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1.
J Lipid Res ; 63(6): 100209, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35460704

RESUMEN

Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels is high. In this research discovery study, we used whole-exome sequencing to identify damaging gene variants that may play significant roles in determining HDL-C levels. We studied 204 individuals with a mean HDL-C level of 27.8 ± 6.4 mg/dl (range: 4-36 mg/dl). Data were analyzed by statistical gene burden testing and by filtering against candidate gene lists. We found 120 occurrences of probably damaging variants (116 heterozygous; four homozygous) among 45 of 104 recognized HDL candidate genes. Those with the highest prevalence of damaging variants were ABCA1 (n = 20), STAB1 (n = 9), OSBPL1A (n = 8), CPS1 (n = 8), CD36 (n = 7), LRP1 (n = 6), ABCA8 (n = 6), GOT2 (n = 5), AMPD3 (n = 5), WWOX (n = 4), and IRS1 (n = 4). Binomial analysis for damaging missense or loss-of-function variants identified the ABCA1 and LDLR genes at genome-wide significance. In conclusion, whole-exome sequencing of individuals with low HDL-C showed the burden of damaging rare variants in the ABCA1 and LDLR genes is particularly high and revealed numerous occurrences in HDL candidate genes, including many genes identified in genome-wide association study reports. Many of these genes are involved in cancer biology, which accords with epidemiologic findings of the association of HDL deficiency with increased risk of cancer, thus presenting a new area of interest in HDL genomics.


Asunto(s)
Estudio de Asociación del Genoma Completo , Hipoalfalipoproteinemias , HDL-Colesterol/genética , Heterocigoto , Humanos , Secuenciación del Exoma
2.
Arterioscler Thromb Vasc Biol ; 40(8): 1935-1941, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32580631

RESUMEN

OBJECTIVE: Genetic determinants of severe hypertriglyceridemia include both common variants with small effects (assessed using polygenic risk scores) plus heterozygous and homozygous rare variants in canonical genes directly affecting triglyceride metabolism. Here, we broadened our scope to detect associations with rare loss-of-function variants in genes affecting noncanonical pathways, including those known to affect triglyceride metabolism indirectly. Approach and Results: From targeted next-generation sequencing of 69 metabolism-related genes in 265 patients of European descent with severe hypertriglyceridemia (≥10 mmol/L or ≥885 mg/dL) and 477 normolipidemic controls, we focused on the association of rare heterozygous loss-of-function variants in individual genes. We observed that compared with controls, severe hypertriglyceridemia patients were 20.2× (95% CI, 1.11-366.1; P=0.03) more likely than controls to carry a rare loss-of-function variant in CREB3L3, which encodes a transcription factor that regulates several target genes with roles in triglyceride metabolism. CONCLUSIONS: Our findings indicate that rare variants in a noncanonical gene for triglyceride metabolism, namely CREB3L3, contribute significantly to severe hypertriglyceridemia. Secondary genes and pathways should be considered when evaluating the genetic architecture of this complex trait.


Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Hipertrigliceridemia/genética , Adulto , Anciano , Apolipoproteína A-V/genética , Femenino , Heterocigoto , Humanos , Lipoproteína Lipasa/genética , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Triglicéridos/metabolismo
3.
J Lipid Res ; 61(3): 455-463, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31888979

RESUMEN

Elevated levels of triglyceride-rich lipoproteins (TRLs), both fasting and postprandial, are associated with increased risk for atherosclerosis. However, guidelines for treatment are defined solely by fasting lipid levels, even though postprandial lipids may be more informative. In the postprandial state, circulating lipids consist of dietary fat transported from the intestine in chylomicrons (CMs; containing ApoB48) and fat transported from the liver in VLDL (containing ApoB100). Research into the roles of endogenous versus dietary fat has been hindered because of the difficulty in separating these particles by ultracentrifugation. CM fractions have considerable contamination from VLDL (purity, 10%). To separate CMs from VLDL, we produced polyclonal antibodies against ApoB100 and generated immunoaffinity columns. TRLs isolated by ultracentrifugation of plasma were applied to these columns, and highly purified CMs were collected (purity, 90-94%). Overall eight healthy unmedicated adult volunteers (BMI, 27.2 ± 1.4 kg/m2; fasting triacylglycerol, 102.6 ± 19.5 mg/dl) participated in a feeding study, which contained an oral stable-isotope tracer (1-13C acetate). We then used this technique on plasma samples freshly collected during an 8 h human feeding study from a subset of four subjects. We analyzed fractionated lipoproteins by Western blot, isolated and derivatized triacylglycerols, and calculated fractional de novo lipogenesis. The results demonstrated effective separation of postprandial lipoproteins and substantially improved purity compared with ultracentrifugation protocols, using the immunoaffinity method. This method can be used to better delineate the role of dietary sugar and fat on postprandial lipids in cardiovascular risk and explore the potential role of CM remnants in atherosclerosis.


