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1.
Genet Med ; 23(8): 1514-1521, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33846581

RESUMEN

PURPOSE: Reports have questioned the dogma of exclusive maternal transmission of human mitochondrial DNA (mtDNA), including the recent report of an admixture of two mtDNA haplogroups in individuals from three multigeneration families. This was interpreted as being consistent with biparental transmission of mtDNA in an autosomal dominant-like mode. The authenticity and frequency of these findings are debated. METHODS: We retrospectively analyzed individuals with two mtDNA haplogroups from 2017 to 2019 and selected four families for further study. RESULTS: We identified this phenomenon in 104/27,388 (approximately 1/263) unrelated individuals. Further study revealed (1) a male with two mitochondrial haplogroups transmits only one haplogroup to some of his offspring, consistent with nuclear transmission; (2) the heteroplasmy level of paternally transmitted variants is highest in blood, lower in buccal, and absent in muscle or urine of the same individual, indicating it is inversely correlated with mtDNA content; and (3) paternally transmitted apparent large-scale mtDNA deletions/duplications are not associated with a disease phenotype. CONCLUSION: These findings strongly suggest that the observed mitochondrial haplogroup of paternal origin resulted from coamplification of rare, concatenated nuclear mtDNA segments with genuine mtDNA during testing. Evaluation of additional specimen types can help clarify the clinical significance of the observed results.


Asunto(s)
ADN Mitocondrial , Mitocondrias , ADN Mitocondrial/genética , Haplotipos , Humanos , Masculino , Mitocondrias/genética , Fenotipo , Estudios Retrospectivos
2.
Am J Med Genet A ; 185(5): 1366-1378, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33522091

RESUMEN

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage-sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi-faceted complications due to haploinsufficiency of BPTF.


Asunto(s)
Ensamble y Desensamble de Cromatina/genética , Epilepsia/genética , Microcefalia/genética , Trastornos del Neurodesarrollo/genética , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Adolescente , Adulto , Niño , Preescolar , Deleción Cromosómica , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Epilepsia/fisiopatología , Facies , Femenino , Haploinsuficiencia/genética , Humanos , Lactante , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Trastornos del Desarrollo del Lenguaje/genética , Trastornos del Desarrollo del Lenguaje/fisiopatología , Masculino , Microcefalia/fisiopatología , Persona de Mediana Edad , Trastornos del Neurodesarrollo/fisiopatología , Fenotipo , Factores de Transcripción/genética , Adulto Joven
3.
Am J Hum Genet ; 105(2): 302-316, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31256877

RESUMEN

Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.


Asunto(s)
ARN Helicasas DEAD-box/genética , Mutación Missense , Proteínas de Neoplasias/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/patología , ARN Helicasas/genética , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Recién Nacido , Masculino , Linaje , Secuenciación del Exoma
4.
Hum Mutat ; 40(8): 1013-1029, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31021519

RESUMEN

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.


Asunto(s)
Proteínas de Unión a la Región de Fijación a la Matriz/genética , Mutación , Trastornos del Neurodesarrollo/genética , Factores de Transcripción/genética , Adolescente , Animales , Niño , Preescolar , Codón de Terminación , Modelos Animales de Enfermedad , Femenino , Reordenamiento Génico , Estudios de Asociación Genética , Humanos , Masculino , Mutación Missense , Polimorfismo de Nucleótido Simple
5.
BioData Min ; 10: 25, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28770004

RESUMEN

BACKGROUND: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG). RESULTS: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing. CONCLUSIONS: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.

6.
J Clin Lipidol ; 10(3): 650-3, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27206954

RESUMEN

Lipoprotein-X, which is composed of phospholipids and non-esterified cholesterol, is an abnormal lipoprotein with a density range similar to LDL-C. The two most common ways which lipoprotein-X accumulates is from reflux of bile salts into plasma or deficiency in lecithin cholesterol acyltransferase. This is a case of severe hypercholesterolemia and liver disease in a 3- year old male that presented with pruritus, pale stool, scleral ictus, and abdominal distention. He was diagnosed with primary sclerosing cholangitis which was confirmed by liver biopsy. Our patient was treated with steroids and immunomodulator therapy which was associated with significant reduction in cholestasis and LDL-C levels. Lipoprotein-X has several properties that make it anti-atherogenic, which raises the question if treatment for hypercholesterolemia should be initiated.


