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1.
Mol Oral Microbiol ; 32(6): 490-499, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28544588

RESUMO

The periodontal pathogen Aggregatibacter actinomycetemcomitans is known to elicit a systemic immune response in the infected host, and occasionally causes non-oral infections. Detailed information on its immunopathological responses and the involvement of bacterial virulence factors remains to be elucidated. The aim of this study was to assess the systemic immune response to A. actinomycetemcomitans oral infection. We used an animal model that simulates systemic dissemination of the bacteria by injecting live wild-type (WT) D7S-1 and a double knockout mutant of leukotoxin and cytolethal distending toxin (ΔltxΔcdt) A. actinomycetemcomitans strains in rat oral mucosa. Draining lymph nodes were examined for regulatory T (Treg) and T helper type 17 (Th17) cell subsets and their associated mediators. An increase in the proportion of Th17 cells and a decrease in Treg cells over the experimental period of 3 weeks were similarly observed for rats challenged with WT and ΔltxΔcdt. Significant upregulation and downregulation of proinflammatory cytokines in the Th17 gene pathway was noted, as well as several qualitative differences between WT and ΔltxΔcdt. Furthermore, we observed differential fold regulation in key genes associated with a proinflammatory response in ΔltxΔcdt-inoculated rats relative to D7S-1 group. This suggests that although the knockout of these two virulence factors (ΔltxΔcdt) may suppress certain proinflammatory genes, it causes similar over-expression of other genes compared with D7S-1, indicating a common factor that still remains in the pathogenicity of A. actinomycetemcomitans.


Assuntos
Aggregatibacter actinomycetemcomitans/imunologia , Imunidade , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Aggregatibacter actinomycetemcomitans/patogenicidade , Animais , Toxinas Bacterianas/genética , Biofilmes , Citocinas/genética , Citocinas/imunologia , Exotoxinas/genética , Feminino , Expressão Gênica , Técnicas de Inativação de Genes , Linfonodos , Modelos Animais , Doenças Periodontais/imunologia , Doenças Periodontais/microbiologia , Ratos , Ratos Sprague-Dawley , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Virulência , Fatores de Virulência/imunologia
3.
Clin Exp Allergy ; 43(5): 512-20, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23600541

RESUMO

BACKGROUND: Identification of risk factors for reduced asthma control could improve the understanding and treatment of asthma. A promoter polymorphism in the 5-lipoxygenase gene affects gene expression and response to asthma therapy, but its impact on disease control remains unclear. OBJECTIVE: We sought to determine if the ALOX5 promoter SP1 tandem repeat polymorphism was associated with changes in cysteinyl leukotriene production, lung function, airway inflammation and asthma control score. METHODS: We analysed 270 children, 6- to 17-years old, with poorly controlled asthma enrolled in a 6-month clinical trial (NCT00604851). In secondary analysis, we associated the ALOX5 promoter SP1 tandem repeat polymorphism genotype (rs59439148) with asthma outcomes using both additive and recessive genetic models. We evaluated FEV1 percent predicted, symptom control, exhaled nitric oxide and urinary LTE4 levels. RESULTS: Of all children, 14.8% (40/270) (and 28% (38/135) of African Americans) carried two non-5-repeat variant alleles of rs59439148. Children who were homozygous for variant alleles had significantly higher urinary LTE4 levels (38 vs. 30 nmol/mol creatinine, P = 0.0134), significantly worse FEV1% predicted (84 vs. 91, P = 0.017) and a trend towards worse asthma control. FEV1% predicted values were significantly negatively correlated with urinary LTE4 (r = -0.192, P = 0.009). CONCLUSION AND CLINICAL RELEVANCE: Carrying two copies of a minor variant ALOX5 promoter SP1 tandem repeat allele contributes to increased cysLT exposure as determined by urinary LTE4 levels, reduced lung function and potentially worse asthma control. ALOX5 promoter SP1 tandem repeat genotype may be a risk factor for worse asthma outcomes.