Asunto(s)
Apolipoproteína B-100/química , Quilomicrones/aislamiento & purificación , Lipoproteínas/aislamiento & purificación , Triglicéridos/aislamiento & purificación , Cromatografía de Afinidad , Quilomicrones/química , Femenino , Voluntarios Sanos , Humanos , Inmunoprecipitación , Lipoproteínas/química , Masculino , Periodo Posprandial , Triglicéridos/química
4.
N Engl J Med ; 376(17): 1647-1658, 2017 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-28402248

RESUMEN

BACKGROUND: A protein that is expressed on capillary endothelial cells, called GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1), binds lipoprotein lipase and shuttles it to its site of action in the capillary lumen. A deficiency in GPIHBP1 prevents lipoprotein lipase from reaching the capillary lumen. Patients with GPIHBP1 deficiency have low plasma levels of lipoprotein lipase, impaired intravascular hydrolysis of triglycerides, and severe hypertriglyceridemia (chylomicronemia). During the characterization of a monoclonal antibody-based immunoassay for GPIHBP1, we encountered two plasma samples (both from patients with chylomicronemia) that contained an interfering substance that made it impossible to measure GPIHBP1. That finding raised the possibility that those samples might contain GPIHBP1 autoantibodies. METHODS: Using a combination of immunoassays, Western blot analyses, and immunocytochemical studies, we tested the two plasma samples (as well as samples from other patients with chylomicronemia) for the presence of GPIHBP1 autoantibodies. We also tested the ability of GPIHBP1 autoantibodies to block the binding of lipoprotein lipase to GPIHBP1. RESULTS: We identified GPIHBP1 autoantibodies in six patients with chylomicronemia and found that these autoantibodies blocked the binding of lipoprotein lipase to GPIHBP1. As in patients with GPIHBP1 deficiency, those with GPIHBP1 autoantibodies had low plasma levels of lipoprotein lipase. Three of the six patients had systemic lupus erythematosus. One of these patients who had GPIHBP1 autoantibodies delivered a baby with plasma containing maternal GPIHBP1 autoantibodies; the infant had severe but transient chylomicronemia. Two of the patients with chylomicronemia and GPIHBP1 autoantibodies had a response to treatment with immunosuppressive agents. CONCLUSIONS: In six patients with chylomicronemia, GPIHBP1 autoantibodies blocked the ability of GPIHBP1 to bind and transport lipoprotein lipase, thereby interfering with lipoprotein lipase-mediated processing of triglyceride-rich lipoproteins and causing severe hypertriglyceridemia. (Funded by the National Heart, Lung, and Blood Institute and the Leducq Foundation.).


Asunto(s)
Autoanticuerpos/sangre , Hiperlipoproteinemia Tipo I/inmunología , Lipoproteína Lipasa/metabolismo , Receptores de Lipoproteína/inmunología , Adulto , Autoanticuerpos/fisiología , Femenino , Humanos , Hiperlipoproteinemia Tipo I/sangre , Inmunoensayo , Lipólisis , Lipoproteína Lipasa/sangre , Masculino , Persona de Mediana Edad , Unión Proteica , Transporte de Proteínas , Receptores de Lipoproteína/metabolismo
5.
J Lipid Res ; 60(11): 1953-1958, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31519763

RESUMEN

Severe hypertriglyceridemia (HTG) is a relatively common form of dyslipidemia with a complex pathophysiology and serious health complications. HTG can develop in the presence of rare genetic factors disrupting genes involved in the triglyceride (TG) metabolic pathway, including large-scale copy-number variants (CNVs). Improvements in next-generation sequencing technologies and bioinformatic analyses have better allowed assessment of CNVs as possible causes of or contributors to severe HTG. We screened targeted sequencing data of 632 patients with severe HTG and identified partial deletions of the LPL gene, encoding the central enzyme involved in the metabolism of TG-rich lipoproteins, in four individuals (0.63%). We confirmed the genomic breakpoints in each patient with Sanger sequencing. Three patients carried an identical heterozygous deletion spanning the 5' untranslated region (UTR) to LPL exon 2, and one patient carried a heterozygous deletion spanning the 5'UTR to LPL exon 1. All four heterozygous CNV carriers were determined to have multifactorial severe HTG. The predicted null nature of our identified LPL deletions may contribute to relatively higher TG levels and a more severe clinical phenotype than other forms of genetic variation associated with the disease, particularly in the polygenic state. The identification of novel CNVs in patients with severe HTG suggests that methods for CNV detection should be included in the diagnostic workup and molecular genetic evaluation of patients with high TG levels.


