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Objective: To investigate the apolipoprotein C-3 (APOC3) gene Sst â polymorphism and its relationship with changes in serum lipids in patients with gestational diabetes mellitus (GDM). Methods: A total of 630 pregnant women with GDM and 1027 normal pregnant controls were covered in the study. The genotype and allele frequencies of APOC3 Sst â polymorphism were analyzed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glucose (Glu) were measured by enzymatic methods. Plasma insulin (INS) was measured by chemiluminescence. Apolipoproteins A 1 (apoA1) and B (apoB) levels were measured by turbidimetric immunoassay. Results: The allele frequencies of S1 and S2 of the APOC3 polymorphism at the Sstâ locus were 0.704 and 0.296 in the GDM group and 0.721 and 0.279 in the control group, respectively. There was no significant difference in genotype frequency and allele frequency of APOC3 Sst â polymorphism between the GDM and the control groups ( P>0.05). In the GDM group, those with S2S2 and S1S2 genotypes had higher plasma HDL-C levels and lower atherogenic index (AI) values than those with S1S1 genotype did, with the differences being statistically significant (all P<0.05). GDM patients were then divided into obesity and non-obesity subgroups. Further subgroup analysis showed that the association of APOC3 genotype with changes in HDL-C levels was observed only in obese GDM patients, while the association of APOC3 genotype with changes in AI values was observed in both obese and nonobese patients. In addition, in obese GDM patients, those with S2S2 genotype had significantly higher plasma TG levels than those with S1S1 and S1S2 genotypes did ( P<0.05 and P<0.01, respectively). In non-obese GDM patients, those with S2S2 genotype had significantly lower apoB/apoA1 ratio than S2S2 carriers did ( P<0.05). No genotype-related effect on lipid and apolipoprotein variations was evident in the normal controls. Conclusion: APOC3 Sst â polymorphism in GDM patients is associated with HDL-C and TG levels as well as AI value and apoB/apoA1 ratio. The changes in lipid levels and apolipoprotein ratio showed BMI-dependent features. However, association between polymorphism at the locus and the development of GDM was not observed.
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Diabetes Gestacional , Femenino , Humanos , Embarazo , Apolipoproteína A-I/genética , Apolipoproteína C-III/genética , Apolipoproteínas B/genética , Apolipoproteínas C/genética , HDL-Colesterol , Diabetes Gestacional/genética , Frecuencia de los Genes , Genotipo , Obesidad/genética , TriglicéridosRESUMEN
Apolipoprotein-CIII (apo-CIII) is involved in triglyceride-rich lipoprotein metabolism and linked to beta-cell damage, insulin resistance, and cardiovascular disease. Apo-CIII exists in four main proteoforms: non-glycosylated (apo-CIII0a), and glycosylated apo-CIII with zero, one, or two sialic acids (apo-CIII0c, apo-CIII1 and apo-CIII2). Our objective is to determine how apo-CIII glycosylation affects lipid traits and type 2 diabetes prevalence, and to investigate the genetic basis of these relations with a genome-wide association study (GWAS) on apo-CIII glycosylation. We conducted GWAS on the four apo-CIII proteoforms in the DiaGene study in people with and without type 2 diabetes (n = 2318). We investigated the relations of the identified genetic loci and apo-CIII glycosylation with lipids and type 2 diabetes. The associations of the genetic variants with lipids were replicated in the Diabetes Care System (n = 5409). Rs4846913-A, in the GALNT2-gene, was associated with decreased apo-CIII0a. This variant was associated with increased high-density lipoprotein cholesterol and decreased triglycerides, while high apo-CIII0a was associated with raised high-density lipoprotein-cholesterol and triglycerides. Rs67086575-G, located in the IFT172-gene, was associated with decreased apo-CIII2 and with hypertriglyceridemia. In line, apo-CIII2 was associated with low triglycerides. On a genome-wide scale, we confirmed that the GALNT2-gene plays a major role i O-glycosylation of apolipoprotein-CIII, with subsequent associations with lipid parameters. We newly identified the IFT172/NRBP1 region, in the literature previously associated with hypertriglyceridemia, as involved in apolipoprotein-CIII sialylation and hypertriglyceridemia. These results link genomics, glycosylation, and lipid metabolism, and represent a key step towards unravelling the importance of O-glycosylation in health and disease.