Assuntos
Araquidonato 5-Lipoxigenase/genética , Asma/genética , Asma/metabolismo , Leucotrienos/biossíntese , Polimorfismo Genético , Adolescente , Alelos , Asma/fisiopatologia , Sítios de Ligação , Criança , Feminino , Frequência do Gene , Genótipo , Humanos , Leucotrieno E4/urina , Leucotrienos/urina , Masculino , Regiões Promotoras Genéticas , Testes de Função Respiratória , Fator de Transcrição Sp1/metabolismo
4.
Clin Genet ; 80(3): 265-72, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21443745

RESUMO

Mutations in the transcription factor PAX9 which plays a critical role in the switching of odontogenic potential from the epithelium to the mesenchyme during tooth development cause autosomal dominant non-syndromic hypodontia primarily affecting molars. Linkage analysis on a family segregating autosomal dominant molar hypodontia with markers flanking and within PAX9 yielded a maximum multipoint LOD score of 3.6. No sequence variants were detected in the coding or 5'- and 3'-untranslated regions (UTRs) of PAX9. However, we identified a novel g.-1258G>A sequence variant in all affected individuals of the family but not in the unaffected family members or in 3088 control chromosomes. This mutation is within a putative 5'-regulatory sequence upstream of PAX9 highly conserved in primates, somewhat conserved in ungulates and carnivores but not conserved in rodents. Bioinformatics analysis of the sequence determined that there was no abolition or creation of a putative binding site for known transcription factors. Based on our previous findings that haploinsufficiency for PAX9 leads to hypodontia, we postulate that the g.-1258G>A variant reduces the expression of PAX9 which underlies the hypodontia phenotype in this family.


Assuntos
Região 5'-Flanqueadora , Anodontia/genética , Transtornos Cromossômicos , Cromossomos Humanos Par 14 , Sequência Conservada , Dente Molar/patologia , Odontogênese/genética , Fator de Transcrição PAX9/genética , Animais , Anodontia/patologia , Sequência de Bases , Carnívoros , Biologia Computacional/métodos , Feminino , Genes Dominantes , Estudos de Associação Genética , Ligação Genética , Genótipo , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Fenótipo , Roedores , Alinhamento de Sequência , Análise de Sequência de DNA
5.
Diabetologia ; 51(6): 978-88, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18421434

RESUMO

AIMS/HYPOTHESIS: We previously used an integrative genetics approach to demonstrate that 5-lipoxygenase (5-LO) deficiency in mice (Alox5 (-/-)) protects against atherosclerosis despite increasing lipid levels and fat mass. In the present study, we sought to further examine the role of 5-LO in adiposity and pancreatic function. METHODS: Alox5 (-/-) and wild-type (WT) mice were characterised with respect to adiposity and glucose/insulin metabolism using in vivo and in vitro approaches. The role of ALOX5 in pancreatic function in human islets was assessed through short interfering RNA (siRNA) knockdown experiments. RESULTS: Beginning at 12 weeks of age, Alox5 (-/-) mice had significantly increased fat mass, plasma leptin levels and fasting glucose levels, but lower fasting insulin levels (p<0.05). Although Alox5 (-/-) mice did not exhibit insulin resistance, they had impaired insulin secretion in response to a bolus glucose injection. Histological analyses revealed that Alox5 (-/-) mice had increased islet area, beta cell nuclear size, and numbers of beta cells/mm(2) islet (p<0.05), indicative of both hyperplasia and hypertrophy. Basal and stimulated insulin secretion in isolated Alox5 (-/-) islets were significantly lower than in WT islets (p<0.05) and accompanied by a three- to fivefold decrease in the expression of the genes encoding insulin and pancreatic duodenal homeobox 1 (Pdx1). Direct perturbation of ALOX5 in isolated human islets with siRNA decreased insulin and PDX1 gene expression by 50% and insulin secretion by threefold (p<0.05). CONCLUSIONS/INTERPRETATION: These results provide strong evidence for pleiotropic metabolic effects of 5-LO on adiposity and pancreatic function and may have important implications for therapeutic strategies targeting this pathway for the treatment of cardiovascular disease.


