>C SNP is functionally important in determining disease outcome.

The outcome of hepatitis B virus (HBV) infection can be affected by host immune factors. Interleukin-18 (IL-18) was originally discovered as an interferon-γ-inducing factor and plays a critical role in immune response. We assessed the association between the clearance of HBV infection and single-nucleotide polymorphisms (SNPs) in the IL-18 gene. Between March 2002 and December 2004, a total of 1,050 Korean subjects were enrolled in the study and divided into two groups: (1) the HBV spontaneous recovery group (n = 320) and (2) the chronic HBV carrier group (n = 730). We analyzed SNPs at four polymorphic sites in the IL-18 gene at positions −667G>T, −148G>C, +8925C>G, and +13925A>C. We observed that the subjects bearing the IL-18 −148C allele [odds ratio (OR), 0.25; confidence interval (CI), 0.09–0.68; P = 0.01], the +8925G allele (OR, 0.36; CI, 0.15–0.88; P = 0.02), and the +13925C allele (OR, 0.25; CI, 0.13–0.82; P = 0.01) were significantly associated with HBV clearance in a recessive model. This study indicates that the −148C, +8925G, and +13925C alleles of the IL-18 gene are likely associated with HBV clearance in a Korean population.

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.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by insulin resistance and hyperglycemia. Leptin inhibits the glucose-stimulated insulin secretion, and leptin receptors are present on beta cells as well as on fat cells, thus enabling leptin to modulate both insulin secretion and action. Therefore, leptin (LEP) and leptin receptor (LEPR) genes could play a role in the regulation of glucose and insulin after an oral glucose load. For the association study of LEP and LEPR with T2DM and metabolic traits, 752 women from Seoul National University Hospital (SNUH data) and 532 women from the Korean Health and Genome Study (KHGS data) were selected. Using the SNUH data, we identified that LEP-632G>A and +4998A>C polymorphisms were marginally associated with T2DM, LEP+4950G>A was significantly associated with several metabolic traits, and LEPR+5193G>A, +7187A>C, +27265G>A, +35861T>C, and +52289A>G showed strongly significant association with body mass index (BMI). We observed reproducibility of these results using the KHGS data; LEP+4950G>A and +4998A>C were significantly associated with systolic blood pressure and low-density lipoprotein cholesterol level, respectively. In conclusion, we observed that several polymorphisms in LEPR that had previous reports of association with BMI were significantly replicated in our samples and newly found that some variations of LEP were associated with T2DM and metabolic traits.

Objective Coronary artery disease is caused by multiple genetic and environmental factors. The disease is also closely associated with cardiovascular conditions such as hypertension. In order to investigate any possible role of hypertension candidate genes in the disease development and progression, we examined the association of the polymorphisms of 31 hypertension candidate genes with coronary artery disease. Methods Genetic polymorphisms of 31 hypertension candidate genes were initially screened by resequencing DNA samples from 24 unrelated individuals in a Korean population. Association analysis was performed using 1284 unrelated Korean men, including 749 coronary artery disease subjects and 535 normal healthy controls. Results We identified a total of 409 single nucleotide polymorphisms including 40 nonsynonymous single nucleotide polymorphisms, 32 insertions/deletions and four microsatellites. Among 40 nonsynonymous single nucleotide polymorphisms, 29 were examined for an association with coronary artery disease. A significant association with coronary artery disease was observed in a polymorphism of the ADD1 gene (Gly460Trp; +29017G/T) (odds ratio 0.71-0.81; P = 0.01-0.04). The same polymorphism was also associated with the number of arteries with significant coronary artery stenosis in the coronary artery disease patients (P = 0.01) as well as the increase in systolic blood pressure (P = 0.02). Conclusions The ADD1 Gly460Trp polymorphism is significantly associated with an increased risk of coronary artery disease as well as blood pressure, indicating that ADD1 plays a role in the pathogenesis of coronary artery disease as well as hypertension.

