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1.
Biomolecules & Therapeutics ; : 107-116, 2019.
Artículo en Inglés | WPRIM | ID: wpr-719634

RESUMEN

The global obesity epidemic and associated metabolic diseases require alternative biological targets for new therapeutic strategies. In this study, we show that a phytochemical sulfuretin suppressed adipocyte differentiation of preadipocytes and administration of sulfuretin to high fat diet-fed obese mice prevented obesity and increased insulin sensitivity. These effects were associated with a suppressed expression of inflammatory markers, induced expression of adiponectin, and increased levels of phosphorylated ERK and AKT. To elucidate the molecular mechanism of sulfuretin in adipocytes, we performed microarray analysis and identified activating transcription factor 3 (Atf3) as a sulfuretin-responsive gene. Sulfuretin elevated Atf3 mRNA and protein levels in white adipose tissue and adipocytes. Consistently, deficiency of Atf3 promoted lipid accumulation and the expression of adipocyte markers. Sulfuretin’s but not resveratrol’s anti-adipogenic effects were diminished in Atf3 deficient cells, indicating that Atf3 is an essential factor in the effects of sulfuretin. These results highlight the usefulness of sulfuretin as a new anti-obesity intervention for the prevention of obesity and its associated metabolic diseases.


Asunto(s)
Animales , Ratones , Factor de Transcripción Activador 3 , Adipocitos , Adiponectina , Tejido Adiposo Blanco , Dieta , Resistencia a la Insulina , Enfermedades Metabólicas , Ratones Obesos , Análisis por Micromatrices , Obesidad , ARN Mensajero
2.
Genomics & Informatics ; : 88-98, 2012.
Artículo en Inglés | WPRIM | ID: wpr-141259

RESUMEN

Lipoprotein lipase (LPL) plays an essential role in the regulation of high-density lipoprotein cholesterol (HDLC) and triglyceride levels, which have been closely associated with cardiovascular diseases. Genetic studies in European have shown that LPL single-nucleotide polymorphisms (SNPs) are strongly associated with lipid levels. However, studies about the influence of interactions between LPL SNPs and lifestyle factors have not been sufficiently performed. Here, we examine if LPL polymorphisms, as well as their interaction with lifestyle factors, influence lipid concentrations in a Korean population. A two-stage association study was performed using genotype data for SNPs on the LPL gene, including the 3' flanking region from 7,536 (stage 1) and 3,703 (stage 2) individuals. The association study showed that 15 SNPs and 4 haplotypes were strongly associated with HDLC (lowest p = 2.86 x 10(-22)) and triglyceride levels (lowest p = 3.0 x 10(-15)). Interactions between LPL polymorphisms and lifestyle factors (lowest p = 9.6 x 10(-4)) were also observed on lipid concentrations. These findings suggest that there are interaction effects of LPL polymorphisms with lifestyle variables, including energy intake, fat intake, smoking, and alcohol consumption, as well as effects of LPL polymorphisms themselves, on lipid concentrations in a Korean population.


Asunto(s)
Región de Flanqueo 3' , Consumo de Bebidas Alcohólicas , Enfermedades Cardiovasculares , Colesterol , Estudios Transversales , Ingestión de Energía , Genotipo , Haplotipos , Estilo de Vida , Lipoproteína Lipasa , Lipoproteínas , Polimorfismo de Nucleótido Simple , Humo , Fumar
3.
Genomics & Informatics ; : 88-98, 2012.
Artículo en Inglés | WPRIM | ID: wpr-141258

RESUMEN

Lipoprotein lipase (LPL) plays an essential role in the regulation of high-density lipoprotein cholesterol (HDLC) and triglyceride levels, which have been closely associated with cardiovascular diseases. Genetic studies in European have shown that LPL single-nucleotide polymorphisms (SNPs) are strongly associated with lipid levels. However, studies about the influence of interactions between LPL SNPs and lifestyle factors have not been sufficiently performed. Here, we examine if LPL polymorphisms, as well as their interaction with lifestyle factors, influence lipid concentrations in a Korean population. A two-stage association study was performed using genotype data for SNPs on the LPL gene, including the 3' flanking region from 7,536 (stage 1) and 3,703 (stage 2) individuals. The association study showed that 15 SNPs and 4 haplotypes were strongly associated with HDLC (lowest p = 2.86 x 10(-22)) and triglyceride levels (lowest p = 3.0 x 10(-15)). Interactions between LPL polymorphisms and lifestyle factors (lowest p = 9.6 x 10(-4)) were also observed on lipid concentrations. These findings suggest that there are interaction effects of LPL polymorphisms with lifestyle variables, including energy intake, fat intake, smoking, and alcohol consumption, as well as effects of LPL polymorphisms themselves, on lipid concentrations in a Korean population.