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Diabetes Mellitus Tipo 2 , Hiperlipidemias , Hipertrigliceridemia , Humanos , Apolipoproteína C-III/genética , Apolipoproteínas C/genética , Diabetes Mellitus Tipo 2/genética , Glicosilación , Estudio de Asociación del Genoma Completo , Triglicéridos , HDL-Colesterol , Receptores Citoplasmáticos y Nucleares/genética , Proteínas de Transporte Vesicular/genética , Proteínas del Citoesqueleto/genética , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
Alzheimer's disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/psicología , Apolipoproteínas C/genética , Apolipoproteínas C/metabolismo , Apolipoproteínas E/metabolismo , Encéfalo/metabolismo , Estudios de Casos y Controles , Cognición , Femenino , Expresión Génica , Predisposición Genética a la Enfermedad , Variación Genética , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Nectinas/genética , Nectinas/metabolismo , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is among the most common and lethal malignancies worldwide. Apolipoproteins (APOs) have been reported increasingly for their relationships with tumors. We aim at exploring the potential relationships of apolipoprotein A (APOA) and apolipoprotein C (APOC) family members with HCC. METHODS: A data set, containing 212 hepatitis B virus-related HCC patients, was used for analysis. The diagnostic and prognostic ability of APOA and APOC family genes was figured out. Risk score models and nomograms were developed for the HCC prognosis prediction. Moreover, molecular mechanism exploration were identified biological processes and metabolic pathways of these genes involved in. Validation analysis was carried out using online website. RESULTS: APOA1, APOC1, APOC3, and APOC4 showed robust diagnosis significance (all P < 0.05). APOA4, APOC3, and APOC4 were associated with the overall survival (OS) while APOA4 and APOC4 were linked to recurrence-free survival (RFS, all P ≤ 0.05). Risk score models and nomograms had the advantage of predicting OS and RFS for HCC. Molecular mechanism exploration indicated that these genes were involved in the steroid metabolic process, the PPAR signaling pathway, and fatty acid metabolism. Besides that, validation analysis revealed that APOC1 and APOC4 had an association with OS; and APOC3 was associated with OS and RFS (all P ≤ 0.05). CONCLUSIONS: APOA1, APOC1, APOC3, and APOC4 are likely to be potential diagnostic biomarkers and APOC3 and APOC4 are likely to be potential prognostic biomarkers for hepatitis B virus-related HCC. They may be involved in the steroid metabolic process, PPAR signaling pathway, and fatty acid metabolism.
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Apolipoproteínas A/genética , Apolipoproteínas C/genética , Carcinoma Hepatocelular/genética , Regulación Neoplásica de la Expresión Génica , Hepatitis/complicaciones , Neoplasias Hepáticas/genética , ARN Mensajero/genética , Apolipoproteínas A/metabolismo , Apolipoproteínas C/metabolismo , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Ontología de Genes , Redes Reguladoras de Genes , Hepatitis/virología , Virus de la Hepatitis B/fisiología , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Nomogramas , Pronóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/metabolismoRESUMEN
The apolipoprotein E-C1-C4-C2 gene cluster at 19q13.32 encodes four amphipathic apolipoproteins. The influence of APOE common polymorphisms on plasma lipid/lipoprotein profile, especially on LDL-related traits, is well recognized; however, little is known about the role of other genes/variants in this gene cluster. In this study, we evaluated the role of common and uncommon/rare genetic variation in this gene region on inter-individual variation in plasma lipoprotein levels in non-Hispanic Whites (NHWs) and African blacks (ABs). In the variant discovery step, the APOE, APOC1, APOC4, APOC2 genes were sequenced along with their flanking and hepatic control regions (HCR1 and HCR2) in 190 subjects with extreme HDL-C/TG levels. The next step involved the genotyping of 623 NHWs and 788 ABs for the identified uncommon/rare variants and common tagSNPs along with additional relevant SNPs selected from public resources, followed by association analyses with lipid traits. A total of 230 sequence variants, including 15 indels were identified, of which 65 were novel. A total of 70 QC-passed variants in NHWs and 108 QC-passed variants in ABs were included in the final association analyses. Single-site association analysis of SNPs with MAF>1% revealed 20 variants in NHWs and 24 variants in ABs showing evidence of association with at least one lipid trait, including several variants exhibiting independent associations from the established APOE polymorphism even after multiple-testing correction. Overall, our study has confirmed known associations and also identified novel associations in this genomic region with various lipid traits. Our data also support the contribution of both common and uncommon/rare variation in this gene region in affecting plasma lipid profile in the general population.