Asunto(s)
Hipercolesterolemia/complicaciones , Hipercolesterolemia/diagnóstico , Hepatopatías/complicaciones , Preescolar , Humanos , Hipercolesterolemia/patología , Hipercolesterolemia/terapia , Masculino
7.
Circ Cardiovasc Genet ; 9(1): 71-8, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26578543

RESUMEN

BACKGROUND: Glucokinase regulatory protein (GCKR) inhibitors offer a novel treatment approach for glucose control in diabetes mellitus; however, their cardiometabolic effects, particularly in relation to increased triglycerides and C-reactive protein (CRP) levels, are of concern. GCKR Leu446Pro is a common variant associated with reduced GCKR function, increased triglycerides, and CRP. METHODS AND RESULTS: We investigated whether a 1-year intensive lifestyle intervention (ILI) for weight loss would avert the unfavorable cardiometabolic effects associated with GCKR Leu446Pro when compared with a diabetes mellitus support and education arm in overweight/obese individuals with type 2 diabetes mellitus with triglyceride (n=3214) and CRP (n=1411) data participating in a randomized lifestyle intervention study for weight loss, Action for Health in Diabetes Mellitus (Look AHEAD). Once demographics, medication use and baseline adiposity, and fitness were accounted for, ILI did not modify the baseline association of GCKR-Leu446Pro with elevated triglycerides (ß±SE=0.067±0.013, P=1.5×10(-7) and ß±SE=0.052±0.015, P=5×10(-4)) or with elevated CRP (ß±SE=0.136±0.034, P=5.1×10(-5)and ß±SE=0.903±0.038, P=0.015) in the overall sample and Non-Hispanic Whites, respectively. The lack of a protective effect from ILI at 1 year when compared with diabetes mellitus support and education (ILI versus diabetes mellitus support and education interaction for triglyceride and CRP change, respectively: P=0.64 and 0.37 in the overall sample; P=0.27 and 0.05 in Non-Hispanic Whites) persisted after additional adjustment for changes in adiposity and fitness. CONCLUSIONS: Moderate improvements in adiposity and fitness with ILI did not mitigate the adverse cardiometabolic effects of GCKR inhibition in overweight/obese individuals with diabetes mellitus.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Adiposidad/genética , Diabetes Mellitus Tipo 2/genética , Estilo de Vida , Mutación Missense , Obesidad/genética , Pérdida de Peso/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Anciano , Sustitución de Aminoácidos , Glucemia/genética , Glucemia/metabolismo , Proteína C-Reactiva/metabolismo , Diabetes Mellitus Tipo 2/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/sangre , Triglicéridos/sangre , Triglicéridos/genética
8.
J Pathol Inform ; 6: 50, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26605115

RESUMEN

BACKGROUND: Genomic medicine has the potential to improve care by tailoring treatments to the individual. There is consensus in the literature that pharmacogenomics (PGx) may be an ideal starting point for real-world implementation, due to the presence of well-characterized drug-gene interactions. Clinical Decision Support (CDS) is an ideal avenue by which to implement PGx at the bedside. Previous literature has established theoretical models for PGx CDS implementation and discussed a number of anticipated real-world challenges. However, work detailing actual PGx CDS implementation experiences has been limited. Anticipated challenges include data storage and management, system integration, physician acceptance, and more. METHODS: In this study, we analyzed the experiences of ten members of the Electronic Medical Records and Genomics (eMERGE) Network, and one affiliate, in their attempts to implement PGx CDS. We examined the resulting PGx CDS system characteristics and conducted a survey to understand the unanticipated implementation challenges sites encountered. RESULTS: Ten sites have successfully implemented at least one PGx CDS rule in the clinical setting. The majority of sites elected to create an Omic Ancillary System (OAS) to manage genetic and genomic data. All sites were able to adapt their existing CDS tools for PGx knowledge. The most common and impactful delays were not PGx-specific issues. Instead, they were general IT implementation problems, with top challenges including team coordination/communication and staffing. The challenges encountered caused a median total delay in system go-live of approximately two months. CONCLUSIONS: These results suggest that barriers to PGx CDS implementations are generally surmountable. Moreover, PGx CDS implementation may not be any more difficult than other healthcare IT projects of similar scope, as the most significant delays encountered were not unique to genomic medicine. These are encouraging results for any institution considering implementing a PGx CDS tool, and for the advancement of genomic medicine.