Asunto(s)
Región de Flanqueo 3' , Consumo de Bebidas Alcohólicas , Enfermedades Cardiovasculares , Colesterol , Estudios Transversales , Ingestión de Energía , Genotipo , Haplotipos , Estilo de Vida , Lipoproteína Lipasa , Lipoproteínas , Polimorfismo de Nucleótido Simple , Humo , Fumar
4.
Genomics & Informatics ; : 106-109, 2012.
Artículo en Inglés | WPRIM | ID: wpr-141255

RESUMEN

Pulse rate is known to be related to diverse phenotypes, such as cardiovascular diseases, lifespan, arrhythmia, hypertension, lipids, diabetes, and menopause. We have reported two genomewide significant genetic loci responsible for the variation in pulse rate as a part of the Korea Association Resource (KARE) project, the genomewide association study (GWAS) that was conducted with 352,228 single nucleoride polymorphisms typed in 8,842 subjects in the Korean population. GJA1 was implied as a functionally causal gene for pulse rate from the KARE study, but lacked evidence of replication. To re-evaluate the association of a locus near GJA1 with pulse rate, we looked up this signal in another GWAS conducted in a Health Examinee-shared cohort of 3,703 samples. Not only we were able to confirm two pulse rate loci (1q32.2a near CD46 and 6q22.13c near LOCL644502) identified in the KARE GWAS, we also replicated a locus (6q22.31c) near GJA1 by the lookup in the Health Examinee GWAS. Considering that the GJA1-encoded protein is a major component of cardiac gap junctions, a functional study might be necessary to validate its genuine molecular biological role in the synchronized contraction of the heart.


Asunto(s)
Femenino , Arritmias Cardíacas , Enfermedades Cardiovasculares , Estudios de Cohortes , Contratos , Uniones Comunicantes , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Corazón , Frecuencia Cardíaca , Hipertensión , Corea (Geográfico) , Menopausia , Fenotipo
5.
Genomics & Informatics ; : 106-109, 2012.
Artículo en Inglés | WPRIM | ID: wpr-141254

RESUMEN

Pulse rate is known to be related to diverse phenotypes, such as cardiovascular diseases, lifespan, arrhythmia, hypertension, lipids, diabetes, and menopause. We have reported two genomewide significant genetic loci responsible for the variation in pulse rate as a part of the Korea Association Resource (KARE) project, the genomewide association study (GWAS) that was conducted with 352,228 single nucleoride polymorphisms typed in 8,842 subjects in the Korean population. GJA1 was implied as a functionally causal gene for pulse rate from the KARE study, but lacked evidence of replication. To re-evaluate the association of a locus near GJA1 with pulse rate, we looked up this signal in another GWAS conducted in a Health Examinee-shared cohort of 3,703 samples. Not only we were able to confirm two pulse rate loci (1q32.2a near CD46 and 6q22.13c near LOCL644502) identified in the KARE GWAS, we also replicated a locus (6q22.31c) near GJA1 by the lookup in the Health Examinee GWAS. Considering that the GJA1-encoded protein is a major component of cardiac gap junctions, a functional study might be necessary to validate its genuine molecular biological role in the synchronized contraction of the heart.


Asunto(s)
Femenino , Arritmias Cardíacas , Enfermedades Cardiovasculares , Estudios de Cohortes , Contratos , Uniones Comunicantes , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Corazón , Frecuencia Cardíaca , Hipertensión , Corea (Geográfico) , Menopausia , Fenotipo
6.
Genomics & Informatics ; : 52-58, 2011.
Artículo en Inglés | WPRIM | ID: wpr-98933

RESUMEN

Osteoporotic fracture (OF), along with bone mineral density (BMD), is an important diagnostic parameter and a clinical predictive risk factor in the assessment of osteoporosis in the elderly population. However, a genomewide association study (GWAS) on OF has not yet been clarified sufficiently. To identify OF-associated genetic variants and candidate genes, we conducted a GWAS in a population-based cohort (Korean Association Resource [KARE], n=1,427 [case: 288 and control: 1139]) and performed a de novo replication study in hospital-based individuals (Asan and Catholic Medical Center [ACMC], n=1,082 [case: 272 and control: 810]). In a combined meta-analysis, a newly identified genetic locus in an intergenic region at 10p11.2 (near genes FZD8 and ANKRD30A ) showed the most significant association (odd ratio [OR] = 2.00, 95% confidence interval [CI] = 1.47~2.74, p=1.27x10(-5)) in the same direction. We provide the first evidence for a common genetic variant influencing OF and genetic information for further investigation in bone metabolism.