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Apolipoproteína C-II/genética , Apolipoproteína C-I/genética , Apolipoproteínas C/genética , Apolipoproteínas E/genética , Etnicidad/genética , Lipoproteínas/sangre , Adulto , Población Negra/genética , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Dislipidemias/sangre , Dislipidemias/genética , Femenino , Estudios de Asociación Genética , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Familia de Multigenes , Polimorfismo de Nucleótido Simple , Triglicéridos/sangre , Población Blanca/genéticaRESUMEN
Background Macrophage cholesterol efflux to high-density lipoproteins ( HDLs ) is the first step of reverse cholesterol transport. The cholesterol efflux capacity ( CEC ) of HDL particles is a protective risk factor for coronary artery disease independent of HDL cholesterol levels. Using a genome-wide association study approach, we aimed to identify pathways that regulate CEC in humans. Methods and Results We measured CEC in 5293 French Canadians. We tested the genetic association between 4 CEC measures and genotypes at >9 million common autosomal DNA sequence variants. These analyses yielded 10 genome-wide significant signals ( P<6.25×10-9) representing 7 loci. Five of these loci harbor genes with important roles in lipid biology ( CETP , LIPC , LPL , APOA 1/C3/A4/A5, and APOE /C1/C2/C4). Except for the APOE /C1/C2/C4 variant ( rs141622900, P nonadjusted=1.0×10-11; P adjusted=8.8×10-9), the association signals disappear when correcting for HDL cholesterol and triglyceride levels. The additional 2 significant signals were near the PPP 1 CB / PLB 1 and RBFOX 3/ ENPP 7 genes. In secondary analyses, we considered candidate functional variants for 58 genes implicated in HDL biology, as well as 239 variants associated with blood lipid levels and/or coronary artery disease risk by genome-wide association study . These analyses identified 27 significant CEC associations, implicating 5 additional loci ( GCKR , LIPG , PLTP , PPARA , and TRIB 1). Conclusions Our genome-wide association study identified common genetic variation at the APOE /C1/C2/C4 locus as a major determinant of CEC that acts largely independently of HDL cholesterol. We predict that HDL -based therapies aiming at increasing CEC will be modulated by changes in the expression of apolipoproteins in this gene cluster.
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Apolipoproteínas C/genética , Apolipoproteínas E/genética , HDL-Colesterol/metabolismo , Colesterol/metabolismo , Enfermedad de la Arteria Coronaria/genética , Macrófagos/metabolismo , Anciano , Apolipoproteína C-I/genética , Apolipoproteína C-II/genética , Canadá , Estudios de Casos y Controles , Enfermedad de la Arteria Coronaria/metabolismo , Femenino , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in developed nations. Therapeutic modulation of dyslipidemia by inhibiting 3'-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is standard practice throughout the world. However, based on findings from Mendelian studies and genetic sequencing in prospective longitudinal cohorts from around the world, novel therapeutic targets regulating lipid and lipoprotein metabolism, such as apoprotein C3, angiopoietin-like proteins 3 and 4, and lipoprotein(a), have been identified. These targets may provide additional avenues to prevent and treat atherosclerotic disease. We therefore review these novel molecular targets by addressing available Mendelian and observational data, therapeutic agents in development, and early outcomes results.
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Aterosclerosis/tratamiento farmacológico , Dislipidemias/tratamiento farmacológico , Acilcoenzima A/antagonistas & inhibidores , Acilcoenzima A/genética , Proteínas Similares a la Angiopoyetina/genética , Proteínas Similares a la Angiopoyetina/metabolismo , Animales , Apolipoproteínas C/genética , Apolipoproteínas C/metabolismo , Aterosclerosis/genética , Aterosclerosis/metabolismo , Dislipidemias/genética , Dislipidemias/metabolismo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Terapia Molecular Dirigida , Estudios ProspectivosAsunto(s)