9.
J Pathol Inform ; 6: 46, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26430534

RESUMEN

Genomic, proteomic, epigenomic, and other "omic" data have the potential to enable precision medicine, also commonly referred to as personalized medicine. The volume and complexity of omic data are rapidly overwhelming human cognitive capacity, requiring innovative approaches to translate such data into patient care. Here, we outline a conceptual model for the application of omic data in the clinical context, called "the omic funnel." This model parallels the classic "Data, Information, Knowledge, Wisdom pyramid" and adds context for how to move between each successive layer. Its goal is to allow informaticians, researchers, and clinicians to approach the problem of translating omic data from bench to bedside, by using discrete steps with clearly defined needs. Such an approach can facilitate the development of modular and interoperable software that can bring precision medicine into widespread practice.

10.
J Cardiovasc Pharmacol ; 66(2): 183-8, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25900265

RESUMEN

Genetic variants within the BUD13-APOA5 gene region are known to be associated with high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels. Recent studies suggest that single nucleotide polymorphisms (SNPs) within this region affect HDL-C response to statin-fibrate combination therapy and low-density lipoprotein cholesterol (LDL-C) response to statin therapy. We hypothesized that SNPs within the BUD13-APOA5 region are associated with TG, HDL-C, and LDL-C response to statin therapy. We examined 1520 observations for 1086 patients from the Personalized Medicine Research Project, a large biorepository at the Marshfield Clinic Research Foundation, who had received statin therapy and been previously genotyped for polymorphisms in the 11q23 chromosomal region. A significant differential response to statin therapy was observed for 3 SNPs. The minor allele at rs11605293 significantly attenuated TG-lowering response to pravastatin (P = 0.000159), whereas the minor allele at rs12806755 was associated with a similar response to lovastatin (P = 0.000192). Genotypes at rs947990 significantly attenuated LDL-C reduction to atorvastatin therapy (P = 0.000668) with some patients with the minor allele having LDL-C increase after therapy. No SNPs within the BUD13-APOA5 region were associated with a significant effect on HDL-C reduction in response to statin therapy. In conclusion, this study suggests that common SNPs within the BUD13-APOA5 can affect TG and LDL-C response to statin therapy in a North American population.


Asunto(s)
Apolipoproteínas A/genética , LDL-Colesterol/sangre , Variación Genética/genética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Proteínas de Unión al ARN/genética , Triglicéridos/sangre , Anciano , Anciano de 80 o más Años , Apolipoproteína A-V , HDL-Colesterol/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Resultado del Tratamiento
11.
Physiol Genomics ; 47(6): 215-24, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25759378

RESUMEN

Overweight/obese individuals with Type 2 diabetes have low adiponectin levels, which may improve with lifestyle changes. We investigated whether genetic variants associated with adiponectin levels in genome-wide association studies (GWAS) would also be related with adiponectin changes in response to an intensive lifestyle intervention (ILI), potentially through mechanisms altering the adipose microenvironment via weight loss and/or improved cardiorespiratory fitness. Look AHEAD was a randomized trial comparing the cardiovascular benefits of ILI-induced weight loss and physical activity compared with diabetes support and education among overweight/obese individuals with Type 2 diabetes. In a subsample of Look AHEAD with adiponectin data and genetic consent (n=1,351), we evaluated the effects of 24 genetic variants, demonstrated by GWAS to be cross-sectionally associated with adiponectin, on adiponectin change 1-yr postintervention. We explored via mediational analyses whether any differential effects by treatment arm were occurring through weight loss and/or improved fitness. A variant, rs222857, in the CLDN7 locus, potentially associated with epithelial barrier integrity and tight junction physiology, and a putative cis expression quantitative trail locus for elongator acetyltransferase complex subunit 5 (ELP5), predicted adiponectin increases within ILI (log-adiponectin in overall sample per copy: ß±SE=0.05±0.02, P=0.008; in non-Hispanic whites: 0.06±0.02, P=0.009). The favorable effects of rs222857 (minor allele frequency 45.5%) appeared to be mediated by mechanisms associated with improved fitness, and not weight loss. This is the first study to identify a genetic variant that modifies adiponectin response to lifestyle intervention in overweight/obese diabetic individuals.