Assuntos
Tecido Adiposo/enzimologia , Tecido Adiposo/fisiologia , Proteínas de Transporte/genética , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Pâncreas/enzimologia , Proteínas Ativadoras de 5-Lipoxigenase , Animais , Araquidonato 5-Lipoxigenase/deficiência , Araquidonato 5-Lipoxigenase/genética , Glicemia/metabolismo , Composição Corporal , Peso Corporal , Cruzamentos Genéticos , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/enzimologia , Ilhotas Pancreáticas/metabolismo , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA/genética , RNA/isolamento & purificação , Interferência de RNA , RNA Interferente Pequeno/genética , Caracteres Sexuais , Doadores de Tecidos
7.
Hypertension ; 38(4): 773-8, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11641285

RESUMO

Genes contributing to common forms of hypertension are largely unknown. A number of studies in humans and in animal models have revealed associations between insulin resistance, dyslipidemia, and elevated hypertension. To identify genes contributing to blood pressure (BP) variation associated with insulin-resistant dyslipidemia, we conducted a genome-wide scan for BP in a set of 18 Dutch families exhibiting the common lipid disorder familial combined hyperlipidemia. Our results reveal a locus on chromosome 4 that exhibits a significant lod score of 3.9 with systolic BP. In addition, this locus also appears to influence plasma free fatty acid levels (lod=2.4). After adjustment for age and gender, the lod score for systolic BP increased to 4.6, whereas the lod score for free fatty acid levels did not change. The chromosome 4 locus contains an attractive candidate gene, alpha-adducin, which has been associated with altered BP in animal studies and in some human populations. However, we found no evidence for an association between 2 intragenic alpha-adducin polymorphisms and systolic BP in this sample. We also observed suggestive evidence for linkage (lod=1.8) of diastolic BP to the lipoprotein lipase gene locus on chromosome 8p, supporting a finding previously observed in a separate insulin-resistant population. In addition, we also obtained suggestive evidence for linkage of systolic BP (lod=2.4) and plasma apolipoprotein B levels (lod=2.0) to a locus on proximal chromosome 19p. In conclusion, our genome scan results support the existence of multiple genetic factors that can influence both BP and plasma lipid parameters.


Assuntos
Pressão Sanguínea/genética , Cromossomos Humanos Par 4/genética , Predisposição Genética para Doença/genética , Genoma Humano , Hiperlipidemias/genética , Adulto , Pressão Sanguínea/fisiologia , Proteínas de Ligação a Calmodulina/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 8/genética , Diástole , Saúde da Família , Feminino , Ligação Genética , Humanos , Hiperlipidemias/fisiopatologia , Escore Lod , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Países Baixos , Sístole
8.
Hum Mol Genet ; 9(14): 2067-74, 2000 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-10958645

RESUMO

Familial combined hyperlipidemia (FCHL) is the most commonly inherited hyperlipidemia in man, with a frequency of +/-1% in the general population and approximately 10% in myocardial infarction survivors. A genomic scan in 18 Dutch FCHL families resulted in the identification of several loci with evidence for linkage. One of these regions, 1p36.2, contains TNFRSF1B which encodes one of the tumor necrosis factor receptors. An intron 4 polymorphic CA-repeat was used to confirm linkage to FCHL. Linear regression analysis using 79 independent sib pairs showed linkage with a quantitative FCHL discriminant function (P = 0.032), and, borderline, with apolipoprotein B levels (P = 0.064). Furthermore, in a case-control study, association was demonstrated since the overall CA-repeat genotype distribution was significantly different among 40 unrelated FCHL patients and 48 unrelated healthy spouse controls (P = 0.029). This difference was due to a significant increase in allele CA271 homozygotes in the FCHL patients (P = 0.019). Mutation analysis of exon 6 in 73 FCHL family members demonstrated the presence of a single nucleotide polymorphism with two alleles, coding for methionine (196M) and arginine (196R). Complete linkage disequilibrium between CA267, CA271 and CA273 and this polymorphism was detected. In 85 hyperlipidemic FCHL subjects, an association was demonstrated between soluble TNFRSF1B plasma concentrations and the CA271-196M haplotype. In conclusion, TNFRSF1B was found to be associated with susceptibility to FCHL. Our data suggest that an as yet unknown disease-associated mutation, linked to alleles 196M and CA271, plays a role in the pathophysiology of FCHL.