Sistemas CRISPR-Cas/genética , Edición Génica/métodos , Edición Génica/tendencias , Terapia Genética/métodos , Terapia Genética/tendencias , Cardiopatías/genética , Cardiopatías/prevención & control , Sustitución de Aminoácidos , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina/deficiencia , Proteínas Similares a la Angiopoyetina/genética , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Apolipoproteína B-100/deficiencia , Apolipoproteína B-100/genética , Apolipoproteínas C/genética , LDL-Colesterol/sangre , Modelos Animales de Enfermedad , Distrofina/genética , Distrofina/metabolismo , Cardiopatías/sangre , Cardiopatías/terapia , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/genética , Hipercolesterolemia/prevención & control , Lipoproteína(a)/deficiencia , Lipoproteína(a)/genética , Ratones , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Mutación , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/genética , Isquemia Miocárdica/prevención & control , Inhibidores de PCSK9 , Seguridad del Paciente , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/prevención & controlRESUMEN
OBJECTIVE: To describe the clinical, biochemical, and genetic features of patients with congenital disorders of glycosylation (CDG) identified in Spain during the last 20 years. STUDY DESIGN: Patients were selected among those presenting with multisystem disease of unknown etiology. The isoforms of transferrin and of ApoC3 and dolichols were analyzed in serum; phosphomannomutase and mannosephosphate isomerase activities were measured in fibroblasts. Conventional or massive parallel sequencing (customized panel or Illumina Clinical-Exome Sequencing TruSight One Gene Panel) was used to identify genes and mutations. RESULTS: Ninety-seven patients were diagnosed with 18 different CDG. Eighty-nine patients had a type 1 transferrin profile; 8 patients had a type 2 transferrin profile, with 6 of them showing an alteration in the ApoC3 isoform profile. A total of 75% of the patients had PMM2-CDG presenting with a heterogeneous mutational spectrum. The remaining patients showed mutations in any of the following genes: MPI, PGM1, GFPT1, SRD5A3, DOLK, DPGAT1, ALG1, ALG6, RFT1, SSR4, B4GALT1, DPM1, COG6, COG7, COG8, ATP6V0A2, and CCDC115. CONCLUSION: Based on literature and on this population-based study of CDG, a comprehensive scheme including reported clinical signs of CDG is offered, which will hopefully reduce the timeframe from clinical suspicion to genetic confirmation. The different defects of CDG identified in Spain have contributed to expand the knowledge of CDG worldwide. A predominance of PMM2 deficiency was detected, with 5 novel PMM2 mutations being described.
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Acetiltransferasas/metabolismo , Apolipoproteínas C/metabolismo , Trastornos Congénitos de Glicosilación/diagnóstico , Trastornos Congénitos de Glicosilación/epidemiología , Acetiltransferasas/genética , Apolipoproteínas C/genética , Estudios de Cohortes , Bases de Datos Factuales , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Humanos , Incidencia , Recién Nacido , Masculino , Mutación , Estudios Retrospectivos , Medición de Riesgo , España/epidemiologíaRESUMEN
BACKGROUND AND AIMS: Concurrent fatty liver in hepatitis B virus (HBV)-infected patients without significant alcohol intake is a frequent and increasingly alarming problem because of the non-alcoholic fatty liver disease pandemic. The risk of HBV-related hepatocellular carcinoma (HCC) development was increased by concomitant obesity and diabetes. Direct evidence of the hepatocarcinogenic effect of fatty liver in chronic HBV remains elusive. We aimed to evaluate the risk of concurrent histologically proven fatty liver in HBV hepatocarcinogenesis. METHODS: We conducted a retrospective cohort study on a liver biopsy cohort of HBV-infected patients without significant alcohol intake to evaluate the prevalence of concurrent histologically proven fatty liver and its association with subsequent HCC development. We also examined nine polymorphisms on six non-alcoholic fatty liver disease-related candidate genes (ADIPOQ, APOC3, GCKR, LEPR, PNPLA3, and PPARG). RESULTS: Among 270 HBV-infected patients, concurrent fatty liver was found in 107 patients (39.6%) and was associated with metabolic risks, cirrhosis (P = 0.016) and PNPLA3 rs738409 CG/GG genotype (P = 0.002). At a median follow-up of 79.9 months, 11 patients (4.1%) developed HCC, and nine of them had concurrent fatty liver. By multivariable Cox analysis, concurrent fatty liver (HR 7.27, 95% confidence interval: 1.52-34.76; P = 0.013), age, cirrhosis, and APOC3 rs2854116 TC/CC genotype (HR 3.93, 95% confidence interval: 1.30-11.84; P = 0.013) were independent factors predicting HCC development. CONCLUSIONS: Concurrent fatty liver is common in HBV-infected patients and an independent risk factor potentiating HBV-associated HCC development by 7.3-fold. The risk of HBV-related HCC is increased by APOC3 gene polymorphism, and further characterization is required by its role.