Asunto(s)
Anciano , Humanos , Densidad Ósea , Estudios de Cohortes , ADN Intergénico , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Osteoporosis , Fracturas Osteoporóticas , Factores de Riesgo
7.
Genomics & Informatics ; : 59-63, 2011.
Artículo en Inglés | WPRIM | ID: wpr-98932

RESUMEN

Obesity provokes many serious human diseases, including various cardiovascular diseases and diabetes. Body mass index (BMI) is a highly heritable trait that is broadly used to diagnose obesity. To identify genetic loci associated with obesity in Asians, we conducted a genome-wide association study (GWAS) of a population of Korean adults (n=6,742, age 40~60 years) and detected six BMI risk loci (TNR, FAM124B, RGS12, NFE2L3, MC4R and FTO) having p<1x10(-5). However, in the replication study, only melanocortin 4 receptor gene (MC4R) (rs9946888, p=4.58x10(-7)) was replicated with marginal significance (p<0.05) in the second cohort (n=5,102, age 40~60 years). This study indicates that each locus associated with BMI has very weak genetic effect.


Asunto(s)
Adulto , Humanos , Pueblo Asiatico , Índice de Masa Corporal , Enfermedades Cardiovasculares , Estudios de Cohortes , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Obesidad , Receptor de Melanocortina Tipo 4
8.
Experimental & Molecular Medicine ; : 71-81, 2011.
Artículo en Inglés | WPRIM | ID: wpr-186266

RESUMEN

There is increasing evidence of a biochemical link between lipid oxidation and bone metabolism. Paraoxonase 1 (PON1) prevents the oxidation of low-density lipoprotein (LDL) and metabolizes biologically active phospholipids in oxidized LDLs. Here, we performed association analyses of genetic variation in PON1 to ascertain its contribution to osteoporotic fractures (OFs) and bone mineral density (BMD). We directly sequenced the PON1 gene in 24 Korean individuals and identified 26 sequence variants. A large population of Korean postmenopausal women (n = 1,329) was then genotyped for eight selected PON1 polymorphisms. BMD at the lumbar spine and femoral neck was measured using dual-energy X-ray absorptiometry. Lateral thoracolumbar (T4-L4) radiographs were obtained for vertebral fracture assessment, and the occurrence of non-vertebral fractures (i.e., wrist, hip, forearm, humerus, rib, and pelvis) was examined using self-reported data. Multivariate analyses showed that none of the polymorphisms was associated with BMD at either site. However, +5989A>G and +26080T>C polymorphisms were significantly associated with non-vertebral and vertebral fractures, respectively, after adjustment for covariates. Specifically, the minor allele of +5989A>G exerted a highly protective effect against non-vertebral fractures (OR = 0.59, P = 0.036), whereas the minor allele of +26080T>C was associated with increased susceptibility to vertebral fractures (OR = 1.73, P = 0.020). When the risk for any OFs (i.e., vertebral or non-vertebral) was considered, the statistical significance of both polymorphisms persisted (P = 0.002-0.010). These results suggest that PON1 polymorphisms could be one of useful genetic markers for OF risk in postmenopausal women.


Asunto(s)
Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Alelos , Arildialquilfosfatasa/genética , Densidad Ósea , Frecuencia de los Genes , Orden Génico , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Haplotipos , Corea (Geográfico)/epidemiología , Desequilibrio de Ligamiento , Tipificación Molecular , Fracturas Osteoporóticas/epidemiología , Polimorfismo Genético , Posmenopausia , Factores de Riesgo
9.
Genomics & Informatics ; : 108-115, 2010.
Artículo en Inglés | WPRIM | ID: wpr-12321