Asunto(s)
Adiponectina/genética , Claudinas/genética , Diabetes Mellitus Tipo 2/genética , Estilo de Vida , Obesidad/genética , Aptitud Física , Polimorfismo de Nucleótido Simple/genética , Adiposidad/genética , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Obesidad/complicaciones
12.
Curr Atheroscler Rep ; 17(4): 491, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25712136

RESUMEN

Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol and premature cardiovascular disease, with a prevalence of approximately 1 in 200-500 for heterozygotes in North America and Europe. Monogenic FH is largely attributed to mutations in the LDLR, APOB, and PCSK9 genes. Differential diagnosis is critical to distinguish FH from conditions with phenotypically similar presentations to ensure appropriate therapeutic management and genetic counseling. Accurate diagnosis requires careful phenotyping based on clinical and biochemical presentation, validated by genetic testing. Recent investigations to discover additional genetic loci associated with extreme hypercholesterolemia using known FH families and population studies have met with limited success. Here, we provide a brief overview of the genetic determinants, differential diagnosis, genetic testing, and counseling of FH genetics.


Asunto(s)
Hiperlipoproteinemia Tipo II/genética , Apolipoproteína B-100/genética , Enfermedad de Acumulación de Colesterol Éster/diagnóstico , Diagnóstico Diferencial , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Hipercolesterolemia/diagnóstico , Hiperlipoproteinemia Tipo II/diagnóstico , Enfermedades Intestinales/diagnóstico , Errores Innatos del Metabolismo Lipídico/diagnóstico , Fitosteroles/efectos adversos , Proproteína Convertasa 9 , Proproteína Convertasas/genética , Receptores de LDL/genética , Serina Endopeptidasas/genética , Xantomatosis Cerebrotendinosa/diagnóstico
13.
Atherosclerosis ; 234(2): 249-53, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24704626

RESUMEN

OBJECTIVE: Individuals with mixed dyslipidemia have elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), and increased risk for coronary disease. Fibrate therapy is commonly used to lower TG and increase HDL-C. Common genetic variants are known to affect the response to fibrate therapy. We sought to identify rare genetic variants (frequency ≤ 1%) in genes involved in TG and HDL-C metabolism that affect the response to fenofibric acid (FA) therapy. METHODS: Four genes with a major role in HDL-C and TG metabolism APOA1, APOC2, APOC-III and LPL were sequenced in 2385 participants with mixed dyslipidemia in a randomized, double-blind, active-controlled study comparing therapy with FA alone, in combination with statins, or statin alone. Rare variants collapsing or SKAT methods were used for the analysis. RESULTS: Synonymous rare variants in the LPL gene were significantly associated with absolute HDL-C change (P = 9 × 10(-4)) and TG percent change (P = 6.76 × 10(-4)) in those treated with FA only. Participants with these rare variants had a 2 mg/dL increase in HDL-C and 39 mg/dL decrease in TG as compared to 6.2 mg/dL increase in HDL-C and 100 mg/dL decrease in TG in those without these variants. Rare variants in the APOC-III gene were associated with a modest 3 mg/dL less reduction in APOB (P = 8.72 × 10(-4)) in those receiving FA and statin. CONCLUSION: In individuals with mixed dyslipidemia rare synonymous variants within LPL gene were associated with attenuated response to FA therapy while APOCIII rare variants were associated with a modest effect on APOB response to FA-statin therapy. These results should be replicated in a similar clinical trial for further confirmation.


Asunto(s)
HDL-Colesterol/sangre , Dislipidemias/tratamiento farmacológico , Fenofibrato/uso terapéutico , Variación Genética , Hipolipemiantes/uso terapéutico , Lipoproteína Lipasa/genética , Triglicéridos/sangre , Apolipoproteína B-100/sangre , Apolipoproteína C-III/genética , Biomarcadores/sangre , Método Doble Ciego , Quimioterapia Combinada , Dislipidemias/sangre , Dislipidemias/diagnóstico , Dislipidemias/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Farmacogenética , Fenotipo , Estudios Prospectivos , Resultado del Tratamiento
14.
PLoS One ; 9(3): e92469, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24651390