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Carcinoma Hepatocelular/etiología , Hepatitis B Crónica/complicaciones , Neoplasias Hepáticas/etiología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Adulto , Apolipoproteínas C/genética , Carcinoma Hepatocelular/epidemiología , Estudios de Cohortes , Complicaciones de la Diabetes/complicaciones , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Neoplasias Hepáticas/epidemiología , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/genética , Obesidad/complicaciones , Polimorfismo Genético , Prevalencia , Estudios Retrospectivos , Riesgo , Factores de RiesgoAsunto(s)
Dieta con Restricción de Grasas , Hiperlipoproteinemia Tipo I/dietoterapia , Hipertrigliceridemia/dietoterapia , Apolipoproteínas C/deficiencia , Apolipoproteínas C/genética , Quilomicrones/sangre , Quilomicrones/genética , Humanos , Hipertrigliceridemia/genética , Lipoproteína Lipasa/deficiencia , Lipoproteína Lipasa/genética , MutaciónRESUMEN
The hypothesis of the present study is that the polymorphisms in the APOC3, CEPT, ACE, and ACTN3 genes can affect the outcome of nutritional intervention and the plasma lipid profile of HIV+ patients. To test the hypothesis, genetic material was collected from buccal cells, and serum was collected for biochemical analysis. Sixty-five patients were analyzed. The incorporation of protease inhibitor (PI) was more frequent in women (77% vs 33% in men). Nutritional intervention improved anthropometric parameters independent of the genotype. Patients with the RR genotype for the ACTN3 R577X polymorphism had lower glycemia (RR = 95.4 ± 6.5 mg/dL, RX = 102.6 ± 10.6 mg/dL, XX = 110.1 ± 16.3 mg/dL; P = .03) and a greater reduction in low-density lipoproteins (LDL) after intervention (LDL: RR = -23.7 ± 15.8 mg/dL, RX = 1.32 ± 5.13 mg/dL, XX = 30.21 ± 24.4 mg/dL; P = .01). Patients using PI had a negative response to dietary intervention regarding the levels of high-density lipoprotein (-2.4 ± 1.70 with PI, 2.56 ± 1.60 mg/dL without PI; P = .02), very low density lipoprotein (0.84 ± 2.73 with IP, -5.46 ± 3.37 mg/dL without PI; P = .03), and triglycerides (1.79 ± 13.22 with PI, -34.00 ± 17.67 mg/dL without PI; P = .052). This response was also independent of the genotype (P > 0.05) and suggested the need for oral lipid-lowering drugs in all HIV+ patients using PI. Our results indicate that the ACTN3 R577X polymorphism is a good predictor of both the lipid profile and the prognosis of nutritional intervention in reducing LDL in HIV+ patients.
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Actinina/genética , Infecciones por VIH/dietoterapia , Infecciones por VIH/genética , Desnutrición/dietoterapia , Polimorfismo de Nucleótido Simple , Actinina/metabolismo , Adulto , Antropometría , Antirretrovirales/administración & dosificación , Antirretrovirales/efectos adversos , Apolipoproteínas C/sangre , Apolipoproteínas C/genética , Glucemia/metabolismo , Colesterol/sangre , Estudios de Cohortes , Dieta , Femenino , Genotipo , Técnicas de Genotipaje , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Desnutrición/sangre , Desnutrición/etiología , Desnutrición/genética , Persona de Mediana Edad , Mucosa Bucal/citología , Mucosa Bucal/metabolismo , Evaluación Nutricional , Cooperación del Paciente , Triglicéridos/sangreRESUMEN
OBJECTIVE: Gout is associated with dyslipidaemia. Association of the apolipoprotein A1-C3-A4 gene cluster with gout has previously been reported in a small study. To investigate a possible causal role for this locus in gout, we tested the association of genetic variants from APOA1 (rs670) and APOC3 (rs5128) with gout. METHODS: We studied data for 2452 controls and 2690 clinically ascertained gout cases of European and New Zealand Polynesian (Maori and Pacific) ancestry. Data were also used from the publicly available Atherosclerosis Risk in Communities study (n = 5367) and the Framingham Heart Study (n = 2984). Multivariate adjusted logistic and linear regression was used to test the association of single-nucleotide polymorphisms with gout risk, serum urate, triglyceride and high-density lipoprotein cholesterol (HDL-C). RESULTS: In Polynesians, the T-allele of rs670 (APOA1) increased (odds ratio, OR = 1.53, P = 4.9 × 10(-6)) and the G-allele of rs5128 (APOC3) decreased the risk of gout (OR = 0.86, P = 0.026). In Europeans, there was a strong trend to a risk effect of the T-allele for rs670 (OR = 1.11, P = 0.055), with a significant protective effect of the G-allele for rs5128 being observed after adjustment for triglycerides and HDL-C (OR = 0.81, P = 0.039). The effect at rs5128 was specific to males in both Europeans and Polynesians. Association in Polynesians was independent of any effect of rs670 and rs5128 on triglyceride and HDL-C levels. There was no evidence for association of either single-nucleotide polymorphism with serum urate levels (P ⩾ 0.10). CONCLUSION: Our data, replicating a previous study, supports the hypothesis that the apolipoprotein A1-C3-A4 gene cluster plays a causal role in gout.
