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1.
J Hum Genet ; 64(6): 573-587, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30911093

RESUMO

Lipids foster energy production and their altered levels have been coupled with metabolic ailments. Indians feature high prevalence of metabolic diseases, yet uncharacterized for genes regulating lipid homeostasis. We performed first GWAS for quantitative lipids (total cholesterol, LDL, HDL, and triglycerides) exclusively in 5271 Indians. Further to corroborate our genetic findings, we investigated DNA methylation marks in peripheral blood in Indians at the identified loci (N = 233) and retrieved gene regulatory features from public domains. Recurrent GWAS loci-CELSR2, CETP, LPL, ZNF259, and BUD13 cropped up as lead signals in Indians, reflecting their universal applicability. Besides established variants, we found certain unreported variants at sub-genome-wide level-QKI, REEP3, TMCC2, FAM129C, FAM241B, and LOC100506207. These variants though failed to attain GWAS significance in Indians, but largely turned out to be active CpG sites in human subcutaneous adipose tissue and showed robust association to two or more lipid traits. Of which, QKI variants showed significant association to all four lipid traits and their designated region was observed to be a key gene regulatory segment denoting active transcription particularly in human subcutaneous adipose tissue. Both established and novel loci were observed to be significantly associated with altered DNA methylation in Indians for specific CpGs that resided in key regulatory elements. Further, gene-based association analysis pinpointed novel GWAS loci-LINC01340 and IQCJ-SCHIP1 for TC; IFT27, IFT88, and LINC02141 for HDL; and TEX26 for TG. Present study ascertains universality of selected known genes and also identifies certain novel loci for lipids in Indians by integrating data from various levels of gene regulation.


Assuntos
Colesterol/genética , Metilação de DNA/genética , Estudo de Associação Genômica Ampla , Metabolismo dos Lipídeos/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Colesterol/sangue , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Feminino , Humanos , Índia/epidemiologia , Lipídeos/sangue , Lipídeos/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Gordura Subcutânea/crescimento & desenvolvimento , Gordura Subcutânea/patologia , Triglicerídeos/sangue , Triglicerídeos/genética
2.
Gene ; 692: 156-169, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30658068

RESUMO

A number of genome-wide association studies (GWASs) have identified several genetic determinants of plasma lipids in European populations, in which analytical approaches have often been based on the linear regression models and the association test between a SNP and each lipid component individually in cross-sectional designs. Since lipid variations are correlated, the consideration of pleiotropy is necessary and using methods that can perform simultaneous association test of multiple longitudinal traits provides more information about the recognition of the pleiotropic variants. To identify new pleiotropic variants and to determine whether loci identified in previous GWASs can also exert the same effect on lipid concentrations in Iranian population, longitudinal measurements of lipid variations were used in a sample of Iranian population (16,353 individuals within 3100 families) that followed up every 3 years and using a two-step model, the associations of 20,036 available SNPs on chromosome 16 were assessed. Twenty variants within the AC009035.1, SLC12A3, CETP, NLRC5, ESRP2 and, C16orf95 genes showed strong evidence for association with HDL-C, cholesterol, and triglycerides with p-values ranging from 1.7 × 10-102 to 6.6 × 10-5. Since many genetic variants associated with lipids still remain to be determined, the results of the present study may provide valuable information on identifying the associations of new genetic loci with lipid variations in other populations.


Assuntos
Lipídeos/sangue , Lipídeos/genética , Polimorfismo de Nucleotídeo Único , Adulto , Proteínas de Transferência de Ésteres de Colesterol/genética , HDL-Colesterol/sangue , HDL-Colesterol/genética , Cromossomos Humanos Par 16 , Feminino , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Irã (Geográfico) , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Linhagem , Proteínas de Ligação a RNA/genética , Membro 3 da Família 12 de Carreador de Soluto/genética , Triglicerídeos/sangue , Triglicerídeos/genética
3.
Lipids Health Dis ; 18(1): 27, 2019 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-30684966