Assuntos
Hiperlipidemia Familiar Combinada/genética , Receptores do Fator de Necrose Tumoral/genética , Adulto , Alelos , Apolipoproteínas B/biossíntese , Estudos de Casos e Controles , Cromossomos Humanos Par 1 , Análise Mutacional de DNA , Éxons , Saúde da Família , Feminino , Ligação Genética , Genótipo , Haplótipos , Humanos , Hiperlipidemia Familiar Combinada/sangue , Íntrons , Modelos Lineares , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores do Fator de Necrose Tumoral/sangue , Receptores Tipo II do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa
9.
J Lipid Res ; 41(4): 573-82, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10744778

RESUMO

Dietary cholesterol is known to raise total and low density lipoprotein cholesterol concentrations in humans and experimental animals, but the response among individuals varies greatly. Here we describe a mouse strain, C57BL/6ByJ (B6By), that is resistant to diet-induced hypercholesterolemia, in contrast to the phenotype seen in other common strains of mice including the closely related C57BL/6J (B6J) strain. Compared to B6J, B6By mice exhibit somewhat lower basal cholesterol levels on a chow diet, and show a relatively modest increase in absolute levels of total and LDL/VLDL cholesterol in response to an atherogenic diet containing 15% fat, 1.25% cholesterol, and 0.5% cholate. Correspondingly, B6By mice are also resistant to diet-induced aortic lesions, with less than 15% as many lesions as B6J. Food intake and cholesterol absorption are similar between B6By and B6J mice. To investigate the gene(s) underlying the resistant B6By phenotype, we performed genetic crosses with the unrelated mouse strain, A/J. A genome-wide scan revealed a locus, designated Diet1, on chromosome 2 near marker D2Mit117 showing highly significant linkage (lod = 9.6) between B6By alleles and hypo-response to diet. Examination of known genes in this region suggested that this locus represents a novel gene affecting plasma lipids and atherogenesis in response to diet.


Assuntos
Arteriosclerose/genética , Colesterol na Dieta/metabolismo , Colesterol/sangue , Hipercolesterolemia/genética , Camundongos Endogâmicos/genética , Animais , Aorta/patologia , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Mapeamento Cromossômico , Ligação Genética , Predisposição Genética para Doença , Absorção Intestinal , Camundongos
10.
J Lipid Res ; 41(2): 245-52, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10681408

RESUMO

Familial combined hyperlipidemia (FCH) is a common genetic lipid disorder with a frequency of 1-2% in the population. In addition to the hypercholesterolemia and/or hypertriglyceridemia that affected individuals exhibit, small, dense LDL particles and decreased HDL-cholesterol levels are traits frequently associated with FCH. Recently, we reported that families with FCH and families enriched for coronary artery disease (CAD) share genetic determinants for the atherogenic lipoprotein phenotype (ALP), a profile presenting with small, dense LDL particles, decreased HDL-cholesterol levels, and increased triglyceride levels. Other studies in normolipidemic populations have shown that the hepatic lipase (HL) gene is linked to HDL-cholesterol levels and that a polymorphism within the HL promoter (-514C-->T) is associated with increased HDL-cholesterol levels as well as larger, more buoyant LDL particles. In the present study, we tested whether the HL gene locus also contributes to ALP in a series of Dutch FCH families using nonparametric sibpair linkage analysis and association analysis. Evidence for linkage of LDL particle size (P < 0.019), HDL-cholesterol (P < 0.003), and triglyceride levels (P < 0.026) to the HL gene locus was observed. A genome scan in a subset of these families exhibited evidence for linkage of PPD (LOD = 2.2) and HDL-cholesterol levels (LOD = 1.2) to the HL gene locus as well. The -514C-->T promoter polymorphism was significantly associated (P < 0.0001) with higher HDL-cholesterol levels in the unrelated males of this population, but not in unrelated females. No association was observed between the polymorphism and LDL particle size or triglyceride levels. Our results provide support that ALP is a multigenic trait and suggest that the relationship between small, dense LDL particles, HDL-cholesterol, and triglyceride levels in FCH families is due, in part, to common genetic factors.