Asunto(s)
Variaciones en el Número de Copia de ADN , Eliminación de Gen , Hipertrigliceridemia/genética , Lipoproteína Lipasa/genética , Biología Computacional , Análisis Mutacional de ADN , Exones , Humanos , Hipertrigliceridemia/metabolismo , Lipoproteína Lipasa/deficiencia , Lipoproteína Lipasa/metabolismo
6.
Eur J Clin Invest ; 46(7): 643-50, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27208892

RESUMEN

BACKGROUND: Coronary heart disease (CHD) risk inversely associates with levels of high-density lipoprotein cholesterol (HDL-C). The protective effect of HDL is thought to depend on its functionality, such as its ability to induce cholesterol efflux. MATERIALS AND METHODS: We compared plasma cholesterol efflux capacity between male familial hypercholesterolaemia (FH) patients with and without CHD relative to their non-FH brothers, and examined HDL constituents including sphingosine-1-phosphate (S1P) and its carrier apolipoprotein M (apoM). RESULTS: Seven FH patients were asymptomatic and six had experienced a cardiac event at a mean age of 39 years. Compared to their non-FH brothers, cholesterol efflux from macrophages to plasma from the FH patients without CHD was 16 ± 22% (mean ± SD) higher and to plasma from the FH patients with CHD was 7 ± 8% lower (P = 0·03, CHD vs. non-CHD). Compared to their non-FH brothers, FH patients without CHD displayed significantly higher levels of HDL-cholesterol, HDL-S1P and apoM, while FH patients with CHD displayed lower levels than their non-FH brothers. CONCLUSIONS: A higher plasma cholesterol efflux capacity and higher S1P and apoM content of HDL in asymptomatic FH patients may play a role in their apparent protection from premature CHD.


Asunto(s)
Apolipoproteínas/metabolismo , HDL-Colesterol/metabolismo , Colesterol/metabolismo , Enfermedad Coronaria/metabolismo , Hiperlipoproteinemia Tipo II/metabolismo , Lipocalinas/metabolismo , Lisofosfolípidos/metabolismo , Macrófagos/metabolismo , Esfingosina/análogos & derivados , Adulto , Anciano , Apolipoproteína A-I/metabolismo , Apolipoproteína A-II/metabolismo , Apolipoproteínas M , Estudios de Casos y Controles , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Plasma/metabolismo , Factores Protectores , Hermanos , Esfingosina/metabolismo , Triglicéridos/metabolismo , Adulto Joven
7.
Am J Hum Genet ; 90(5): 796-808, 2012 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-22521419

RESUMEN

Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding a nuclear factor of kappa light chain enhancer in B cells (NF-kB) activator within skin epidermis, account for PSORS2. Here, we describe fifteen additional rare missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There were more CARD14 rare variants in cases than in controls (burden test p value = 0.0015). Some variants were only seen in a single case, and these included putative pathogenic mutations (c.424G>A [p.Glu142Lys] and c.425A>G [p.Glu142Gly]) and the generalized-pustular-psoriasis mutation, c.413A>C (p.Glu138Ala); these three mutations lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial-psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities; in particular, putative pathogenic variants led to levels >2.5× higher than did wild-type CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with tumor necrosis factor alpha (TNF-α) to achieve significant increases in NF-kB levels. Transcriptome profiling of wild-type and variant CARD14 transfectants in keratinocytes differentiated probably pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped, and meta-analysis revealed an association between psoriasis and rs11652075 (c.2458C>T [p.Arg820Trp]; p value = 2.1 × 10(-6)). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw*0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease.


Asunto(s)
Proteínas Adaptadoras de Señalización CARD/genética , Guanilato Ciclasa/genética , Proteínas de la Membrana/genética , FN-kappa B/genética , FN-kappa B/metabolismo , Psoriasis/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , Estudios de Casos y Controles , Epidermis/metabolismo , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Guanilato Ciclasa/metabolismo , Antígenos HLA-C/genética , Antígenos HLA-C/metabolismo , Humanos , Queratinocitos , Proteínas de la Membrana/metabolismo , Mutación Missense , Polimorfismo Genético , Piel/patología , Transcriptoma , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Población Blanca/genética
8.
Brain Behav Immun ; 47: 58-65, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25535857