RESUMO

BACKGROUND: Chest pain is a serious symptom that is routinely investigated as a sign of coronary artery disease. Non-cardiac chest pain (NCCP) is indistinguishable from ischemic chest pain and both are considered serious and receive similar medical investigations. Although NCCP is not associated with cardiovascular diseases (CVDs), patients with NCCP may become anxious and frightened from developing coronary events. So, it will be valuable to improve modifiable cardiovascular risk factors in such subjects to reduce fear from CVDs. Because vitamin D deficiency was considered as a possible modifiable cardiovascular risk factor, our aim was to investigate association between serum vitamin D and cardiovascular risk variables in subjects with NCCP. METHODS: A cross-sectional study involved 104 subjects who underwent cardiac catheterization that did not reveal any cardiac origin for their chest pain. 25-hydroxyvitamin D was measured by electrochemiluminescence immunoassay, glucose was measured by hexokinase method, hemoglobin A1c (HbA1c) was measured by turbidimetric inhibition immunoassay and lipid profile was measured by enzymatic colorimetric assays. RESULTS: High density lipoprotein cholesterol (HDL-C) was significantly higher in subjects with sufficient vitamin D compared to those with insufficient or deficient vitamin D (p-value< 0.01). 25-hydroxyvitamin D was positively associated with HDL-C (p-value< 0.01) and inversely associated with HbA1c (p-value = 0.02). 25-hydroxyvitamin D was not significantly correlated with other cardiovascular biomarkers including blood pressure, glucose, and other components of lipid profile (p-values> 0.05). CONCLUSIONS: low serum vitamin D could be involved in reducing HDL-C and increasing HbA1c and thus it may increase cardiovascular risk in subjects with NCCP.


Assuntos
Doenças Cardiovasculares/genética , HDL-Colesterol/genética , Vitamina D/análogos & derivados , Vitamina D/genética , Idoso , Biomarcadores/sangue , Cateterismo Cardíaco , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/patologia , Dor no Peito/sangue , Dor no Peito/genética , Dor no Peito/patologia , HDL-Colesterol/sangue , Feminino , Estudos de Associação Genética , Hemoglobina A Glicada/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Vitamina D/sangue
4.
Nat Commun ; 10(1): 376, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670697

RESUMO

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.


Assuntos
Exercício , Loci Gênicos/genética , Lipídeos/sangue , Lipídeos/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Brasil , Proteínas de Ligação ao Cálcio/genética , Colesterol/sangue , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Hispano-Americanos/genética , Humanos , Proteínas com Homeodomínio LIM/genética , Metabolismo dos Lipídeos/genética , Masculino , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Proteínas Musculares/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Triglicerídeos/sangue , Triglicerídeos/genética , Adulto Jovem
5.
Lipids Health Dis ; 17(1): 285, 2018 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-30545366

RESUMO

BACKGROUND: The focus of studies on high-density lipoproteins (HDL) has shifted from HDL-cholesterol (HDL-C) to HDL function. We recently demonstrated that low USF1 expression in mice and humans associates with high plasma HDL-C and low triglyceride levels, as well as protection against obesity, insulin resistance, and atherosclerosis. Here, we studied the impact of USF1 deficiency on HDL functional capacity and macrophage atherogenic functions, including inflammation, cholesterol efflux, and cholesterol accumulation. METHODS: We used a congenic Usf1 deficient mice in C57Bl/6JRccHsd background and blood samples were collected to isolate HDL for structural and functional studies. Lentiviral preparations containing the USF1 silencing shRNA expression vector were used to silence USF1 in human THP-1 and Huh-7 cells. Cholesterol efflux from acetyl-LDL loaded THP-1 macrophages was measured using HDL and plasma as acceptors. Gene expression analysis from USF1 silenced peritoneal macrophages was carried out using Affymetrix protocols. RESULTS: We show that Usf1 deficiency not only increases HDL-C levels in vivo, consistent with elevated ABCA1 protein expression in hepatic cell lines, but also improves the functional capacity of HDL particles. HDL particles derived from Usf1 deficient mice remove cholesterol more efficiently from macrophages, attributed to their higher contents of phospholipids. Furthermore, silencing of USF1 in macrophages enhanced the cholesterol efflux capacity of these cells. These findings are consistent with reduced inflammatory burden of USF1 deficient macrophages, manifested by reduced secretion of pro-inflammatory cytokines MCP-1 and IL-1ß and protection against inflammation-induced macrophage cholesterol accumulation in a cell-autonomous manner. CONCLUSIONS: Our findings identify USF1 as a novel factor regulating HDL functionality, showing that USF1 inactivation boosts cholesterol efflux, reduces macrophage inflammation and attenuates macrophage cholesterol accumulation, linking improved macrophage cholesterol metabolism and inflammatory pathways to the antiatherogenic function of USF1 deficiency.