RESUMEN

Epistasis has been suggested to underlie part of the missing heritability in genome-wide association studies. In this study, we first report an analysis of gene-gene interactions affecting HDL cholesterol (HDL-C) levels in a candidate gene study of 2,091 individuals with mixed dyslipidemia from a clinical trial. Two additional studies, the Atherosclerosis Risk in Communities study (ARIC; n = 9,713) and the Multi-Ethnic Study of Atherosclerosis (MESA; n = 2,685), were considered for replication. We identified a gene-gene interaction between rs1532085 and rs12980554 (P = 7.1 × 10(-7)) in their effect on HDL-C levels, which is significant after Bonferroni correction (P(c) = 0.017) for the number of SNP pairs tested. The interaction successfully replicated in the ARIC study (P = 7.0 × 10(-4); P(c) = 0.02). Rs1532085, an expression QTL (eQTL) of LIPC, is one of the two SNPs involved in another, well-replicated gene-gene interaction underlying HDL-C levels. To further investigate the role of this eQTL SNP in gene-gene interactions affecting HDL-C, we tested in the ARIC study for interaction between this SNP and any other SNP genome-wide. We found the eQTL to be involved in a few suggestive interactions, one of which significantly replicated in MESA. Importantly, these gene-gene interactions, involving only rs1532085, explain an additional 1.4% variation of HDL-C, on top of the 0.65% explained by rs1532085 alone. LIPC plays a key role in the lipid metabolism pathway and it, and rs1532085 in particular, has been associated with HDL-C and other lipid levels. Collectively, we discovered several novel gene-gene interactions, all involving an eQTL of LIPC, thus suggesting a hub role of LIPC in the gene-gene interaction network that regulates HDL-C levels, which in turn raises the hypothesis that LIPC's contribution is largely via interactions with other lipid metabolism related genes.


Asunto(s)
HDL-Colesterol/sangre , Epistasis Genética , Estudios de Asociación Genética , Sitios de Carácter Cuantitativo , Anciano , Anciano de 80 o más Años , Aterosclerosis/epidemiología , Aterosclerosis/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Hiperlipidemias/epidemiología , Hiperlipidemias/genética , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Ensayos Clínicos Controlados Aleatorios como Asunto , Riesgo , Estados Unidos/epidemiología
15.
Am J Cardiol ; 112(9): 1287-92, 2013 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-23891427

RESUMEN

It is not known whether genetic variants in the cholesteryl ester transfer protein (CETP) gene are associated with recurrent coronary heart disease events or mortality in secondary prevention patients. Among 3,717 patients with acute coronary syndrome or coronary artery bypass grafting (CABG) enrolled in a prospective genetic registry, we evaluated whether CETP gene variants previously shown to be associated with reduced CETP activity and high-density lipoprotein cholesterol increase ("A" allele for both TaqIB [rs708272] and rs12149545) are associated with a reduction in recurrent myocardial infarction (MI), recurrent revascularization, or death. At 4.5 years of follow-up, 439 recurrent MI, 698 recurrent revascularizations, and 756 deaths occurred. Using an additive model of inheritance, the "A" allele for rs708272 was not associated with recurrent MI (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.78 to 1.17 for AG; HR 0.89, 95% CI 0.67 to 1.19 for AA; compared with GG genotype), recurrent revascularization (HR 1.13, 95% CI 0.95 to 1.33 for AG; HR 1.05, 95% CI 0.84 to 1.32 for AA), or mortality (HR 1.02, 95% CI 0.86 to 1.19 for AG; HR 1.11, 95% CI 0.91 to 1.37 for AA) in the overall cohort. Similar results were seen for the "A" allele for rs12149545. In the CABG subgroup, AG genotype for rs708272 was associated with an increased mortality (HR 1.38, 95% CI 1.06 to 1.79) compared with GG genotype. Results remained consistent using dominant model of inheritance. In conclusion, genetic CETP variants were not associated with recurrent MI or recurrent revascularization in overall cohort with a possible mortality increase in patients who underwent CABG.


Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/genética , Enfermedad de la Arteria Coronaria/genética , ADN/genética , Polimorfismo de Nucleótido Simple , Anciano de 80 o más Años , Proteínas de Transferencia de Ésteres de Colesterol/sangre , Puente de Arteria Coronaria , Enfermedad de la Arteria Coronaria/mortalidad , Enfermedad de la Arteria Coronaria/cirugía , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Masculino , Pronóstico , Estudios Prospectivos , Recurrencia , Tasa de Supervivencia/tendencias , Estados Unidos/epidemiología
16.
Circ Cardiovasc Genet ; 6(4): 391-9, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23861364