RESUMEN

Sleep disturbance has been associated with inflammation and cytokine activity, and we previously described genetic associations between cytokine polymorphisms and sleep maintenance and duration among adults with HIV/AIDS. Although sleep onset insomnia (SOI) is also a commonly reported sleep problem, associations between cytokine biomarkers and SOI have not been adequately studied. The purpose of this study was to describe SOI in relation to cytokine plasma concentrations and gene polymorphisms in a convenience sample of 307 adults (212 men, 72 women, and 23 transgender) living with HIV/AIDS. Based on the Pittsburgh Sleep Quality Index item that asks the time it usually took to fall asleep in the past month, participants were categorized as either >30min to fall asleep (n=70, 23%) or 30min or less to fall asleep (n=237). Plasma cytokines were analyzed, and genotyping was conducted for 15 candidate genes involved in cytokine signaling: interferon-gamma (IFNG), IFNG receptor 1 (IFNGR1), interleukins (IL1R2, IL2, IL4, IL6, IL8, IL10, IL13, IL17A), nuclear factor of kappa light polypeptide gene enhancer in B cells (NFKB1 and NFKB2), and tumor necrosis factor alpha (TNFA). Demographic and clinical variables were evaluated as potential covariates. After adjusting for genomic estimates of ancestry, self-reported race/ethnicity and viral load, SOI was associated with higher IL-13 plasma levels and with six single nucleotide polymorphisms (SNPs): IL1B rs1143642 and rs1143623, IL6 rs4719714, IL13 rs1295686, NFKB1 rs4648110, and TNFA rs2857602. In addition, the IL1B rs1143642 polymorphism was associated with plasma levels of IL-1ß in adjusted analyses. This study strengthens the evidence for an association between inflammation and sleep disturbance, particularly self-report of habitual SOI. In this chronic illness population, the cytokine polymorphisms associated with SOI provide direction for future personalized medicine intervention research.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Citocinas/sangre , Citocinas/genética , Infecciones por VIH/complicaciones , Polimorfismo de Nucleótido Simple , Trastornos del Inicio y del Mantenimiento del Sueño/genética , Adulto , Anciano , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Sueño/genética , Trastornos del Inicio y del Mantenimiento del Sueño/sangre , Trastornos del Inicio y del Mantenimiento del Sueño/complicaciones , Adulto Joven
9.
Arterioscler Thromb Vasc Biol ; 34(10): 2254-60, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25127531

RESUMEN

OBJECTIVE: Apolipoprotein A-V (apoA-V) is a low-abundance plasma protein that modulates triacylglycerol homeostasis. Gene transfer studies were undertaken in apoa5 (-/-) mice to define the mechanism underlying the correlation between the single-nucleotide polymorphism c.553G>T in APOA5 and hypertriglyceridemia. APPROACH AND RESULTS: Adeno-associated virus (AAV) 2/8-mediated gene transfer of wild-type apoA-V induced a dramatic lowering of plasma triacylglycerol in apoa5 (-/-) mice, whereas AAV2/8-Gly162Cys apoA-V (corresponding to the c.553G>T single-nucleotide polymorphism: rs2075291; p.Gly185Cys when numbering includes signal sequence) had a modest effect. Characterization studies revealed that plasma levels of wild-type and G162C apoA-V in transduced mice were similar and within the physiological range. Fractionation of plasma from mice transduced with AAV2/8-G162C apoA-V indicated that, unlike wild-type apoA-V, >50% of G162C apoA-V was recovered in the lipoprotein-free fraction. Nonreducing SDS-PAGE immunoblot analysis provided evidence that G162C apoA-V present in the lipoprotein-free fraction, but not that portion associated with lipoproteins, displayed altered electrophoretic mobility consistent with disulfide-linked heterodimer formation. Immunoprecipitation followed by liquid chromatography/mass spectrometry of human plasma from subjects homozygous for wild-type APOA5 and c.553G>T APOA5 revealed that G162C apoA-V forms adducts with extraneous plasma proteins including fibronectin, kininogen-1, and others. CONCLUSIONS: Substitution of Cys for Gly at position 162 of mature apoA-V introduces a free cysteine that forms disulfide bonds with plasma proteins such that its lipoprotein-binding and triacylglycerol-modulation functions are compromised.