RESUMEN

Hypertension is the most prevalent disease worldwide and is itself a risk factor for cerebral, cardiac, and renal diseases. The inconsistency of candidate genes suggested by previous genomewide association studies (GWASs) may be due to not only differences in study design and genetic or environmental background but also the difference in the power of analysis between continuous traits and discrete traits. We analyzed 352,228 single nucleotide polymorphisms (SNPs) in 8842 unrelated Koreans obtained from Ansan and Ansung cohorts. We performed a series of GWA analyses using three different phenotype models; young hypertensive cases (278 subjects) versus elderly normotensive controls (680 subjects); the upper 25% (2211 hypertensive cases) versus the lower 25% of the SBP distribution (2211 hypotensive controls); and finally SBP and DBP as continuous traits (8842 subjects). The numbers of young hypertensive cases and elderly normotensive controls were not large enough to achieve genomewide significance. The model comparing the upper 25% subjects to the lower 25% of subjects showed a power that was approximate to that of QTL analysis. Two neighboring SNPs of the ATP2B1 gene, rs17249754 (SBP, p=2.53-10; DBP, p=1.28x10-8) and rs7136259 (SBP, p=1.30x10-9; DBP, p=6.41x10-8), were associated with both SBP and DBP. Interestingly, a SNP of the RPL6 gene, rs11066280, revealed a significant genomewide association with SBP in men only (p=3.85x10-8), and four SNPs located near the MAN2A1 gene showed a strong association with DBP only in elderly men aged 60-70 years (e.g., rs6421827, p=4.86x10-8). However, we did not observe any gene variant attaining genome-wide significance consistently in the three phenotype models except for the ATP2B1 gene variants. In general, the association signal with blood pressure was stronger in women than in men. Genes identified in GWASs are expected to open the way for prevention, early diagnosis, and personalized treatment of hypertension.


Asunto(s)
Anciano , Femenino , Humanos , Masculino , Presión Sanguínea , Estudios de Casos y Controles , Estudios de Cohortes , Diagnóstico Precoz , Hipertensión , Fenotipo , Polimorfismo de Nucleótido Simple , Factores de Riesgo
10.
Genomics & Informatics ; : 122-130, 2010.
Artículo en Inglés | WPRIM | ID: wpr-12319

RESUMEN

Abnormal hematological values are associated with various disorders including cancer and cardiovascular, metabolic, infectious, and immune diseases. We report the copy number variations (CNVs) in clinically relevant hematological parameters, including hemoglobin level, red and white blood cell counts, platelet counts, and red blood cell (RBC) volume. We describe CNVs in several loci associated with these hematological parameters in 8,842 samples from Korean population-based studies. The data that we evaluated included four RBC parameters, one platelet parameter, and one associated with total white blood cell (WBC) count, exceeding the genome-wide significance. We show that CNVs in hematological parameters are associated with some loci, different from previously associated loci reported in single nucleotide polymorphism (SNP) association studies.


Asunto(s)
Recuento de Células Sanguíneas , Plaquetas , Proteína Coat de Complejo I , Eritrocitos , Estudio de Asociación del Genoma Completo , Hemoglobinas , Enfermedades del Sistema Inmune , Recuento de Leucocitos , Leucocitos , Recuento de Plaquetas , Polimorfismo de Nucleótido Simple
11.
Genomics & Informatics ; : 131-137, 2010.
Artículo en Inglés | WPRIM | ID: wpr-12318

RESUMEN

Genome-wide association studies (GWASs) have greatly contributed to the identification of common variants responsible for numerous complex traits. There are, however, unavoidable limitations in detecting causal and/or rare variants for traits in this approach, which depends on an LD-based tagging SNP microarray chip. In an effort to detect potential casual and/or rare variants for complex traits, such as type 2 diabetes (T2D) and triglycerides (TGs), we conducted a targeted resequencing of loci identified by the Korea Association REsource (KARE) GWAS. The target regions for resequencing comprised whole exons, exon-intron boundaries, and regulatory regions of genes that appeared within 1 Mb of the GWA signal boundary. From 124 individuals selected in population-based cohorts, a total of 0.7 Mb target regions were captured by the NimbleGen sequence capture 385K array. Subsequent sequencing, carried out by the Roche 454 Genome Sequencer FLX, generated about 110,000 sequence reads per individual. Mapping of sequence reads to the human reference genome was performed using the SSAHA2 program. An average of 62.2% of total reads was mapped to targets with an average 22X-fold coverage. A total of 5,983 SNPs (average 846 SNPs per individual) were called and annotated by GATK software, with 96.5% accuracy that was estimated by comparison with Affymetrix 5.0 genotyped data in identical individuals. About 51% of total SNPs were singletons that can be considered possible rare variants in the population. Among SNPs that appeared in exons, which occupies about 20% of total SNPs, 304 nonsynonymous singletons were tested with Polyphen to predict the protein damage caused by mutation. In total, we were able to detect 9 and 6 potentially functional rare SNPs for T2D and triglycerides, respectively, evoking a further step of replication genotyping in independent populations to prove their bona fide relevance to traits.