Assuntos
HDL-Colesterol/genética , Colesterol/genética , Lipoproteínas HDL/genética , Fatores Estimuladores Upstream/genética , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Quimiocina CCL2/genética , Colesterol/sangue , Expressão Gênica/genética , Humanos , Inflamação/sangue , Inflamação/genética , Inflamação/patologia , Resistência à Insulina/genética , Lipoproteínas HDL/sangue , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/patologia , Masculino , Camundongos , Camundongos Knockout , Obesidade/sangue , Obesidade/genética , Obesidade/patologia
6.
Endocrinol. diabetes nutr. (Ed. impr.) ; 65(7): 387-393, ago.-sept. 2018. tab
Artigo em Inglês | IBECS | ID: ibc-176124

RESUMO

Background: There is little evidence of the association between CETP SNPs and obesity and/or related metabolic parameters. Objective: To analyze the association of the polymorphism rs1800777 of the CETP gene with anthropometric parameters, lipid profile, metabolic syndrome and its components, and adipokine levels in obese subjects without type 2 diabetes mellitus or hypertension. Design: A population of 1005 obese subjects was analyzed. Electrical bioimpedance was performed, and blood pressure, presence of metabolic syndrome, dietary intake, physical activity, and biochemical tests were recorded. Results: Nine hundred and sixty eight patients (96.3%) had the GG genotype, 37 patients the GA genotype (3.7%) (no AA genotype was detected). Fat mass (delta: 4.4±1.1kg; p=0.04), waist circumference (delta: 5.6±2.1cm; p=0.02), and waist to hip ratio (delta: 0.04±0.01cm; p=0.01) were higher in A allele carriers than in non-A allele carriers. HDL cholesterol levels were lower in A allele carriers than in non-A allele carriers (delta: 4.2±1.0mg/dL; p=0.04). In the logistic regression analysis, the GA genotype was associated to an increased risk of central obesity (OR 7.55, 95% CI 1.10-55.70, p=0.02) and low HDL cholesterol levels (OR 2.46, 95% CI 1.23-4.91, p=0.014). Conclusion: The CETP variant at position +82 is associated to lower HDL cholesterol levels, increased fat mass, and central obesity in obese subjects. These results may suggest a potential role of this variant gene in pathophysiology of adipose tissue


Antecedentes: Existen pocas evidencias en relación a la asociación entre los SNP de CETP y la presencia de obesidad y/o parámetros metabólicos relacionados. Objetivo: Examinar la asociación del polimorfismo (rs1800777) del gen CETP con parámetros antropométricos, perfil lipídico, presencia de síndrome metabólico y sus diferentes componentes y los niveles de adipocitoquinas en sujetos con obesidad sin diabetes mellitus ni hipertensión. Diseño: Se analizó una población de 1.005 sujetos con obesidad. Se registró una bioimpedancia, presión arterial, presencia de síndrome metabólico, ingesta dietética, ejercicio físico y parámetros bioquímicos. Resultados: Novecientos sesenta y ocho pacientes (96,3%) tuvieron el genotipo GG y 37 pacientes presentaron el genotipo GA (3,7%) (no se detectó genotipo AA). La masa grasa (delta: 4,4±1,1kg; p=0,04), circunferencia de la cintura (delta: 5,6±2,1cm; p=0,02), relación cintura-cadera (delta: 0,04±0,01cm; p=0,01) fueron mayores en los portadores del alelo A. El colesterol HDL fue menor en los portadores del alelo A (delta: 4,2±1,0mg/dl; p=0,04). En el análisis de regresión logística la presencia del alelo A se asoció con un mayor riesgo de obesidad central (OR: 7,55; IC 95%: 1,10-55,70; p=0,02) y un mayor riesgo de colesterol HDL bajo (OR: 2,46; IC 95%: 1,23-4,91; p=0,014). Conclusión: La variante CETP en la posición +82 se asocia a unos niveles más bajos de colesterol HDL, a un mayor porcentaje de masa grasa y obesidad central en personas con obesidad. Estos resultados podrían sugerir un posible papel de esta variante en la fisiopatología del tejido adiposo


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Proteínas de Transferência de Ésteres de Colesterol/fisiologia , HDL-Colesterol/fisiologia , Síndrome Metabólica/etiologia , Obesidade/metabolismo , Polimorfismo Genético/fisiologia , HDL-Colesterol/genética , Tecido Adiposo/fisiopatologia , Adipócitos , Estudos Transversais/métodos , Estudos Prospectivos , Antropometria/métodos , Pressão Sanguínea/fisiologia , Comportamento Alimentar/fisiologia
7.
Genet Epidemiol ; 42(7): 636-647, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30156736

RESUMO

Complex traits can share a substantial proportion of their polygenic heritability. However, genome-wide polygenic correlations between pairs of traits can mask heterogeneity in their shared polygenic effects across loci. We propose a novel method (weighted maximum likelihood-regional polygenic correlation [RPC]) to evaluate polygenic correlation between two complex traits in small genomic regions using summary association statistics. Our method tests for evidence that the polygenic effect at a given region affects two traits concurrently. We show through simulations that our method is well calibrated, powerful, and more robust to misspecification of linkage disequilibrium than other methods under a polygenic model. As small genomic regions are more likely to harbor specific genetic effects, our method is ideal to identify heterogeneity in shared polygenic correlation across regions. We illustrate the usefulness of our method by addressing two questions related to cardiometabolic traits. First, we explored how RPC can inform on the strong epidemiological association between high-density lipoprotein cholesterol and coronary artery disease (CAD), suggesting a key role for triglycerides metabolism. Second, we investigated the potential role of PPARγ activators in the prevention of CAD. Our results provide a compelling argument that shared heritability between complex traits is highly heterogeneous across loci.