Asunto(s)
Apolipoproteínas A/metabolismo , Disulfuros/metabolismo , Hipertrigliceridemia/metabolismo , Animales , Apolipoproteína A-V , Apolipoproteínas/deficiencia , Apolipoproteínas/genética , Apolipoproteínas A/genética , Biomarcadores/sangre , Estudios de Casos y Controles , Dependovirus , Modelos Animales de Enfermedad , Técnicas de Transferencia de Gen , Vectores Genéticos , Células HEK293 , Humanos , Hipertrigliceridemia/sangre , Hipertrigliceridemia/genética , Masculino , Ratones , Ratones Noqueados , Polimorfismo de Nucleótido Simple , Unión Proteica , Transducción Genética , Transfección , Triglicéridos/sangre
10.
J Cardiovasc Electrophysiol ; 25(3): 271-277, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24237655

RESUMEN

BACKGROUND: The prediction of atrial fibrillation (AF) following catheter ablation of atrial flutter (Afl) would be helpful to facilitate targeted arrhythmia monitoring and anti-coagulation strategies. A single nucleotide polymorphism, rs2200733, is strongly associated with AF. We sought to characterize the association between rs2200733 and prevalent Afl and to determine if the variant could predict AF after cavotricuspid isthmus ablation. METHODS AND RESULTS: We performed a genetic association study of 295 patients with Afl and/or AF and 469 controls using multivariable logistic regression. The variant was then assessed as a predictor of incident AF after cavotricuspid isthmus ablation in 87 consecutive typical Afl patients with Cox proportional hazards models. The rs2200733 rare allele was associated with an adjusted 2.06-fold increased odds of isolated Afl (95% CI: 1.13-3.76, P = 0.019) and an adjusted 2.79-fold increased odds of a combined phenotype of AF and Afl (95% CI: 1.81-4.28, P < 0.001). Following catheter ablation for Afl, carrier status of rs2200733 failed to predict an increased risk of AF either among all subjects (adjusted HR: 0.94; 95% CI: 0.58-1.53, P = 0.806) or among those with isolated Afl (adjusted HR: 1.29; 95% CI: 0.51-3.26, P = 0.585). CONCLUSIONS: Our study demonstrates that Afl, whether occurring in isolation or along with AF, is associated with the rs2200733 AF risk allele. Genetic carrier status of rs2200733 failed to predict an increased risk of incident or recurrent AF following catheter ablation for Afl. These findings suggest that the causal mechanism associated with rs2200733 is germane to both AF and Afl.


Asunto(s)
Fibrilación Atrial/genética , Aleteo Atrial/genética , Ablación por Catéter/efectos adversos , Cromosomas Humanos Par 4/genética , Variación Genética/genética , Válvula Tricúspide , Adulto , Anciano , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/etiología , Aleteo Atrial/diagnóstico , Aleteo Atrial/cirugía , Femenino , Estudios de Seguimiento , Estudios de Asociación Genética/métodos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Resultado del Tratamiento , Válvula Tricúspide/cirugía
11.
Brain Behav Immun ; 40: 95-103, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24632226

RESUMEN

Fatigue has been associated with inflammation and cytokine activity among adults, but this relationship has not been evaluated among adults living with HIV. Diurnal patterns of fatigue have been previously identified in adults with HIV/AIDS. Thus, the purpose of this study was to describe these fatigue patterns in relation to cytokine plasma concentrations and gene polymorphisms. A convenience sample of 317 adults living with HIV/AIDS completed a measure of fatigue in the morning and evening for three consecutive days; participants reporting low levels of both morning and evening fatigue (n=110) or high levels of fatigue in the morning and evening (n=114) were included in the analysis, resulting in a final sample of 224 adults (151 men, 55 women, and 18 transgender). Plasma cytokines were analyzed, and genotyping was conducted for 15 candidate genes involved in cytokine signaling: interferon-gamma (IFNG), IFNG receptor 1 (IFNGR1), interleukins (IL), nuclear factor of kappa light polypeptide gene enhancer in B cells (NFKB-1 and -2), and tumor necrosis factor alpha (TNFA). Demographic and clinical variables were evaluated as potential covariates. Controlling for genomic estimates of ancestry and self-reported race/ethnicity and gender, the high fatigue pattern was associated with five single nucleotide polymorphisms (SNPs): IL1B rs1071676 and rs1143627, IL4 rs2243274, and TNFA rs1800683 and rs1041981. The IL1B and TNFA polymorphisms were not associated with plasma levels of IL-1ß or TNFα, respectively. This study strengthens the evidence for an association between inflammation and fatigue. In this chronic illness population, the cytokine polymorphisms associated with high levels of morning and evening fatigue provide direction for future personalized medicine intervention research.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Citocinas/genética , Fatiga/genética , Infecciones por VIH/complicaciones , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Citocinas/sangre , Fatiga/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
12.
Circ Genom Precis Med ; 17(3): e004320, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38804128

RESUMEN

BACKGROUND: Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT). METHODS: We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies. RESULTS: Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicate NKX2-5 and TTN as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of NKX2-5 and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate SCN5A, SCN10A, and TTN/CCDC141. Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals. CONCLUSIONS: Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility.