Assuntos
Hiperlipidemia Familiar Combinada/enzimologia , Hiperlipidemia Familiar Combinada/genética , Lipase/genética , Lipoproteínas/sangue , Fígado/enzimologia , Adulto , HDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/enzimologia , Doença da Artéria Coronariana/genética , Feminino , Ligação Genética , Humanos , Hiperlipidemia Familiar Combinada/sangue , Masculino , Pessoa de Meia-Idade , Fenótipo
11.
Int J Obes Relat Metab Disord ; 24(11): 1381-91, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11126332

RESUMO

OBJECTIVE: To search for novel genes contributing to adiposity in familial combined hyperlipidemia (FCH), a disorder characterized by abdominal obesity, hyperlipidemia and insulin resistance, using a 10cM genome-wide scan. DESIGN: Plasma leptin and soluble tumor necrosis factor receptor superfamily members 1A and 1B (sTNFRSF1A and sTNFRSF1B, also known as sTNFR1 and sTNFR2) were analyzed as unadjusted and adjusted quantitative phenotypes of adiposity, in addition to body mass index (BMI), in multipoint and single-point analyses. In the second stage of analysis, an important chromosome 1 positional candidate gene, the leptin receptor (LEPR), was studied. SUBJECTS: Eighteen Dutch pedigrees with familial combined hyperlipidemia (FCH) (n= 198) were analyzed to search for chromosomal regions harboring genes contributing to adiposity. RESULTS: Multipoint analysis of the genome scan data identified linkage (log of odds, LOD, 3.4) of leptin levels to a chromosomal region defined by D1S3728 and D1S1665, flanking the leptin receptor (LEPR) gene by approximately 9 and 3 cM, respectively. The LOD score decreased to 1.8 with age- and gender-adjusted leptin levels. Notably, BMI also mapped to this region with an LOD score of 1.2 (adjusted BMI: LOD 0.5). Two polymorphic DNA markers in LEPR and their haplotypes revealed linkage to unadjusted and adjusted BMI and leptin, and an association with leptin levels was found as well. In addition, the marker D8S1110 showed linkage (LOD 2.8) with unadjusted plasma concentrations of soluble TNFRSF1A. BMI gave a LOD score of 0.6. Moreover, a chromosome 10 q-ter locus, AFM198ZB, showed linkage with adjusted BMI (LOD 3.3). CONCLUSION: These data provide evidence that a human chromosome 1 locus, harboring the LEPR gene, contributes to plasma leptin concentrations, adiposity and body weight in humans affected with this insulin resistant dyslipidemic syndrome. Novel loci on chromosome 8 and 10 qter need further study.


Assuntos
Antígenos CD/genética , Ligação Genética , Hiperlipidemias/genética , Resistência à Insulina/genética , Leptina/genética , Obesidade/genética , Receptores de Superfície Celular , Receptores do Fator de Necrose Tumoral/genética , Adulto , Antígenos CD/sangue , Índice de Massa Corporal , Proteínas de Transporte/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 8 , Feminino , Genoma Humano , Genótipo , Humanos , Leptina/sangue , Escore Lod , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Países Baixos , Fenótipo , Receptores para Leptina , Receptores do Fator de Necrose Tumoral/sangue , Receptores Tipo I de Fatores de Necrose Tumoral , Análise de Regressão
12.
Science ; 290(5497): 1709-11, 2000 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-11186392

RESUMO

We obtain sterols from the animal and plant food that we eat. How these plant and animal sterols are absorbed, transported around the body, and excreted has been the subject of much investigation. In a Perspective, Allayee and colleagues discuss a new study (Berge et al.) that implicates two new ABC transporter proteins in the efflux of plant and animal sterols from gut epithelial cells into the gut lumen.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Colesterol/metabolismo , Absorção Intestinal , Erros Inatos do Metabolismo Lipídico/genética , Lipoproteínas/genética , Sitosteroides/sangue , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/química , Transportadores de Cassetes de Ligação de ATP/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Transporte Biológico Ativo , Colesterol na Dieta/administração & dosagem , Colesterol na Dieta/metabolismo , Colesterol na Dieta/farmacologia , Cromossomos Humanos Par 2 , Proteínas de Ligação a DNA , Regulação da Expressão Gênica , Humanos , Mucosa Intestinal/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Lipoproteínas/química , Lipoproteínas/metabolismo , Fígado/metabolismo , Receptores X do Fígado , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Receptores Nucleares Órfãos , Receptores Citoplasmáticos e Nucleares/metabolismo , Sitosteroides/metabolismo
13.
Arterioscler Thromb Vasc Biol ; 19(11): 2730-6, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10559018