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Apolipoproteína A-I/genética , Gota/genética , Familia de Multigenes/genética , Adulto , Apolipoproteína C-III/genética , Apolipoproteínas C/genética , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Nativos de Hawái y Otras Islas del Pacífico/genética , Factores de Riesgo , Ácido Úrico/metabolismo , Población Blanca/genéticaRESUMEN
BACKGROUND: Hypercholesterolemia arising from abnormal lipid metabolism is one of the critical risk factors for coronary artery disease (CAD), however the roles of genetic variants in lipid metabolism-related genes on premature CAD (≤ 60 years old) development still require further investigation. We herein genotyped four single nucleotide polymorphisms (SNPs) in lipid metabolism-related genes (rs1132899 and rs5167 in APOC4, rs1801693 and rs7765781 in LPA), aimed to shed light on the influence of these SNPs on individual susceptibility to early-onset CAD. METHODS: Genotyping of the four SNPs (rs1132899, rs5167, rs1801693 and rs7765781) was performed in 224 premature CAD cases and 297 control subjects (≤ 60 years old) using polymerase chain reaction-ligation detection reaction (PCR-LDR) method. The association of these SNPs with premature CAD was performed with SPSS software. RESULTS: Multivariate logistic regression analysis showed that C allele (OR = 1.50, P = 0.027) and CC genotype (OR = 2.84, P = 0.022) of APOC4 rs1132899 were associated with increased premature CAD risk, while the other three SNPs had no significant effect. Further stratified analysis uncovered a more evident association with the risk of premature CAD among male subjects (C allele, OR = 1.65, and CC genotype, OR = 3.33). CONCLUSIONS: Our data provides the first evidence that APOC4 rs1132899 polymorphism was associated with an increased risk of premature CAD in Chinese subjects, and the association was more significant among male subjects.
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Apolipoproteínas C/genética , Pueblo Asiatico/genética , Enfermedad de la Arteria Coronaria/genética , Etnicidad/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Análisis de Varianza , Estudios de Casos y Controles , Enfermedad de la Arteria Coronaria/sangre , Femenino , Humanos , Lípidos/sangre , Lipoproteína(a)/genética , Masculino , Persona de Mediana Edad , Análisis Multivariante , Factores de Riesgo , Fumar/efectos adversosRESUMEN
Type 2 diabetes mellitus (T2DM) and its complications are linked to environmental, clinical, and genetic factors. This review analyses the disorders of lipids and their genetics with respect to coronary artery disease (CAD) associated with T2DM. Cell organelles, hepatitis C-virus infection, reactive oxygen species produced in mitochondria, and defective insulin signaling due to the arrest of G1 phase to S phase transition of ß-cells have significant roles in the precipitation of the diseases. Adiponectin is anti-inflammatory and anti-atherosclerotic and improves insulin resistance. Low-density lipoprotein (LDL) is atherosclerotic, and LDL-cholesterol in T2DM is associated with high-cardiovascular risk. Further, LDL cholesterol reduction significantly reduces cardiovascular morbidity and mortality. High-density lipoprotein (HDL) is also anti-atherosclerotic due to HDL associated paraoxonase-1 serum enzyme, which prevents LDL oxidative modifications and the development of CAD. Moreover, elevated apolipoprotein B and apolipoprotein A-I (ApoB/ApoA-I) ratio in plasma is also a risk factor for CAD. LDL receptor, adiponectin, and endocannabinoid receptor-1 genes are independently associated with CAD and T2DM. Polymorphism of Apo E2 (epsilon2) is a positive factor to increase the T2DM risk and Apo E4 (epsilon4) is a negative factor to reduce the disease risk. Taq 1B polymorphism of cholesterol ester transfer protein (CETP) gene contributes to the development of atherosclerosis, whereas haplotypes of APOA5, APOC3, APOC4, and APOC5 genes are in the same cluster and are independently associated with high plasma triglyceride level, CAD and T2DM. In conclusion, because various genes, LDLR, CETP, APOA5, Apo E, Apo B, and Apo A-I, are associated with the precipitation of CAD associated with T2DM, a personalized diet-gene intervention therapy may be advocated to reduce the disease precipitation.