Asunto(s)
Estudio de Asociación del Genoma Completo , Taquicardia Supraventricular , Humanos , Taquicardia Supraventricular/genética , Predisposición Genética a la Enfermedad , Taquicardia por Reentrada en el Nodo Atrioventricular/genética , Polimorfismo de Nucleótido Simple , Conectina/genética , Transcriptoma
14.
J Am Heart Assoc ; 12(24): e030796, 2023 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-38084718

RESUMEN

BACKGROUND: African American smokers have 2.5 times higher risk for stroke compared with nonsmokers (higher than other races). About 50% of the African American population carry 1 or 2 genetic variants (G1 and G2; rare in other races) of the apolipoprotein L1 gene (APOL1). Studies showed these variants may be associated with stroke. However, the role of the APOL1 risk variants in tobacco-related stroke is unknown. METHODS AND RESULTS: In a cross-sectional study, we examined whether APOL1 risk variants modified the relationship between tobacco smoking and stroke prevalence in 513 African American adults recruited at University of California, San Francisco. Using DNA, plasma, and questionnaires we determined APOL1 variants, smoking status, and stroke prevalence. Using logistic regression models, we examined the association between smoking (ever versus never smokers) and stroke overall, and among carriers of APOL1 risk variants (1 or 2 risk alleles), and noncarriers, separately. Among participants, 41% were ever (current and past) smokers, 54% were carriers of the APOL1 risk variants, and 41 had a history of stroke. The association between smoking and stroke differed by APOL1 genotype (Pinteraction term=0.014). Among carriers, ever versus never smokers had odds ratio (OR) 2.46 (95% CI, 1.08-5.59) for stroke (P=0.034); OR 2.00 (95% CI, 0.81-4.96) among carriers of 1 risk allele, and OR 4.72 (95% CI, 0.62-36.02) for 2 risk alleles. Among noncarriers, smoking was not associated with a stroke. CONCLUSIONS: Current and past smokers who carry APOL1 G1 and/or G2 risk variants may be more susceptible to stroke among the African American population.


Asunto(s)
Predisposición Genética a la Enfermedad , Accidente Cerebrovascular , Adulto , Humanos , Apolipoproteína L1/genética , Fumadores , Negro o Afroamericano/genética , Estudios Transversales , Prevalencia , Genotipo , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/genética , Factores de Riesgo , Apolipoproteínas
15.
medRxiv ; 2023 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-37162992

RESUMEN

Introduction: Among African Americans, tobacco smokers have 2.5 times higher risk for stroke compared to non-smokers; the tobacco-related stroke risk being higher than in other races/ethnicities. About one half of African Americans carry at least one of two genetic variants (G1 and G2; rare in other races) of apolipoprotein L1 (apoL1), a component of high-density lipoproteins. Several studies showed APOL1 G1/G2 risk variants associate with stroke. However, the role of APOL1 variants in tobacco-related stroke is unknown. Methods: In a cross-sectional study, we examined whether APOL1 risk variants modify the relationship between smoking and stroke in 513 African American adults (median age 58 years, 52% female) recruited through the University of California, San Francisco Lipid Clinic. Using DNA, plasma, and questionnaires we determined APOL1 variants, smoking status, and history of stroke. Using unstratified and stratified multivariable logistic regression models we examined the association between smoking history (ever smokers vs. never smokers) and odds of stroke overall, and among carriers of risk variants and non-carriers, separately. Results: Among participants, 41% were ever (current and past) smokers, 54% were carriers of the APOL1 risk variant, and 41 have had stroke. In all stroke cases, where full medical records were available, stroke types were determined to be an ischemic, and not hemorrhagic, stroke. The association of smoking history and stroke differed by APOL1 genotype status in the unstratified model (Pinteraction term=0.016). Among carriers of risk variants, ever smokers had odds ratio (OR) =2.88 for stroke compared to never smokers (P=0. 0.038). The OR for stroke comparing ever vs. never smokers showed a dose-response trend among carriers of one risk allele of 2.35 and two risk alleles of 4.96. Among non-carriers, smoking history was not associated with a stroke. Conclusion: In conclusion, current and past smokers who carry APOL1 G1 and/or G2 risk variants may be more susceptible to stroke, in particular ischemic stroke, among African Americans.