Assuntos
Desequilíbrio de Ligação/genética , Herança Multifatorial/genética , HDL-Colesterol/genética , Simulação por Computador , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/genética , Loci Gênicos , Genoma Humano , Estudo de Associação Genômica Ampla , Haplótipos/genética , Humanos , Modelos Genéticos , PPAR gama/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Tiazolidinedionas/uso terapêutico
8.
Gene ; 677: 176-181, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30053459

RESUMO

BACKGROUND: The correlation between single nucleotide polymorphisms (SNPs) of milk fat globule-epidermal growth factor 8 (MFGE8) and metabolic syndrome (MetS) and metabolism-related indicators are limited. The present study explored the relation in Chinese adults. METHODS: We conducted a nested case-control study based on the Rural Chinese Cohort Study including 408 people with MetS and 408 controls matched by baseline sex, age (±2 years), marital status, and residence village. Four polymorphisms were selected and genotyped by using the SNPscan Genotyping system. Conditional logistic regression was used to estimate the association of MFGE8 polymorphisms with MetS incidence, and linear regression was used to assess the association with metabolism-related indicators in controls. RESULTS: We found no significant association of MFGE8 SNPs with MetS incidence or systolic blood pressure, or triglycerides level, or fasting plasma glucose (P > 0.05). However, MFGE8 rs4932450 was negatively associated with high-density lipoprotein cholesterol (HDL-C) level under the dominant model (ß = -0.0218, P = 0.007) and the additive model (ß = -0.0175, P = 0.012) and positively associated with diastolic blood pressure (DBP) under the recessive model (ß = 4.8848, P = 0.011). The rs3784751 SNP was associated with increased waist circumference (WC) in controls (ß = 0.0307, P = 0.028). CONCLUSIONS: MFGE8 polymorphisms were not associated with MetS but were related to DBP, HDL-C level, and WC in Chinese adults.


Assuntos
Antígenos de Superfície/genética , Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença/genética , Síndrome Metabólica/genética , Proteínas do Leite/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Pressão Sanguínea/genética , Estudos de Casos e Controles , HDL-Colesterol/genética , Estudos de Coortes , Feminino , Humanos , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Triglicerídeos/sangue , Circunferência da Cintura/genética
9.
Lipids Health Dis ; 17(1): 98, 2018 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-29712557

RESUMO

BACKGROUND: Several candidate genes have been identified in relation to lipid metabolism, and among these, lipoprotein lipase (LPL) and apolipoprotein E (APOE) gene polymorphisms are major sources of genetically determined variation in lipid concentrations. This study investigated the association of two single nucleotide polymorphisms (SNPs) at LPL, seven tagging SNPs at the APOE gene, and a common APOE haplotype (two SNPs) with blood lipids, and examined the interaction of these SNPs with dietary factors. METHODS: The population studied for this investigation included 660 individuals from the Prevention of Cancer by Intervention with Selenium (PRECISE) study who supplied baseline data. The findings of the PRECISE study were further replicated using 1238 individuals from the Caerphilly Prospective cohort (CaPS). Dietary intake was assessed using a validated food-frequency questionnaire (FFQ) in PRECISE and a validated semi-quantitative FFQ in the CaPS. Interaction analyses were performed by including the interaction term in the linear regression model adjusted for age, body mass index, sex and country. RESULTS: There was no association between dietary factors and blood lipids after Bonferroni correction and adjustment for confounding factors in either cohort. In the PRECISE study, after correction for multiple testing, there was a statistically significant association of the APOE haplotype (rs7412 and rs429358; E2, E3, and E4) and APOE tagSNP rs445925 with total cholesterol (P = 4 × 10- 4 and P = 0.003, respectively). Carriers of the E2 allele had lower total cholesterol concentration (5.54 ± 0.97 mmol/L) than those with the E3 (5.98 ± 1.05 mmol/L) (P = 0.001) and E4 (6.09 ± 1.06 mmol/L) (P = 2 × 10- 4) alleles. The association of APOE haplotype (E2, E3, and E4) and APOE SNP rs445925 with total cholesterol (P = 2 × 10- 6 and P = 3 × 10- 4, respectively) was further replicated in the CaPS. Additionally, significant association was found between APOE haplotype and APOE SNP rs445925 with low density lipoprotein cholesterol in CaPS (P = 4 × 10- 4 and P = 0.001, respectively). After Bonferroni correction, none of the cohorts showed a statistically significant SNP-diet interaction on lipid outcomes. CONCLUSION: In summary, our findings from the two cohorts confirm that genetic variations at the APOE locus influence plasma total cholesterol concentrations, however, the gene-diet interactions on lipids require further investigation in larger cohorts.