The genetic effects of FLT3 polymorphisms on BMD and fracture risk in postmenopausal women were studied. We found that FLT3+13348C>T polymorphism and haplotype 2 were significantly associated with low BMD and high risk of fracture. Introduction: FMS-related tyrosine kinase 3 (FLT3) has been shown to play a critical role in the development of myelolymphoid progenitors and in the development of osteoclasts, but any possible genetic effect of FLT3 on bone metabolism has not been studied. Materials and Methods: To study a possible genetic effect of FLT3, we directly sequenced the FLT3 gene in 24 Korean individuals and identified 23 sequence variants. Seven polymorphisms were selected and genotyped in Korean postmenopausal women (n = 946). Results: We found that FLT3+13348C>T was associated with low BMD at the lumbar spine (p = 0.04) and femoral neck (p = 0.04). Haplotype analysis revealed that FLT3-ht2 (TTCTT) containing the rare allele in the +13348 position also showed significant association with low BMD in the lumbar spine (p = 0.04) and femoral neck (p = 0.05). Consistent with these results, the FLT3+13348C>T polymorphism and FLT3-ht2 were also significantly associated with high risk of fracture in the vertebrae (OR = 1.44–1.58; p = 0.03–0.04 and OR = 1.45–1.59; p = 0.02–0.03, respectively) and in any sites (OR = 1.34–1.81; p = 0.02–0.03 and OR = 1.34–1.81; p = 0.02–0.03, respectively). Conclusions: These results suggest that FLT3 polymorphisms play a role in determination of BMD and subsequent fractures in postmenopausal women.

Dendritic cells (DCs), the most abundant antigen-presenting cells in the lung, have been drawing attention for their roles in specific allergic responses to aeroallergens with support of Th lymphocytes, and in persistent inflammatory changes in allergic asthma. To identify genetic factors that may be involved in the asthma susceptibility and development of the disease phenotypes, we examined association of DC-specific DCNP1 polymorphisms with the disease risk. The case-control study revealed association of the nucleotide variants with serum immunoglobulin E (IgE) levels specific for Dermatophagoides farinae (Der f 1) and Dermatophagoides pteronyssinus (Der p 1), major aeroallergens of dust mites, among subjects with asthma. In particular, the T-allele-carrying genotype frequencies for one of the variants (c.-1289C>T) located in the promoter region were found increased in the asthmatic group with low levels of the mite-specific IgE (odds ratio (OR)=0.63 (0.48-0.83) for Der p 1). Results from functional analyses indicated that the promoter variant would affect the gene expression by modulating DNA-protein interaction. We propose that the genetic polymorphism of DCNP1 may influence production of specific IgE by altering DC functions in the mite allergen presenting and/or processing. The functional relevance of the genetic variation would provide an important insight into the genetic basis of allergic response to the mite antigens.

Introduction: ITGA1 is involved in the early remodeling of osteoarthritic cartilage and plays an essential role in the regulation of mesenchymal stem cell proliferation and cartilage production. We investigated the association between bone parameters and ITGA1 polymorphisms and their haplotype linkage disequilibrium (LD) blocks (BL_hts). Genetic susceptibility to osteoporosis was studied in 946 postmenopausal Korean women. Methods: We identified 67 genetic polymorphisms in ITGA1 region by direct sequencing (n=114). Eight SNPs were genotyped to further investigate their potential involvement in osteoporosis in postmenopausal women (n=946). Areal BMD of the lumbar spine and proximal femur was measured using dual-energy X-ray absorptiometry. Results: The SNPs, +73187CNT (exon 3) and +76969TNG (intron 5), and their BL_hts were associated with bone mineral density (BMD) at various femur sites (p=0.009–0.05). Moreover, +159174ANC (intron 28) and its haplotype BL3_ht1 showed a highly significant association with risk of non-vertebral fracture (p=0.002–0.005) and the minor allele of +159174ANC showed a protective effect. Conclusions: These results are suggestive of the association of ITGA1 with osteoporosis and related risk in postmenopausal women.

Oxidative stress has been recently suggested to play a part in the development of osteoporosis. Catalase is a major antioxidant enzyme that detoxifies hydrogen peroxide by converting it into water and oxygen, thereby preventing cellular injury by oxidative stress.To examine the associations between the catalase gene (CAT) polymorphisms and bone mineral density (BMD) and bone turnover markers in postmenopausal Korean women.All exons, their boundaries and the promoter region (approximately 1.5 kb) were directly sequenced in 24 individuals. Among 18 variants identified by a direct sequence method, four polymorphisms were selected and genotyped in all study participants (n = 560). BMD at the lumbar spine and proximal femur was measured using dual-energy x ray absorptiometry. Serum osteocalcin concentrations and bone-specific alkaline phosphatase activity were determined by an immunoradiometric assay and an immunoassay, respectively.The mean (standard deviation) age of the participants was 59.4 (7.2) years. Multivariate analysis showed an association of the +22348C--T polymorphism with BMD at the lumbar spine (p = 0.01 in the dominant model) and at femur neck (p = 0.05 in the dominant model), and with serum osteocalcin level (p = 0.008 in the dominant model). Haplotype analyses showed that HT4 (-20T, +144C, +22348T, +33078A) was significantly associated with higher BMD at various sites (p0.001-0.03) and with lower serum osteocalcin levels (p = 0.01 in the codominant model).These findings indicate that the +22348C--T polymorphism and HT4 of CAT may be useful genetic markers for bone metabolism.