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Enfermedad de la Arteria Coronaria/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Dislipidemias/complicaciones , Adiponectina/genética , Adiponectina/metabolismo , Apolipoproteína A-V , Apolipoproteína C-III/genética , Apolipoproteína E2/genética , Apolipoproteína E4/genética , Apolipoproteínas A/genética , Apolipoproteínas C/genética , Arildialquilfosfatasa/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol/genética , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Dislipidemias/genética , Dislipidemias/metabolismo , Puntos de Control de la Fase G1 del Ciclo Celular , Hepatitis C/metabolismo , Humanos , Mitocondrias/metabolismo , Polimorfismo Genético , Especies Reactivas de Oxígeno/metabolismo , Receptor Cannabinoide CB1/genética , Receptores de LDL/genética , Factores de RiesgoRESUMEN
Metabolic disorders and hypersensitivities affect tolerability and impact adherence to highly active antiretroviral therapy (HAART). The aim of this study was to determine the prevalence of C-482T/T-455C variants in the Apolipoprotein C3 (APOC3) promoter gene and Human leukocyte antigen (HLA)-B*57:01, known to impact lipid metabolic disorders and hypersensitivity respectively; and to correlate genotypes with gender, CD4+ cell count and viral load in an HIV infected cohort in northern South Africa. Frequencies of C-482 and T-455 polymorphisms in APOC3 were determined by restriction fragment length polymorphism analysis. Allele determination for HLA-B was performed with Assign SBT software in an HLA library. Analysis of APOC3 C-482 site revealed a prevalence of 196/199 (98.5%) for CC, 1/199 (0.5%) for CT and 2/199 (1.0%) for TT genotype (p = 0.000 with 1° of freedom; χ2 = 126.551). For the T-455 site, prevalences were: 69/199 (35%) for TT and 130/199 (65%) for the CC genotype (p = 0.000 with 1° of freedom; χ2 = 199). There was no association between gender and the presence of -482 (p = 1; χ2 = 0.00001) or -455 genotypes (p = 0.1628; χ2 = 1.9842). There was no significant difference in the increase in CD4+ cell count irrespective of genotypes. Significant increases in CD4+ cell count were observed in males and females considering the -455C genotype, but not in males for the -455T genotype. Viral load decreases were significant with the -455C and -482C genotypes irrespective of gender. HLA-B*57:01 was not identified in the study cohort. The apparently high prevalence of APOC3 T-455CC genotype needs confirmation with a larger samples size and triglyceride measurements to support screening of patients to pre-empt HAART associated lipid disorders.
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Apolipoproteínas C/genética , Infecciones por VIH/genética , Antígenos HLA-B/genética , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Adolescente , Adulto , Recuento de Linfocito CD4 , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de Restricción , SudáfricaRESUMEN
Apolipoprotein A5 (APOA5) and C3 (APOC3) genes are involved in the PPAR lipid metabolism pathway and thus associated with elevated triglyceride levels. However, whether APOA5 and APOC3 genetic polymorphisms affect intramuscular fat deposition and other meat quality traits remains unknown in pigs. One hundred and seventy-one Kele pigs were sampled to investigate genetic variants in the APOA5 and APOC3 genes and their association with seven pork quality traits. We identified 5 single nucleotide polymorphisms (SNPs) in the promoter region of the APOA5 gene and 17 SNPs in the APOC3 gene. Linkage disequilibrium analysis revealed 5 complete linkage disequilibria among these 22 SNPs. We found that 10 SNPs were significantly correlated with meat quality traits, including the mutation A5/-769 in the APOA5 gene, which was significantly associated with cooked weight percentage, and 9 SNPs in the APOC3 gene that were significantly associated with drip loss rate, meat color value of longissimus dorsi muscle and shear force. Therefore, these SNP markers will be useful for marker-assisted selection for improved pork quality.
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Apolipoproteínas A/genética , Apolipoproteínas C/genética , Carne/análisis , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Sus scrofa/genética , Animales , Calidad de los Alimentos , Frecuencia de los Genes , Desequilibrio de Ligamiento , Fenotipo , TriglicéridosRESUMEN
The aim of this study was to estimate the role of matrix metalloproteinases activity (MMP-9, TIMP-1) and gene polymorphism at the patients with metabolic syndrome in combination with paroxysmal form of atrial fibrillation. The 60 patients with metabolic syndrome in combination with paroxysmal form of atrial fibrillation were investigated with estimation of serum levels of MMP-9, TIMP-1 and mutation of genes of angiotenzinogen 1 Thr 174 Met, angiotenzinogen 2 Met 235 Thr and apolipoprorein C3 C3238 G. In patients with metabolic syndrome in combination with paroxysmal form of atrial fibrillation the significant increase synthesis of MMP-9 level can lead to increase of atrial fibrillation paroxysms because of increase synthesis of collagen tissue in myocard and vessel walls. Also the significant high incidence of angiotenzinogen 2 Met 235 Thr mutation was established.