Assuntos
Apolipoproteínas E/genética , Doenças Cardiovasculares/genética , Dieta , Lipídeos/sangue , Alelos , Índice de Massa Corporal , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/patologia , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Lipídeos/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Triglicerídeos/sangue , Triglicerídeos/genética
10.
Proc Natl Acad Sci U S A ; 115(18): 4672-4677, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29588416

RESUMO

Programmed cell death 5 (PDCD5) has been associated with human cancers as a regulator of cell death; however, the role of PDCD5 in the endothelium has not been revealed. Thus, we investigated whether PDCD5 regulates protein kinase B (PKB/AKT)-endothelial nitric oxide synthase (eNOS)-dependent signal transduction in the endothelium and affects atherosclerosis. Endothelial-specific PDCD5 knockout mice showed significantly reduced vascular remodeling compared with wild-type (WT) mice after partial carotid ligation. WT PDCD5 competitively inhibited interaction between histone deacetylase 3 (HDAC3) and AKT, but PDCD5L6R, an HDAC3-binding-deficient mutant, did not. Knockdown of PDCD5 accelerated HDAC3-AKT interaction, AKT and eNOS phosphorylation, and nitric oxide (NO) production in human umbilical vein endothelial cells. Moreover, we found that serum PDCD5 levels reflect endothelial NO production and are correlated with diabetes mellitus, high-density lipoprotein cholesterol, and coronary calcium in human samples obtained from the cardiovascular high-risk cohort. Therefore, we conclude that PDCD5 is associated with endothelial dysfunction and may be a novel therapeutic target in atherosclerosis.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Remodelação Vascular , Animais , Proteínas Reguladoras de Apoptose/genética , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , HDL-Colesterol/genética , HDL-Colesterol/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Endotélio Vascular/patologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/genética , Proteínas Proto-Oncogênicas c-akt/genética
11.
Gene ; 659: 118-122, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29548861

RESUMO

BACKGROUND: Mechanisms of metabolic syndrome (MetS) causation are complex, genetic and environmental factors are important factors for the pathogenesis of MetS In this study, we aimed to evaluate familial and genetic influences on metabolic syndrome risk factor and also assess association between FTO (rs1558902 and rs7202116) and CETP(rs1864163) genes' single nucleotide polymorphisms (SNP) with low HDL_C in the Tehran Lipid and Glucose Study (TLGS). MATERIALS AND METHODS: The design was a cross-sectional study of 1776 members of 227 randomly-ascertained families. Selected families contained at least one affected metabolic syndrome and at least two members of the family had suffered a loss of HDL_C according to ATP III criteria. In this study, after confirming the familial aggregation with intra-trait correlation coefficients (ICC) of Metabolic syndrome (MetS) and the quantitative lipid traits, the genetic linkage analysis of HDL_C was performed using conditional logistic method with adjusted sex and age. RESULTS: The results of the aggregation analysis revealed a higher correlation between siblings than between parent-offspring pairs representing the role of genetic factors in MetS. In addition, the conditional logistic model with covariates showed that the linkage results between HDL_C and three marker, rs1558902, rs7202116 and rs1864163 were significant. CONCLUSIONS: In summary, a high risk of MetS was found in siblings confirming the genetic influences of metabolic syndrome risk factor. Moreover, the power to detect linkage increases in the one parameter conditional logistic model regarding the use of age and sex as covariates.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Proteínas de Transferência de Ésteres de Colesterol/genética , HDL-Colesterol/sangue , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único , Adulto , HDL-Colesterol/genética , Estudos Transversais , Feminino , Ligação Genética , Humanos , Irã (Geográfico) , Modelos Logísticos , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Locos de Características Quantitativas , Adulto Jovem
12.
BMC Cancer ; 18(1): 88, 2018 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-29357836