Bone mineral density (BMD) is a major factor for determining bone strength and osteoporotic fracture risk, and is determined by environmental and multiple genetic factors. KIT, which encodes a transmembrane receptor with tyrosine kinase activity, plays an important role in the differentiation of osteoclasts. We examined the associations between KIT gene polymorphisms and BMD in postmenopausal Korean women. All exons, their boundaries, and the promoter region (approximately 1.5 kb) from 24 individuals were directly sequenced. Eighteen polymorphisms were identified, and three single-nucleotide polymorphisms (SNPs) were genotyped in all study participants (n = 946). BMD at the lumbar spine and femoral neck was measured using dual-energy X-ray absorptiometry. The mean age of the study subjects was 58.9 ± 7.5 years, and the mean number of years since menopause was 9.6 ± 7.9 years. None of the three SNPs (−1694G>T, +41894A>G, and +49512G>A) was significantly associated with BMD value. However, multivariate analysis showed that the ht3 (−1694T-+41894A-+49512G) was significantly associated with lower BMD at the femoral neck (P = 0.007 in the recessive model). These findings indicate that KIT-ht3 may be a useful genetic marker for osteoporosis and that KIT may have a role on bone metabolism in humans.

The number of cases of the metabolic syndrome is increasing dramatically in Western countries. However, the evaluation of the metabolic syndrome is limited in Asian countries. Thus, our objectives were: 1) to investigate parameters of the metabolic syndrome defined by the National Cholesterol Education Program (NCEP)-Adult Treatment Panel III (ATPIII) in the subjects representing Korean general population and 2) the modification of which factor is most effective in reducing the metabolic syndrome. A total of 10,044 (5024 rural and 5020 urban) Korean men and women in the age range 40–69 yr voluntarily participated in this community-based cross-sectional study (a rural and an urban community was selected). Anthropometric parameters (weight, height, waist and hip circumference and blood pressure), social factors (smoking, alcohol, exercise and education status) as well as biochemical parameters (fasting glucose and insulin, lipids and body composition) were measured. Twenty-six point one per cent of the total subjects were classified as having the metabolic syndrome. Age- and sex-adjusted prevalences were 29.3 and 22.3% in the rural and urban community, respectively (p

Plexin A2 (PLXNA2) is a receptor that recognizes secreted or membrane-bound semaphorin 3A, which is implicated in neural regulation of bone metabolism. In the present study, we identified 48 genetic polymorphisms in PLXNA2 by resequencing, and 10 single nucleotide polymorphisms (SNPs) were selected for further investigation into their potential involvement in osteoporosis in a postmenopausal population (n=560). Two SNPs, +14G>A (Gln5Arg) and +183429C>T (Tyr1621Tyr), and Block1-ht2 were associated with risk of vertebral fracture (p=0.01–0.05), and three SNPs, +799G>A (Ala267Thr), +135391G>A, and +190531G>C, were associated with bone mineral density at various femur sites (p=0.003–0.03). Particularly, the minor allele of +14G>A was associated with a protective effect on vertebral fracture and higher lumbar bone mineral density, suggesting that +14G>A may be a useful marker for osteoporosis and its related fracture. These results provide, for the first time, evidence supporting the association of PLXNA2 with osteoporosis in postmenopausal women.