RESUMEN

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) and triglycerides are cardiovascular risk factors susceptible to lifestyle behavior modification and genetics. We hypothesized that genetic variants identified by genome-wide association studies as associated with HDL-C or triglyceride levels modify 1-year treatment response to an intensive lifestyle intervention, relative to a usual care of diabetes mellitus support and education. METHODS AND RESULTS: We evaluated 82 single-nucleotide polymorphisms, which represent 31 loci demonstrated by genome-wide association studies to be associated with HDL-C and triglycerides, in 3561 participants who consented for genetic studies and met eligibility criteria. Variants associated with higher baseline HDL-C levels, cholesterol ester transfer protein (CETP) rs3764261 and hepatic lipase (LIPC) rs8034802, were found to be associated with HDL-C increases with intensive lifestyle intervention (P=0.0038 and 0.013, respectively) and had nominally significant treatment interactions (P=0.047 and 0.046, respectively). The fatty acid desaturase-2 rs1535 variant, associated with low baseline HDL-C (P=0.017), was associated with HDL-C increases with intensive lifestyle intervention (0.0037) and had a nominal treatment interaction (P=0.035). Apolipoprotein B (rs693) and LIPC (rs8034802) single-nucleotide polymorphisms showed nominally significant associations with HDL-C and triglyceride changes with intensive lifestyle intervention and a treatment interaction (P<0.05). Phosphatidylglycerophosphate synthase-1 single-nucleotide polymorphisms (rs4082919) showed the most significant triglyceride treatment interaction in the full cohort (P=0.0009). CONCLUSIONS: This is the first study to identify genetic variants modifying lipid responses to a randomized lifestyle behavior intervention in overweight or obese individuals with diabetes mellitus. The effects of genetic factors on lipid changes may differ from the effects on baseline lipids and are modifiable by behavioral intervention.


Asunto(s)
HDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/genética , Obesidad/genética , Triglicéridos/sangre , Anciano , Apolipoproteínas B/genética , Terapia Conductista , Proteínas de Transferencia de Ésteres de Colesterol/genética , Estudios de Cohortes , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/terapia , Ácido Graso Desaturasas/genética , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Lipasa/genética , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/terapia , Polimorfismo de Nucleótido Simple , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética
17.
J Lipid Res ; 54(7): 1980-7, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23633496

RESUMEN

Individuals with mixed dyslipidemia, including high triglycerides (TGs) and low high density lipoprotein cholesterol (HDL-C), have increased risk for coronary events. We examined the effect of rare genetic variants in the APOA5 gene region on plasma HDL-C, apolipoprotein A-I (apoA-I), and TG response to fenofibric acid monotherapy and in combination with statins. The APOA5 gene region was sequenced in 1,612 individuals with mixed dyslipidemia in a randomized trial of fenofibric acid alone and in combination with statins. Student's t-test and rare variant burden tests were used to examine plasma HDL-C, apoA-I, and TG response. Rare APOA5 promoter region variants were associated with decreased HDL-C and apoA-I levels in response to fenofibric acid therapy; rare missense variants were associated with increased TG response to combination therapy. Further study is needed to examine the effect of these rare variants on coronary outcomes in this population in response to fenofibric acid monotherapy or combined with statins.


Asunto(s)
Apolipoproteínas A/genética , HDL-Colesterol/sangre , Dislipidemias/tratamiento farmacológico , Fenofibrato/análogos & derivados , Variación Genética/genética , Regiones Promotoras Genéticas/genética , Aminoácidos/farmacología , Apolipoproteína A-I/sangre , Apolipoproteína A-V , Dislipidemias/sangre , Dislipidemias/genética , Femenino , Fenofibrato/uso terapéutico , Humanos , Masculino , Triglicéridos/sangre
18.
J Clin Lipidol ; 7(1): 82-7, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23351586

RESUMEN

Tangier disease is a rare autosomal-recessive disorder caused by mutation in the ATP binding cassette transporter 1 (ABCA1) gene. Typically, Tangier disease manifests with symptoms and signs resulting from the deposition of cholesteryl esters in nonadipose tissues; chiefly, in peripheral nerves leading to neuropathy and in reticulo-endothelial organs, such as liver, spleen, lymph nodes, and tonsils, causing their enlargement and discoloration. An association with early cardiovascular disease can be variable. We describe a patient with a unique phenotype of Tangier disease from a novel splice site mutation in the ABCA1 gene that is associated with a central nervous system presentation resembling multiple sclerosis, and the presence of premature atherosclerosis.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Enfermedad de Tangier/genética , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/metabolismo , Adulto , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Colonoscopía , Sustancia Propia/metabolismo , Sustancia Propia/patología , Análisis Mutacional de ADN , Femenino , Humanos , Imagen por Resonancia Magnética , Músculo Esquelético/patología , Mutación , Linaje , Fenotipo , Enfermedad de Tangier/diagnóstico , Tomografía Computarizada por Rayos X
19.
Circ Cardiovasc Genet ; 6(1): 82-8, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23247143