RESUMO

BACKGROUND: Scavenger receptor class B type I (SR-BI) has been reported to be involved in carcinogenesis of several human cancers. However, it is currently unknown whether SR-BI plays a role in clear cell renal cell carcinoma (ccRCC). Here, we aimed to evaluate a tumor promotive mechanism for SR-BI in ccRCC. METHODS: The expression of SR-BI was evaluated by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot and immunohistochemistry (IHC) in ccRCC tissues and cell lines. Lipid droplets in ccRCC tissues and normal kidney tissues were examined by Oil Red O (ORO) and hematoxylin-eosin (HE) staining. The correlation between SR-BI mRNA levels and clinicopathological features was analyzed by Pearson's chi-square test or Fisher's exact test. Kaplan-Meier analysis and Cox model were used to evaluate the difference in progression-free survival (PFS) associated with expression of SR-BI. Inhibition of SR-BI was conducted by using small interfering RNA (siRNA). In vitro assays were performed to assess the impact of SR-BI knockdown on cell biological behaviors. High density lipoprotein (HDL)-cholesterol content in ccRCC cells and extracellular media was also measured after transfection with siRNA. RESULTS: The expression of SR-BI was markedly up-regulated in ccRCC tissues and tumor cell lines. ORO and HE staining revealed huge amounts of lipid droplets accumulation in ccRCC. Clinical analysis showed that over-expression of SR-BI was positively associated with tumor size, grade, distant metastasis and inversely correlated with PFS. Furthermore, SR-BI was proved to be an independent prognostic marker in ccRCC patients. The inhibition of SR-BI attenuated the tumorous behaviors of ccRCC cells, expression of metastasis and AKT pathway related proteins. The content of HDL-cholesterol was reduced in cells while increased in extracellular media after transfection with si-SR-BI. CONCLUSIONS: Our results demonstrate that SR-BI functions as an oncogene and promotes progression of ccRCC. SR-BI may serve as a potential prognostic biomarker and therapeutic target for ccRCC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Prognóstico , Receptores Depuradores Classe B/genética , Adulto , Idoso , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , HDL-Colesterol/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , RNA Mensageiro/genética
13.
Genet Epidemiol ; 42(2): 134-145, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29226385

RESUMO

Genome-wide association studies (GWAS) for complex diseases have focused primarily on single-trait analyses for disease status and disease-related quantitative traits. For example, GWAS on risk factors for coronary artery disease analyze genetic associations of plasma lipids such as total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides (TGs) separately. However, traits are often correlated and a joint analysis may yield increased statistical power for association over multiple univariate analyses. Recently several multivariate methods have been proposed that require individual-level data. Here, we develop metaUSAT (where USAT is unified score-based association test), a novel unified association test of a single genetic variant with multiple traits that uses only summary statistics from existing GWAS. Although the existing methods either perform well when most correlated traits are affected by the genetic variant in the same direction or are powerful when only a few of the correlated traits are associated, metaUSAT is designed to be robust to the association structure of correlated traits. metaUSAT does not require individual-level data and can test genetic associations of categorical and/or continuous traits. One can also use metaUSAT to analyze a single trait over multiple studies, appropriately accounting for overlapping samples, if any. metaUSAT provides an approximate asymptotic P-value for association and is computationally efficient for implementation at a genome-wide level. Simulation experiments show that metaUSAT maintains proper type-I error at low error levels. It has similar and sometimes greater power to detect association across a wide array of scenarios compared to existing methods, which are usually powerful for some specific association scenarios only. When applied to plasma lipids summary data from the METSIM and the T2D-GENES studies, metaUSAT detected genome-wide significant loci beyond the ones identified by univariate analyses. Evidence from larger studies suggest that the variants additionally detected by our test are, indeed, associated with lipid levels in humans. In summary, metaUSAT can provide novel insights into the genetic architecture of a common disease or traits.


Assuntos
Estudo de Associação Genômica Ampla , Metanálise como Assunto , Idoso , HDL-Colesterol/genética , LDL-Colesterol/genética , Doença da Artéria Coronariana/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Triglicerídeos/genética
14.
Hum Genomics ; 11(1): 29, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-29162152