Although the prevalence of chronic obstructive pulmonary disease (COPD) and its relationship with respiratory symptoms are well documented, few studies have focused on individuals with normal lung function, particularly in developed regions of Asia. The purpose of this report is to examine the relationship between respiratory symptoms and FEV1 in a population-based sample of Korean men and women with normal lung function. Subjects comprised 7518 individuals aged 40–69 years without airflow obstruction based on spirometric testing and in the absence of a medical history of pulmonary disease. Respiratory symptoms included chronic cough, chronic phlegm, wheezing, and shortness of breath. In men, the age-adjusted mean FEV1 was lower by 165 ml in smokers and 133 ml in nonsmokers in the presence versus the absence of wheezing (p < 0.05). While walking at a usual pace, FEV1 in smoking men was 210 ml lower in the presence versus the absence of shortness of breath (p < 0.05). Among nonsmoking men, overall shortness of breath and shortness of breath while walking uphill were associated with a lower FEV1 by 56 and 80 ml, respectively) versus those who reported having no shortness of breath (p < 0.05). Respiratory symptoms were unrelated to FEV1 in women smokers, although only 3.5% smoked cigarettes. In nonsmoking women, FEV1 was lower by an average of 89 ml in the presence versus the absence of wheezing (p < 0.001). Nonsmoking women also had a lower FEV1 in the presence of shortness of breath (overall, while at rest, and while walking uphill or at a usual pace, p < 0.001). Our findings suggest that respiratory symptoms are associated with a lower FEV1 in men and nonsmoking women with normal lung function. Whether respiratory symptoms can be used to identify individuals at risk for developing COPD needs further study.

Bone mineral density (BMD), the major factor determining bone strength, is closely related to osteoporotic fracture risk and is determined largely by multiple genetic factors. Semaphorin 7a (SEMA7A), a recently described member of the semaphorin family, has been shown to play a critical role in the activation of monocyte/macrophages that share progenitors with bone-resorbing osteoclasts and thus might contribute to osteoclast development. In the present study, we directly sequenced the SEMA7A gene in 24 Korean individuals, and identified 15 sequence variants. Five polymorphisms (+15667GA, +15775CG, +16285CT, +19317CT, +22331AG) were selected and genotyped in postmenopausal Korean women (n = 560) together with measurement of the areal BMD (g/cm2) of the anterior-posterior lumbar spine and the non-dominant proximal femur using dual-energy X-ray absorptiometry. We found that polymorphisms of the SEMA7A gene were associated with the BMD of the lumbar spine and femoral neck. SEMA7A + 15775CG and SEMA7A+22331AG were associated with low BMD of the femoral neck (P = 0.02) and lumbar spine (P = 0.04) in a recessive model. SEMA7A-ht4 also showed an association with risk of vertebral fracture (OR = 1.87-1.93, P = 0.02-0.03). Our results suggest that variations in SEMA7A may play a role in decreased BMD and risk of vertebral fracture.

Leptin plays an important role in regulating adipose-tissue mass. Leptin controls energy balance and food intake through the leptin receptor in the hypothalamus of the brain, which suggests that some polymorphisms of the leptin receptor gene (LEPR) might contribute to obesity or obesity-related diseases. In an effort to identify genetic polymorphisms in a potential candidate gene for obesity and type 2 diabetes mellitus (T2DM) in the Korean population, we have sequenced the LEPR gene. Thirty-five sequence variants were identified (including 9 novel polymorphisms): 1 single nucleotide polymorphism (SNP) in the promoter region, 1 SNP in the 5' UTR, 8 SNPs in exons (3 non-synonymous SNPs), 23 SNPs in introns, 1 ins/del in the 3' UTR, and 1 SNP in the 3' downstream region. To investigate possible association of LEPR polymorphisms with body mass index (BMI) and the risk of T2DM, we genotyped for 11 polymorphisms in the Korean population (n = 1,463). Using statistical analyses, no significant associations between the genetic polymorphisms in the LEPR gene and the risk of T2DM were detected. However, one non-synonymous SNP in exon 3, +5193G > A (Arg109Lys), showed marginal association with BMI (P = 0.02) and gene dose-dependent genetic effects were observed. The present study provides information about additional genetic polymorphisms in LEPR and positive associations of those polymorphisms with BMI in the Korean population.