16.
J Biol Chem ; 286(22): 19735-43, 2011 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-21478160

RESUMEN

Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) is an endothelial cell protein that transports lipoprotein lipase (LPL) from the subendothelial spaces to the capillary lumen. GPIHBP1 contains two main structural motifs, an amino-terminal acidic domain enriched in aspartates and glutamates and a lymphocyte antigen 6 (Ly6) motif containing 10 cysteines. All of the cysteines in the Ly6 domain are disulfide-bonded, causing the protein to assume a three-fingered structure. The acidic domain of GPIHBP1 is known to be important for LPL binding, but the involvement of the Ly6 domain in LPL binding requires further study. To assess the importance of the Ly6 domain, we created a series of GPIHBP1 mutants in which each residue of the Ly6 domain was changed to alanine. The mutant proteins were expressed in Chinese hamster ovary (CHO) cells, and their expression level on the cell surface and their ability to bind LPL were assessed with an immunofluorescence microscopy assay and a Western blot assay. We identified 12 amino acids within GPIHBP1, aside from the conserved cysteines, that are important for LPL binding; nine of those were clustered in finger 2 of the GPIHBP1 three-fingered motif. The defective GPIHBP1 proteins also lacked the ability to transport LPL from the basolateral to the apical surface of endothelial cells. Our studies demonstrate that the Ly6 domain of GPIHBP1 is important for the ability of GPIHBP1 to bind and transport LPL.


Asunto(s)
Proteínas Portadoras/metabolismo , Células Endoteliales/metabolismo , Lipoproteína Lipasa/metabolismo , Sustitución de Aminoácidos , Animales , Células CHO , Proteínas Portadoras/genética , Cricetinae , Cricetulus , Humanos , Lipoproteína Lipasa/genética , Mutación Missense , Mapeo Peptídico/métodos , Estructura Terciaria de Proteína , Transporte de Proteínas/fisiología , Receptores de Lipoproteína
17.
Cerebrovasc Dis ; 33(1): 80-5, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22134093

RESUMEN

BACKGROUND: Gene variants associated with disease could reveal novel mechanisms. We searched for single nucleotide polymorphisms (SNPs) associated with noncardioembolic stroke (nonCES). METHODS: We tested 24,926 SNPs in or near genes for association with nonCES in the Vienna Study (551 cases, 815 controls) and then evaluated the associated SNPs in the UCSF-CC Study (570 cases, 1,604 controls) first in pooled DNA samples and then in individual DNA samples. We then asked whether the risk alleles of the SNPs associated with increased risk in both studies were also associated with increased risk of nonCES in the German Study (728 cases, 1,041 controls). RESULTS: Six of the 46 SNPs that were associated with nonCES in both the Vienna and the UCSF-CC Studies were also associated with nonCES in the German Study: rs362277 in HTT (OR 1.39, 90% CI 1.12-1.71), rs2924914 near CSMD1 (OR 1.22, 90% CI 1.04-1.43), rs1264352 near DDR1 (OR 1.20, 90% CI 1.02-1.41), rs544115 in NEU3 (OR 1.63, 90% CI 1.02-2.62), rs12481805 in UMODL1 (OR 1.31, 90% CI 1.01-1.81), and rs2857595 near NCR3 (OR 1.15, 90% CI 1.00-1.32). Accounting for multiple testing of 46 SNPs, these 6 SNPs had a false discovery rate of 0.69. CONCLUSIONS: Some of the 6 SNPs may be associated with nonCES but most may be false positives. These 6 SNPs merit investigation in additional nonCES study populations.


Asunto(s)
Polimorfismo de Nucleótido Simple , Accidente Cerebrovascular/genética , Anciano , Anciano de 80 o más Años , Austria , Proteínas de Unión al Calcio/genética , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Receptor con Dominio Discoidina 1 , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Alemania , Humanos , Modelos Logísticos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Receptor 3 Gatillante de la Citotoxidad Natural/genética , Neuraminidasa/genética , Oportunidad Relativa , Ohio , Proteínas Tirosina Quinasas Receptoras/genética , Medición de Riesgo , Factores de Riesgo , San Francisco , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Proteínas Supresoras de Tumor
18.
Pediatr Blood Cancer ; 59(1): 52-6, 2012 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-21793187

RESUMEN

BACKGROUND: Ewing sarcoma is a malignant bone tumor characterized by a high frequency of somatic EWSR1 translocations. Ewing sarcoma is less common in people of African or African-American ancestry, suggesting a genetic etiology. PROCEDURE: Germline DNA from white patients with Ewing sarcoma (n = 135), white controls with Wilms tumor (n = 200), and African-American controls (n = 285) was genotyped at 21 SNPs in the EWSR1 gene. Intron 7 of EWSR1, the most common site of translocation, was also sequenced in all subjects. Genetic variation between groups was evaluated statistically using exact logistic regression and Fisher exact tests. RESULTS: One SNP in EWSR1 (rs2857461) showed a low level of statistical association with the diagnosis of Ewing sarcoma compared to Wilms tumor. The odds ratio for having Ewing sarcoma in people with at least one copy of the minor allele of rs2857461 was 3.57 (95% confidence interval 0.79-21.7; P = 0.07). No other SNPs or variations in intron 7 of EWSR1 were associated with Ewing sarcoma. The median relative difference in minor allele frequencies between white subjects with Ewing sarcoma and African-American controls at the evaluated EWSR1 SNPs was 45%. CONCLUSIONS: Variations in EWSR1 at known SNPs or across intron 7 are not associated with the diagnosis of Ewing sarcoma. EWSR1 does not appear to be an Ewing sarcoma susceptibility gene. The genetic basis for this disease remains unknown.