RESUMO

Familial combined hyperlipidemia (FCHL) is a common lipid disorder characterized by elevated levels of plasma cholesterol and triglycerides that is present in 10% to 20% of patients with premature coronary artery disease. To study the pathophysiological basis and genetics of FCHL, we previously reported recruitment of 18 large families. We now report linkage studies of 14 candidate genes selected for their potential involvement in the aspects of lipid and lipoprotein metabolism that are altered in FCHL. We used highly polymorphic markers linked to the candidate genes, and these markers were analyzed using several complementary, nonparametric statistical allele-sharing linkage methodologies. This current sample has been extended over the one in which we identified an association with the apolipoprotein (apo) AI-CIII-AIV gene cluster. We observed evidence for linkage of this region and FCHL (P<0.001), providing additional support for its involvement in FCHL. We also identified a new locus showing significant evidence of linkage to the disorder: the lecithin:cholesterol acyltransferase (LCAT) locus (P<0.0006) on chromosome 16. In addition, analysis of the manganese superoxide dismutase locus on chromosome 6 revealed a suggestive linkage result in this sample (P<0.006). Quantitative traits related to FCHL also provided some evidence of linkage to these regions. No evidence of linkage to the lipoprotein lipase gene, the microsomal triglyceride transfer protein gene, or several other genes involved in lipid metabolism was observed. The data suggest that the lecithin:cholesterol acyltransferase and apolipoprotein AI-CIII-AIV loci may act as modifying genes contributing to the expression of FCHL.


Assuntos
Cromossomos Humanos Par 16 , Ligação Genética , Hiperlipidemia Familiar Combinada/enzimologia , Hiperlipidemia Familiar Combinada/genética , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Adulto , Idoso , Alelos , Apolipoproteína A-I/genética , Apolipoproteína C-III , Apolipoproteínas A/genética , Apolipoproteínas C/genética , Saúde da Família , Feminino , Expressão Gênica , Marcadores Genéticos , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Núcleo Familiar , Superóxido Dismutase/genética
14.
Am J Hum Genet ; 65(2): 397-412, 1999 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10417282

RESUMO

Familial combined hyperlipidemia (FCHL) is a common familial lipid disorder characterized by a variable pattern of elevated levels of plasma cholesterol and/or triglycerides. It is present in 10%-20% of patients with premature coronary heart disease. The genetic etiology of the disease, including the number of genes involved and the magnitude of their effects, is unknown. Using a subset of 35 Dutch families ascertained for FCHL, we screened the genome, with a panel of 399 genetic markers, for chromosomal regions linked to genes contributing to FCHL. The results were analyzed by use of parametric-linkage methods in a two-stage study design. Four loci, on chromosomes 2p, 11p, 16q, and 19q, exhibited suggestive evidence for linkage with FCHL (LOD scores of 1.3-2.6). Markers within each of these regions were then examined in the original sample and in additional Dutch families with FCHL. The locus on chromosome 2 failed to show evidence for linkage, and the loci on chromosome 16q and 19q yielded only equivocal or suggestive evidence for linkage. However, one locus, near marker D11S1324 on the short arm of human chromosome 11, continued to show evidence for linkage with FCHL, in the second stage of this design. This region does not contain any strong candidate genes. These results provide evidence for a candidate chromosomal region for FCHL and support the concept that FCHL is complex and heterogeneous.


Assuntos
Cromossomos Humanos Par 11/genética , Ligação Genética , Genoma Humano , Hiperlipidemia Familiar Combinada/genética , Adulto , Feminino , Marcadores Genéticos , Genótipo , Humanos , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Dados de Sequência Molecular , Herança Multifatorial , Países Baixos , Núcleo Familiar , Linhagem , Projetos de Pesquisa , Estatísticas não Paramétricas
15.
Curr Opin Lipidol ; 10(2): 113-22, 1999 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10327279

RESUMO

Familial combined hyperlipidemia (FCHL) is a complex genetic disorder of unknown etiology. Recently, 'modifier' genes of the FCHL phenotype, such as the apolipoprotein AI-CIII-AIV gene cluster and LPL, have been identified in several populations. A 'major' gene for FCHL has been identified in a Finnish isolate which maps to a region syntenic to murine chromosome 3 where a locus for combined hyperlipidemia has been identified. We review these and other recent studies which indicate that FCHL is genetically heterogeneous.