Although the prevalence of insomnia and the association of insomnia with menopause have been well reported, not much work has been conducted in population-based research on insomnia and menopause in Korea. The purpose of the present report was to determine overall and different prevalence of insomnia by menopausal status, and the relationship between insomnia and menopause in a population-based sample of middle-aged Korean women. A total of 96.1% of 2497 randomly selected middle-aged Korean women participated. Insomnia was defined as occurring three times a week or more in the previous month. Subjects were categorized into three groups: premenopaues, perimenopause, and postmenopause. The overall prevalence of insomnia in middle-aged Korean women was 14.3%. The most common symptom of insomnia was difficulty maintaining sleep (9.7%), followed by difficulty initiating sleep (7.9%), and early morning awakening (7.5%). Multiple logistic regression analysis revealed that menopause was independently associated with insomnia after adjusting for confounding factors such as age, income, and depression. Perimenopause was significantly associated with a dramatic increase in the risk of insomnia, but there was no significant association for postmenopause. The major finding is that insomnia is significantly associated with the menopausal transition. The prevalence of insomnia increases significantly by the transition from premenopause to perimenopause, but not to postmenopause. A further prospective study is needed to investigate the influence of menopause on insomnia.

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.

In an effort to identify genetic polymorphisms in potential candidate genes for type 2 diabetes mellitus (T2DM), we have sequenced the transforming growth factor beta-induced gene (TGFBI), and examined the association with T2DM and diabetic phenotypes in a Korean T2DM study (775 T2DM patients and 316 normal controls). Twenty-eight polymorphisms were identified in TGFBI. Although no significant associations were detected with the risk of T2DM, one SNP in intron 16 (c.2011+137C>T) and one SNP in the 3' untranslated region (UTR) (c.2589T>G), showed significant association with the levels of insulin and body mass index (BMI) among nondiabetic controls. The lower insulin and BMI were observed in individuals who carry one or two copies of minor alleles than others. For example, the highest BMI (24.21 kg/m(2)) in individuals with homozygote major alleles (T) of c.2589T>G (n=99), the intermediate BMI (23.68 kg/m(2)) in individuals with heterozygote alleles (n=156), and the lowest BMI (22.69 kg/m(2)) in individuals with homozygote minor alleles (G) (n=57, P=0.005) were observed. The present study provides, for the first time, information about genetic polymorphisms in TGFBI and positive associations of those polymorphisms with levels of insulin and BMI in the Korean population.

The prevalence of undiagnosed airflow obstruction is difficult to measure since it requires screening in population-based samples to identify individuals free of clinical symptoms. The purpose of this report is to examine the prevalence of undiagnosed airflow obstruction and its relation with respiratory symptoms in middle-age adults in the Korean Health and Genome (KHG) Study.The KHG study is an ongoing population-based study of Korean adults aged 40 to 69 years. The current report includes 8,140 men and women without a pulmonary disorder or obstructive lung disease. In this sample, undiagnosed airflow obstruction was defined on the basis of spirometric testing and in the absence of a medical history or a recognized pulmonary disorder. Respiratory symptoms included chronic cough, chronic phlegm, wheezing, and shortness of breath.Undiagnosed airflow obstruction was observed in 12.4% of the men (470 of 3,806 subjects) and in 3.5% of the women (152 of 4,334 subjects). In men, the age-adjusted prevalence of undiagnosed airflow obstruction increased consistently with increasing number of respiratory symptoms. In those who smoked, there was a 2.3-fold excess in its prevalence when three or more symptoms were present, as compared to when they were absent (27.4% vs 12.0%, p0.001). A 2.4-fold excess (20.6% vs 8.5%, p = 0.004) was observed in nonsmoking men, in whom respiratory symptoms were consistently less common than in those who smoked. Respiratory symptoms were unrelated to undiagnosed airflow obstruction in women smokers, although only 3.9% smoked cigarettes. In women who were nonsmokers, the prevalence of undiagnosed airflow obstruction increased from 2.3% in those without a respiratory symptom to 6.0% when three or more symptoms were present (p = 0.003).Findings suggest that undiagnosed airflow obstruction is common in Korea with several respiratory symptoms. Whether respiratory symptoms with associations with undiagnosed airflow obstruction can be used to design early intervention strategies that prevent or delay the onset of COPD and its disabling consequences warrants further 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 > or = 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.