Asunto(s)
Alelos , Neoplasias Óseas/genética , Proteínas de Unión a Calmodulina/genética , Frecuencia de los Genes , Intrones , Polimorfismo de Nucleótido Simple , Proteínas de Unión al ARN/genética , Sistema de Registros , Sarcoma de Ewing/genética , Adolescente , Neoplasias Óseas/diagnóstico , Niño , Preescolar , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Masculino , Proteína EWS de Unión a ARN , Estudios Retrospectivos , Factores de Riesgo , Sarcoma de Ewing/diagnóstico , Tumor de Wilms/diagnóstico , Tumor de Wilms/genética
19.
Sci Rep ; 12(1): 556, 2022 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-35017578

RESUMEN

Despite the association between cognitive impairment and delirium, little is known about whether genetic differences that confer cognitive resilience also confer resistance to delirium. To investigate whether older adults without postoperative delirium, compared with those with postoperative delirium, are more likely to have specific single nucleotide polymorphisms (SNPs) in the FKBP5, KIBRA, KLOTHO, MTNR1B, and SIRT1 genes known to be associated with cognition or delirium. This prospective nested matched exploratory case-control study included 94 older adults who underwent orthopedic surgery and screened for postoperative delirium. Forty-seven subjects had incident delirium, and 47 age-matched controls were not delirious. The primary study outcome was genotype frequency for the five SNPs. Compared with participants with delirium, those without delirium had higher adjusted odds of KIBRA SNP rs17070145 CT/TT [vs. CC; adjusted odds ratio (aOR) 2.80, 95% confidence interval (CI) 1.03, 7.54; p = 0.04] and MTNR1B SNP rs10830963 CG/GG (vs. CC; aOR 4.14, 95% CI 1.36, 12.59; p = 0.01). FKBP5 SNP rs1360780 CT/TT (vs. CC) demonstrated borderline increased adjusted odds of not developing delirium (aOR 2.51, 95% CI 1.00, 7.34; p = 0.05). Our results highlight the relevance of KIBRA, MTNR1B, and FKBP5 in understanding the complex relationship between delirium, cognition, and sleep, which warrant further study in larger, more diverse populations.


Asunto(s)
Genotipo
20.
Hum Mol Genet ; 18(6): 1140-7, 2009 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-19091795

RESUMEN

Functionally significant heterozygous mutations in the Melanocortin-4 receptor (MC4R) have been implicated in 2.5% of early onset obesity cases in European cohorts. The role of mutations in this gene in severely obese adults, particularly in smaller North American patient cohorts, has been less convincing. More recently, it has been proposed that mutations in a phylogenetically and physiologically related receptor, the Melanocortin-3 receptor (MC3R), could also be a cause of severe human obesity. The objectives of this study were to determine if mutations impairing the function of MC4R or MC3R were associated with severe obesity in North American adults. We studied MC4R and MC3R mutations detected in a total of 1821 adults (889 severely obese and 932 lean controls) from two cohorts. We systematically and comparatively evaluated the functional consequences of all mutations found in both MC4R and MC3R. The total prevalence of rare MC4R variants in severely obese North American adults was 2.25% (CI(95%): 1.44-3.47) compared with 0.64% (CI(95%): 0.26-1.43) in lean controls (P < 0.005). After classification of functional consequence, the prevalence of MC4R mutations with functional alterations was significantly greater when compared with controls (P < 0.005). In contrast, the prevalence of rare MC3R variants was not significantly increased in severely obese adults [0.67% (CI(95%): 0.27-1.50) versus 0.32% (CI(95%): 0.06-0.99)] (P = 0.332). Our results confirm that mutations in MC4R are a significant cause of severe obesity, extending this finding to North American adults. However, our data suggest that MC3R mutations are not associated with severe obesity in this population.


Asunto(s)
Predisposición Genética a la Enfermedad , Mutación/genética , Obesidad Mórbida/genética , Receptor de Melanocortina Tipo 3/genética , Receptor de Melanocortina Tipo 4/genética , Adulto , Estudios de Casos y Controles , Línea Celular , Estudios de Cohortes , Biología Computacional , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Mutantes/metabolismo , América del Norte , Delgadez/genética
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