Assuntos
Hiperlipidemia Familiar Combinada/genética , Fatores Etários , Animais , Modelos Animais de Doenças , Finlândia , Ligação Genética , Humanos , Hiperlipidemia Familiar Combinada/diagnóstico , Hiperlipidemia Familiar Combinada/enzimologia , Resistência à Insulina/genética , Camundongos , Modelos Biológicos , Fenótipo
16.
Am J Hum Genet ; 63(2): 577-85, 1998 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9683614

RESUMO

Small, dense LDL particles consistently have been associated with hypertriglyceridemia, premature coronary artery disease (CAD), and familial combined hyperlipidemia (FCH). Previously, we have observed linkage of LDL particle size with four separate candidate-gene loci in a study of families enriched for CAD. These loci contain the genes for manganese superoxide dismutase (MnSOD), on chromosome 6q; for apolipoprotein AI-CIII-AIV, on chromosome 11q; for cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT), on chromosome 16q; and for the LDL receptor (LDLR), on chromosome 19p. We have now tested whether these loci also contribute to LDL particle size in families ascertained for FCH. The members of 18 families (481 individuals) were typed for genetic markers at the four loci, and linkage to LDL particle size was assessed by nonparametric sib-pair linkage analysis. The presence of small, dense LDL (pattern B) was much more frequent in the FCH probands (39%) than in the spouse controls (4%). Evidence for linkage was observed at the MnSOD (P=.02), CETP/LCAT (P=.03), and apolipoprotein AI-CIII-AIV loci (P=.005) but not at the LDLR locus. We conclude that there is a genetically based association between FCH and small, dense LDL and that the genetic determinants for LDL particle size are shared, at least in part, among FCH families and the more general population at risk for CAD.


Assuntos
Mapeamento Cromossômico , Doença das Coronárias/genética , Glicoproteínas , Hiperlipidemia Familiar Combinada/genética , Lipoproteínas LDL/genética , Adulto , Apolipoproteína A-I/genética , Apolipoproteína C-II , Apolipoproteínas A/genética , Apolipoproteínas C/genética , Proteínas de Transporte/genética , Proteínas de Transferência de Ésteres de Colesterol , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 6 , Família , Feminino , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Fenótipo , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Receptores de LDL/genética , Superóxido Dismutase/genética , População Branca/genética
17.
J Clin Invest ; 94(2): 877-84, 1994 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8040344

RESUMO

In a previous survey of inbred mouse strains on an atherogenic diet, we observed that the susceptibility to aortic atherosclerotic lesion formation was associated with the accumulation of lipid peroxidation products, induction of inflammatory genes, and the activation of NF-kB-like transcription factors (Liao, F., A. Andalibi, F. C. deBeer, A. M. Fogelman, and A.J. Lusis. 1993. J. Clin. Invest. 91:2572-2579). We hypothesized that the inflammation-related processes were stimulated by oxidized lipids, since injection of minimally oxidized LDL (MM-LDL) activated the same set of genes. We now report that the induction of inflammatory genes and activation of NF-kB-like transcription factors cosegregate with aortic atherosclerotic lesion formation in BXH recombinant inbred strains derived from parental C57BL/6J (susceptible) and C3H/HeJ (resistant) mice. In addition, the accumulation of hepatic conjugated dienes exhibited a significant correlation with inflammatory gene activation. These results provide strong evidence for the role of inflammatory mediators inducible by oxidative stress in atherogenesis. They also suggest that a major gene contributing to aortic lesion development in this mouse model, designated Ath-1, may control either the accumulation of lipid peroxides in tissues or the cellular responses to such lipid peroxides.


Assuntos
Arteriosclerose/etiologia , Regulação da Expressão Gênica , Peroxidação de Lipídeos , NF-kappa B/metabolismo , Proteína Amiloide A Sérica/genética , Animais , Apolipoproteínas A/genética , Arteriosclerose/genética , Heme Oxigenase (Desciclizante)/genética , Lipopolissacarídeos/farmacologia , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Ativação Transcricional
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