The tumor necrosis factor (TNF) and TNF receptor (TNF-TNFR) superfamily plays crucial roles in immune regulation and host immune responses. The superfamily has been also associated with many immune-mediated diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease, and diabetes. In order to investigate genetic variants of the TNF-TNFR superfamily, a total of 63 known single nucleotide polymorphisms (SNPs) in the coding region (cSNPs) of the TNF-TNFR superfamily genes were selected from the public SNP database. Among 63 cSNPs tested in this study, only 24 SNPs (38%) were validated to be polymorphic in the Korean population by primer extension-based SNP genotyping. By means of the new enhanced single strand conformational polymorphism (SSCP) method, we also identified a total of 78 SNPs, including 48 known SNPs and 30 novel SNPs, in the 44 human TNF-TNFR superfamily genes. The newly discovered SNPs in the TNF-TNFR superfamily genes revealed that the Korean population had very different patterns of allele frequency compared with African or white populations, whereas Korean allele frequencies were highly similar to those of Asian (correlation coefficient r = 0.88, p < 0.046). A higher similarity of allele frequency was observed between Korean and Japanese populations (r = 0.90, p < 0.001). The validated SNPs in the TNF-TNFR superfamily would be valuable for association studies with several immune-mediated human diseases.

The incidence of type 2 diabetes is rising rapidly because of an increase in the incidence of being overweight and obesity. Identification of genetic determinants for complex diseases, such as type 2 diabetes, may provide insight into disease pathogenesis. The aim of the study was to investigate the shared genetic factors that predispose individuals to being overweight and developing type 2 diabetes. We conducted genome-wide linkage analyses for type 2 diabetes in 386 affected individuals (269 sibpairs) from 171 Korean families and association analyses with single-nucleotide polymorphisms of candidate genes within linkage regions to identify genetic variants that predispose individuals to being overweight and developing type 2 diabetes. Through fine-mapping analysis of chromosome 4q34-35, we detected a locus potentially linked (nonparametric linkage 2.81, logarithm of odds 2.27, P=6×10(-4)) to type 2 diabetes in overweight or obese individuals (body mass index, BMI≥23 kg m(-2)). Multiple regression analysis with type 2 diabetes-related phenotypes revealed a significant association (false discovery rate (FDR) P=0.006 for rs13144140; FDR P=0.002 for rs6830266) between GPM6A (rs13144140) and BMI and waist-hip ratio, and between NEIL3 (rs6830266) and insulin level from 1314 normal individuals. Our systematic search of genome-wide linkage and association studies, demonstrate that a linkage peak for type 2 diabetes on chromosome 4q34-35 contains two type 2 diabetes-related genes, GPM6A and NEIL3.

Background CXCR3 is a chemokine receptor that plays important roles in mediating chemotactic signals and modulating the activation of lymphocytes. We have previously conducted a case-control study by using a candidate gene approach to investigate the association of CXCR3 polymorphisms with the risk of asthma. Results from the epidemiologic study showed that a common nucleotide variant in the CXCR3 intron (rs2280964G>A) was associated with disease susceptibility (1006 cases and 384 control subjects; odds ratio, 0.81; 95% CI, 0.69-0.94; P = .007). Objective The aim of our study was to evaluate the epidemiologic study and provide functional evidence for the association of rs2280964G>A with asthma by investigating the effects of intronic variant on chemokine-mediated phenotypes of human-derived T cells. Methods We used cell line–based in vitro and human primary T cell–based ex vivo studies to examine the functional consequences of the intronic polymorphism, focusing on the regulation of gene expression, splicing, and immune responsiveness toward activating signals. Results We present functional evidence indicating that the rs2280964A allele significantly correlates with decreased CXCR3 gene expression, which would lead to variation in immune cell responses to chemokine-cytokine signals in vitro and ex vivo that includes a decrease in chemotactic activity. Conclusion These findings, in conjunction with those of our previous epidemiologic studies, might implicate a functional link between a common nucleotide variant of a chemokine receptor gene, CXCR3 , and a cause for a complex-trait disease, asthma.

Increased expression of glucose transporter1 (GLUT1) has been reported in many human cancers. We hypothesized that the degree of GLUT1 might provide a useful biological information in gastric adenocarcinoma. RT-PCR and immunostaining were used to analyze GLUT1 expression in gastric cancer. RT-PCR showed GLUT1 expression was not largely detected in normal gastric tissue but was detected in cancerous gastric tissue of counterpart. By immunohistochemistry, GLUT1 protein was absent in normal gastric epithelium and intestinal metaplasia. 11 of 65 patients with gastric adenocarcinoma had specific GLUT1 immunostaining in a plasma membrane pattern with varied intensities. GLUT1 protein did not show any significant correlation with tumor stage and nodal metastasis (p>0.05 by Mann-Whitney test). However, the positive immunostaining for GLUT1 is associated with intestinal differentiation (p=0.003). Our results suggest that GLUT1 protein is associated with intestinal type of gastric cancer.