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Fibrilación Atrial/sangre , Metaloproteinasa 9 de la Matriz/sangre , Síndrome Metabólico/complicaciones , Inhibidor Tisular de Metaloproteinasa-1/sangre , Adulto , Angiotensina I/genética , Angiotensina II/genética , Apolipoproteínas C/genética , Fibrilación Atrial/etiología , Fibrilación Atrial/genética , Estudios de Casos y Controles , Humanos , Masculino , Persona de Mediana Edad , Mutación , Polimorfismo GenéticoRESUMEN
BACKGROUND: Genome-wide association studies (GWAS) have become a major strategy for genetic dissection of human complex diseases. Analysing multiple phenotypes jointly may improve both our ability to detect genetic variants with multiple effects and our understanding of their common features. Allelic associations for multiple biochemical traits (serum alanine aminotransferase, aspartate aminotransferase, butrylycholinesterase (BCHE), C-reactive protein (CRP), ferritin, gamma glutamyltransferase (GGT), glucose, high-density lipoprotein cholesterol (HDL), insulin, low-density lipoprotein cholesterol (LDL), triglycerides and uric acid), and body-mass index, were examined. METHODS: We aimed to identify common genetic variants affecting more than one of these traits using genome-wide association analysis in 2548 adolescents and 9145 adults from 4986 Australian twin families. Multivariate and univariate associations were performed. RESULTS: Multivariate analyses identified eight loci, and univariate association analyses confirmed two loci influencing more than one trait at p < 5 × 10-8. These are located on chromosome 8 (LPL gene affecting HDL and triglycerides) and chromosome 19 (TOMM40/APOE-C1-C2-C4 gene cluster affecting LDL and CRP). A locus on chromosome 12 (OASL gene) showed effects on GGT, LDL and CRP. The loci on chromosomes 12 and 19 unexpectedly affected LDL cholesterol and CRP in opposite directions. CONCLUSIONS: We identified three possible loci that may affect multiple traits and validated 17 previously-reported loci. Our study demonstrated the usefulness of examining multiple phenotypes jointly and highlights an anomalous effect on CRP, which is increasingly recognised as a marker of cardiovascular risk as well as of inflammation.
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2',5'-Oligoadenilato Sintetasa/genética , Apolipoproteína C-II/genética , Apolipoproteína C-I/genética , Apolipoproteínas C/genética , Apolipoproteínas E/genética , Enfermedades Cardiovasculares/genética , Lipoproteína Lipasa/genética , Proteínas de Transporte de Membrana/genética , Adolescente , Adulto , Alelos , Enfermedades en Gemelos , Femenino , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Análisis Multivariante , Fenotipo , RiesgoRESUMEN
UNLABELLED: The aim of the work was to study the clinical and genetic factors at children with obese that predispose to the development of MS, and the development of algorithm for generating risk of MS. MATERIALS AND METHODS: Two comparable age and sex groups of children--148 children with obesity and 46--with normal body weight. We assessed anthropometric indices, blood pressure (BP), lipid profile, carbohydrate metabolism, the level of uric acid. 83 children with obesity were genotyped for polymorphisms: I/D gene ACE, G-75A ApoA1, S19W ApoA5, Sstl ApoC3, E2/E3/E4 ApoE and W/R ADRB3. RESULTS: 98,0% of children had abdominal obesity. In 35,8% was identified high blood pressure. In 47,4% was diagnosed hypo-alpha cholesterolemia and/or hypertriglyceridemia (HTG). In 21,0% of children was identified hyperglycemia. 25,7%were suffered from hyperuricemia. Among the genotyped children 57,0% of homo-and heterozygous carriers of D allele ACE gene had high blood pressure. More than half of the holders of 19W-allele ApoA5 (68,5%),--75A-allele of ApoA1 (56,0%), 52-allele of the gene ApoC3 (53,0%), E4-ApoE gene (85,7%), in the heterozygous state had metabolic TG and/or HDL. In 60,3% of the carriers W/W genotype of ADRB3 gene revealed a combination of hyperglycemia with hyperinsulinemia and/or TG. CONCLUSION: As a result of, aiming aimed at early detection of the major manifestations of MS clinical and genetic study was revealed stable combination of constitutional, metabolic and molecular-genetic factors. Based on these data was developed algorithm for forming groups at risk of MS and individual tactics to prevent and/or therapy.