RESUMEN

BACKGROUND: High levels of cardiac troponin T, measured by a highly sensitive assay (hs-cTnT), are strongly associated with incident coronary heart disease and heart failure. To date, no large-scale genome-wide association study of hs-cTnT has been reported. We sought to identify novel genetic variants that are associated with hs-cTnT levels. METHODS AND RESULTS: We performed a genome-wide association in 9491 European Americans and 2053 blacks free of coronary heart disease and heart failure from 2 prospective cohorts: the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Genome-wide association studies were conducted in each study and race stratum. Fixed-effect meta-analyses combined the results of linear regression from 2 cohorts within each race stratum and then across race strata to produce overall estimates and probability values. The meta-analysis identified a significant association at chromosome 8q13 (rs10091374; P=9.06×10(-9)) near the nuclear receptor coactivator 2 (NCOA2) gene. Overexpression of NCOA2 can be detected in myoblasts. An additional analysis using logistic regression and the clinically motivated 99th percentile cut point detected a significant association at 1q32 (rs12564445; P=4.73×10(-8)) in the gene TNNT2, which encodes the cardiac troponin T protein itself. The hs-cTnT-associated single-nucleotide polymorphisms were not associated with coronary heart disease in a large case-control study, but rs12564445 was significantly associated with incident heart failure in Atherosclerosis Risk in Communities Study European Americans (hazard ratio=1.16; P=0.004). CONCLUSIONS: We identified 2 loci, near NCOA2 and in the TNNT2 gene, at which variation was significantly associated with hs-cTnT levels. Further use of the new assay should enable replication of these results.


Asunto(s)
Aterosclerosis/sangre , Aterosclerosis/genética , Población Negra/genética , Estudio de Asociación del Genoma Completo , Troponina T/sangre , Población Blanca/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Coactivador 2 del Receptor Nuclear/genética , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Características de la Residencia , Factores de Riesgo , Troponina T/genética
20.
J Lipid Res ; 53(11): 2425-8, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22896670

RESUMEN

The mixed dyslipidemia phenotype is characterized by elevated triglycerides (TG), low HDL cholesterol (HDL-C), increased ApoB levels, and premature coronary atherosclerosis. Fibrate-statin combination therapy reduces ApoB levels and coronary events in the mixed dyslipidemia population. We sought to identify gene-gene interactions that affect ApoB response to statin-fenofibric acid therapy in the mixed dyslipidemia population. Using a predefined subset of single-nucleotide polymorphisms (SNPs) that were previously associated with TG, VLDL, or HDL-C, we applied gene-gene interaction testing in a randomized, double-blind, clinical trial examining the response to fenofibric acid (FNA) and its combination with statin in 1,865 individuals with mixed dyslipidemia. Of 11,783 possible SNP pairs examined, we detected a single significant interaction between rs12130333, located within the ANGPTL3 gene region, and rs4240705, within the RXRA gene, on ApoB reduction after statin-FNA therapy (P = 4.0 × 10(-6)). ApoB response to therapy gradually reduced with the increasing number of T alleles in the rs12130333 but only in the presence of the GG genotype of rs4240705. Individuals doubly homozygous for the minor alleles at rs12130333 and rs4240705 showed a paradoxical increase of 1.8% in ApoB levels after FNA-statin combination therapy. No gene-gene interaction was identified other than an interaction between SNPs in the ANGPTL3 and RXRA regions, which results in the inhibition of ApoB reduction in response to statin-FNA therapy. Further study is required to examine the clinical applicability of this genetic interaction and its effect on coronary events.


Asunto(s)
Angiopoyetinas/genética , Apolipoproteínas B/metabolismo , Apolipoproteínas/metabolismo , Dislipidemias/tratamiento farmacológico , Dislipidemias/genética , Fenofibrato/análogos & derivados , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Polimorfismo de Nucleótido Simple/genética , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina , Atorvastatina , Femenino , Fenofibrato/administración & dosificación , Fenofibrato/uso terapéutico , Fluorobencenos/uso terapéutico , Ácidos Heptanoicos/uso terapéutico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Masculino , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Rosuvastatina Cálcica , Simvastatina/uso terapéutico , Sulfonamidas/uso terapéutico
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