Asunto(s)
Humanos , Estudios de Cohortes , Exones , Genoma , Estudio de Asociación del Genoma Completo , Corea (Geográfico) , Polimorfismo de Nucleótido Simple , Secuencias Reguladoras de Ácidos Nucleicos , Triglicéridos
12.
Genomics & Informatics ; : 57-64, 2009.
Artículo en Inglés | WPRIM | ID: wpr-190153

RESUMEN

Fibrinogen alpha chain (FGA), a subunit of fibrinogen, might be a potential player for type 2 diabetes mellitus (T2DM), since the plasma levels of fibrinogen is known to be related to the incidence of T2DM. To elucidate the potential role of FGA in T2DM, we investigated whether FGA genetic variations are relevant in T2DM in the Korean population. Seven FGA single nucleotide polymorphisms (SNPs) were genotyped in Ansung and Ansan cohorts (474 T2DM subjects and 470 normal controls) in Korea. The association between SNPs and T2DM was determined by logistic regression analysis. Genetic relevance of SNPs to T2DM-related phenotypes was investigated by multiple linear regression analysis. Statistical analysis revealed that among seven FGA SNPs, significant associations with T2DM were observed in FGA rs2070011 (p=0.013-0.034, OR=0.72~ 0.79), rs6050 (p=0.026~0.048, OR=1.24~1.37), and rs2070022 (p=0.016~0.039, OR=0.70~0.72). Two SNPs, rs2070011 and rs6050, also showed significant association with T2DM-related phenotypes such as triglyceride (p=0.005~0.011 for rs2070011 and p=0.003~0.008 for rs6050), total cholesterol (p=0.01 for rs2070011 and p=0.024 for rs6050) and fasting glucose (p=0.035~ 0.036 for rs2070011 and p=0.048 for rs6050) in 470 normal controls. Our association study implies that FGA might be an important genetic factor in T2DM pathogenesis in the Korean population by affecting plasma lipid and glucose levels.


Asunto(s)
Colesterol , Estudios de Cohortes , Diabetes Mellitus Tipo 2 , Ayuno , Fibrinógeno , Variación Genética , Glucosa , Incidencia , Corea (Geográfico) , Modelos Lineales , Modelos Logísticos , Fenotipo , Plasma , Polimorfismo de Nucleótido Simple
13.
Experimental & Molecular Medicine ; : 523-532, 2008.
Artículo en Inglés | WPRIM | ID: wpr-84650

RESUMEN

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.


Asunto(s)
Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pueblo Asiatico , Estudios de Cohortes , Bases de Datos Genéticas , Diabetes Mellitus Tipo 2/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Lipoproteína Lipasa/genética , Polimorfismo de Nucleótido Simple
14.
Experimental & Molecular Medicine ; : 418-426, 2008.
Artículo en Inglés | WPRIM | ID: wpr-171131

RESUMEN

Osteonecrosis of the femoral head (ONFH) is known as death of the cellular portion of the femoral head due to an interruption in the vascular supply. The underlying pathophysiology regarding bone cell death remains uncertain. Recently, several studies have shown that autoimmune disorders were related to the development of osteonecrosis. This study investigated the genetic effects of Interleukin 23 receptor (IL23R) polymorphisms regarding the risk of ONFH. Ten SNPs were selected and genotyped in 443 ONFH patients and 273 control subjects in order to perform the genetic association analysis. It was found that polymorphisms of the IL23R gene (rs4655686, rs1569922 and rs7539625) were significantly associated with an increased risk of ONFH (P values; 0.0198-0.0447, OR; 1.30-1.49). Particularly, a stratified analysis based on etiology (alcohol, steroid or idiopathic) showed that the associations between these polymorphisms and ONFH were most significant in idiopathic ONFH patients (P values; 0.0001-0.0150, OR; 1.45-2.17). These results suggest that IL23R polymorphisms may play an important role in the development of ONFH.


Asunto(s)
Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios de Casos y Controles , Necrosis de la Cabeza Femoral/genética , Frecuencia de los Genes , Haplotipos , Corea (Geográfico) , Ligamiento Genético , Polimorfismo de Nucleótido Simple , Receptores de Interleucina/genética
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