RESUMO

BACKGROUND: Peptidylglycine-α-amidating monooxygenase (PAM) may play a role in the secretion of atrial natriuretic peptide (ANP), which is a hormone involved in the maintenance of blood pressure (BP). The objective of the present study was to determine whether PAM is a novel candidate gene for hypertension (HTN). RESULTS: A total of 2153 Korean participants with normotension and HTN were included. Genotype data were obtained using the Korean Chip. The rs13175330 polymorphism of the PAM gene was selected from the ten single nucleotide polymorphisms (SNPs) most strongly associated with BP. The presence of the G allele of the PAM rs13175330 A>G SNP was associated with a higher risk of HTN after adjustments for age, sex, BMI, smoking, and drinking [OR 1.607 (95% CI 1.220-2.116), p = 0.001]. The rs13175330 G allele carriers in the HTN group treated without antihypertensive therapy (HTN w/o therapy) had significantly higher systolic and diastolic BP than the AA carriers, whereas the G allele carriers in the HTN group treated with antihypertensive therapy (HTN w/ therapy) showed significantly higher diastolic BP. Furthermore, rs13175330 G allele carriers in the HTN w/o therapy group had significantly increased levels of insulin, insulin resistance, and oxidized low-density lipoprotein (LDL) and significantly decreased LDL-cholesterol levels and LDL particle sizes compared to the AA carriers. CONCLUSION: These results suggest that the PAM rs13175330 A>G SNP is a novel candidate gene for HTN in the Korean population. Additionally, the PAM rs13175330 G allele might be associated with insulin resistance and LDL atherogenicity in patients with HTN.


Assuntos
Amidina-Liases/genética , Hipertensão/genética , Oxigenases de Função Mista/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Pressão Sanguínea/genética , Estudos de Casos e Controles , HDL-Colesterol/sangue , HDL-Colesterol/genética , Feminino , Predisposição Genética para Doença , Humanos , Hipertensão/etiologia , Insulina/sangue , Resistência à Insulina/genética , Lipoproteínas LDL/sangue , Lipoproteínas LDL/genética , Masculino , Pessoa de Meia-Idade
16.
PLoS Genet ; 13(10): e1007079, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29084231

RESUMO

Lipid and lipoprotein subclasses are associated with metabolic and cardiovascular diseases, yet the genetic contributions to variability in subclass traits are not fully understood. We conducted single-variant and gene-based association tests between 15.1M variants from genome-wide and exome array and imputed genotypes and 72 lipid and lipoprotein traits in 8,372 Finns. After accounting for 885 variants at 157 previously identified lipid loci, we identified five novel signals near established loci at HIF3A, ADAMTS3, PLTP, LCAT, and LIPG. Four of the signals were identified with a low-frequency (0.005

Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene/genética , Metabolismo dos Lipídeos/genética , Lipídeos/genética , Lipoproteínas/genética , Polimorfismo de Nucleotídeo Único/genética , Triglicerídeos/genética , HDL-Colesterol/genética , Exoma/genética , Finlândia , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal/métodos
17.
Genet Epidemiol ; 41(8): 756-768, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28875524

RESUMO

A genome-wide association study (GWAS) correlates marker and trait variation in a study sample. Each subject is genotyped at a multitude of SNPs (single nucleotide polymorphisms) spanning the genome. Here, we assume that subjects are randomly collected unrelateds and that trait values are normally distributed or can be transformed to normality. Over the past decade, geneticists have been remarkably successful in applying GWAS analysis to hundreds of traits. The massive amount of data produced in these studies present unique computational challenges. Penalized regression with the ℓ1 penalty (LASSO) or minimax concave penalty (MCP) penalties is capable of selecting a handful of associated SNPs from millions of potential SNPs. Unfortunately, model selection can be corrupted by false positives and false negatives, obscuring the genetic underpinning of a trait. Here, we compare LASSO and MCP penalized regression to iterative hard thresholding (IHT). On GWAS regression data, IHT is better at model selection and comparable in speed to both methods of penalized regression. This conclusion holds for both simulated and real GWAS data. IHT fosters parallelization and scales well in problems with large numbers of causal markers. Our parallel implementation of IHT accommodates SNP genotype compression and exploits multiple CPU cores and graphics processing units (GPUs). This allows statistical geneticists to leverage commodity desktop computers in GWAS analysis and to avoid supercomputing. AVAILABILITY: Source code is freely available at https://github.com/klkeys/IHT.jl.


Assuntos
Estudo de Associação Genômica Ampla , Modelos Genéticos , Algoritmos , Índice de Massa Corporal , HDL-Colesterol/genética , LDL-Colesterol/genética , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Triglicerídeos/genética
18.
Arterioscler Thromb Vasc Biol ; 37(10): 1956-1962, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28860221

RESUMO

OBJECTIVE: Cholesterol efflux capacity (CEC) has emerged as a biomarker of coronary artery disease risk beyond plasma high-density lipoprotein (HDL) cholesterol (HDL-C) level. However, the determinants of CEC are incompletely characterized. We undertook a large-scale family-based population study to identify clinical, biochemical, and HDL particle parameter determinants of CEC, characterize reasons for the discordancy with HDL-C, quantify its heritability, and assess its stability over 10 to 12 years. APPROACHES AND RESULTS: CEC was quantified in 1988 individuals from the GRAPHIC (Genetic Regulation of Arterial Pressure of Humans in the Community) cohort, comprising individuals from 2 generations from 520 white nuclear families. Serum lipid and lipoprotein levels were determined by ultracentrifugation or nuclear magnetic resonance and HDL particle size and number quantified by nuclear magnetic resonance. Ninety unrelated individuals had repeat CEC measurements in samples collected after 10 to 12 years. CEC was positively correlated with HDL-C (R=0.62; P<0.0001). Among clinical and biochemical parameters, age, systolic blood pressure, alcohol consumption, serum albumin, triglycerides, phospholipids, and lipoprotein(a) were independently associated with CEC. Among HDL particle parameters, HDL particle number, particle size, and apolipoprotein A-II level were independently associated with CEC. Serum triglyceride level partially explained discordancy between CEC and HDL-C. CEC measurements in samples collected 10 to 12 years apart were strongly correlated (r=0.73; P<0.0001). Heritability of CEC was 0.31 (P=3.89×10-14) without adjustment for HDL-C and 0.13 (P=1.44×10-3) with adjustment. CONCLUSIONS: CEC is a stable trait over time, is influenced by specific clinical, serum, and HDL particle parameters factors beyond HDL-C, can be maintained in persons with a low plasma HDL-C by elevated serum triglyceride level, and is modestly independently heritable.


Assuntos
HDL-Colesterol/sangue , Doença das Coronárias/sangue , Adolescente , Adulto , Transporte Biológico , Biomarcadores/sangue , HDL-Colesterol/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Triglicerídeos/sangue , Adulto Jovem
19.
J Lipid Res ; 58(11): 2162-2170, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28870971

RESUMO

HDL cholesterol (HDL-C) remains a superior biochemical predictor of CVD risk, but its genetic basis is incompletely defined. In patients with extreme HDL-C concentrations, we concurrently evaluated the contributions of multiple large- and small-effect genetic variants. In a discovery cohort of 255 unrelated lipid clinic patients with extreme HDL-C levels, we used a targeted next-generation sequencing panel to evaluate rare variants in known HDL metabolism genes, simultaneously with common variants bundled into a polygenic trait score. Two additional cohorts were used for validation and included 1,746 individuals from the Montréal Heart Institute Biobank and 1,048 individuals from the University of Pennsylvania. Findings were consistent between cohorts: we found rare heterozygous large-effect variants in 18.7% and 10.9% of low- and high-HDL-C patients, respectively. We also found common variant accumulation, indicated by extreme polygenic trait scores, in an additional 12.8% and 19.3% of overall cases of low- and high-HDL-C extremes, respectively. Thus, the genetic basis of extreme HDL-C concentrations encountered clinically is frequently polygenic, with contributions from both rare large-effect and common small-effect variants. Multiple types of genetic variants should be considered as contributing factors in patients with extreme dyslipidemia.


Assuntos
HDL-Colesterol/sangue , HDL-Colesterol/genética , Genótipo , Adulto , Idoso , Feminino , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade
20.
Curr Atheroscler Rep ; 19(11): 43, 2017 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-28944433

RESUMO

PURPOSE OF REVIEW: High-density lipoproteins (HDL) are involved in reverse cholesterol transport. Results from randomized trials of HDL-targeting therapies, including cholesteryl ester transfer protein (CETP) inhibitors, have shown a lack of benefit in unsegmented populations. These observations could be explained by inter-individual variability of clinical responses to such agents depending on the patients' genotypes. In parallel, although lowering of LDL cholesterol (LDL-c) with statin therapy reduces the risk of vascular events in a wide range of individuals, inter-individual variability exists with regard to LDL-c-lowering response as well as efficacy in reducing major cardiovascular events. RECENT FINDINGS: Pharmacogenomic analyses were performed in the dal-OUTCOMES and dal-PLAQUE-2 studies. Beneficial and concordant results were observed in patients with the favorable genotype when treated with the CETP inhibitor dalcetrapib. Similarly, previous studies revealed genetic variants associated with differential LDL-c response to statin therapy. In this review, we discuss the pharmacogenetic determinants of HDL-targeting and statin therapy responses in light of the latest available published data, and their potential therapeutic applications.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipolipemiantes/uso terapêutico , Lipoproteínas HDL/metabolismo , Anticolesterolemiantes/uso terapêutico , HDL-Colesterol/genética , HDL-Colesterol/metabolismo , Ensaios Clínicos como Assunto , Genótipo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipoproteínas HDL/genética , Farmacogenética
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