RESUMO
Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.
Assuntos
Negro ou Afro-Americano/genética , Diuréticos/sangue , Variação Genética/genética , Hipertensão/sangue , Hipertensão/genética , População Branca/genética , Diuréticos/efeitos adversos , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/tratamento farmacológico , Lipídeos/sangueRESUMO
OBJECTIVE: Worldwide, the highest frequencies of APOL1-associated kidney variants are found in indigenous West Africans among whom small vessel disease (SVD) ischemic stroke is the most common stroke phenotype. The objective of this study was to investigate the association and effect sizes of 23 selected SNPs in 14 genes of relevance, including the APOL1 G1 variants, with the occurrence of SVD ischemic stroke among indigenous West African participants in the Stroke Investigative Research and Education Network (SIREN) Study. MATERIALS AND METHODS: Cases were consecutively recruited consenting adults (aged 18 years or older) with neuroimaging-confirmed first clinical stroke. Stroke-free controls were ascertained using a locally validated version of the Questionnaire for Verifying Stroke-Free Status (QVSFS). Logistic regression models adjusting for known vascular risk factors were fitted to assess the associations of the 23 SNPs in rigorously phenotyped cases (N = 154) of SVD ischemic stroke and stroke-free (N = 483) controls. RESULTS: Apolipoprotein L1 (APOL1) rs73885319 (OR = 1.52; CI: 1.09-2.13, P-value = .013), rs2383207 in CDKN2A/CDKN2B (OR = 3.08; CI: 1.15-8.26, P -value = .026) and rs2107595 (OR = 1.70; CI: 1.12-2.60, P-value = .014) and rs28688791 (OR = 1.52; CI: 1.03-2.26, P-value = .036) in HDAC9 gene were associated with SVD stroke at 0.05 significance level. Polymorphisms in other genes did not show significant associations. CONCLUSION: This is the first report of a specific association of APOL1 with a stroke subtype. Further research is needed to confirm these initial findings and deepen understanding of the genetics of stroke in people of African ancestry with possible implications for other ancestries as all humans originated from Africa.
Assuntos
Apolipoproteína L1/genética , Predisposição Genética para Doença/genética , Acidente Vascular Cerebral/genética , Adulto , Idoso , População Negra/genética , Isquemia Encefálica/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p18/genética , Feminino , Genótipo , Histona Desacetilases/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Fatores de RiscoRESUMO
BACKGROUND AND AIMS: Adiponectin, an adipose-secreted protein that has been linked to insulin sensitivity, plasma lipids, and inflammatory patterns, is an established biomarker for metabolic health. Despite clinical relevance and high heritability, the determinants of plasma adiponectin levels remain poorly understood. METHODS AND RESULTS: We conducted the first epigenome-wide cross-sectional study of adiponectin levels using methylation data on 368,051 cytosine-phosphate-guanine (CpG) sites in CD4+ T-cells from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 991). We fit linear mixed models, adjusting for age, sex, study site, T-cell purity, and family. We have identified a positive association (regression coefficient ± SE = 0.01 ± 0.001, P = 3.4 × 10-13) between plasma adiponectin levels and methylation of a CpG site in CPT1A, a key player in fatty acid metabolism. The association was replicated (n = 474, P = 0.0009) in whole blood samples from the Amish participants of the Heredity and Phenotype Intervention (HAPI) Heart Study as well as White (n = 592, P = 0.0005) but not Black (n = 243, P = 0.18) participants of the Bogalusa Heart Study (BHS). The association remained significant upon adjusting for BMI and smoking in GOLDN and HAPI but not BHS. We also identified associations between methylation loci in RNF145 and UFM1 and plasma adiponectin in GOLDN and White BHS participants, although the association was not robust to adjustment for BMI or smoking. CONCLUSION: We have identified and replicated associations between several biologically plausible loci and plasma adiponectin. These findings support the importance of epigenetic processes in metabolic traits, laying the groundwork for future translational applications.
Assuntos
Adiponectina/sangue , Carnitina O-Palmitoiltransferase/genética , Metilação de DNA , Epigênese Genética , Adulto , Negro ou Afro-Americano/genética , Ilhas de CpG , Estudos Transversais , Epigenômica/métodos , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Proteínas/genética , Estados Unidos/epidemiologia , População Branca/genéticaRESUMO
African Americans have the highest prevalence of hypertension in the United States. Blood pressure (BP) control is important to reduce cardiovascular disease-related morbidity and mortality in this ethnic group. Genetic variants have been found to be associated with BP response to treatment. Previous pharmacogenetic studies of BP response to treatment in African Americans suffer limitations of small sample size as well as a limited number of candidate genes, and often focused on one antihypertensive treatment. Using 1131 African-American treatment-naive participants from the Genetics of Hypertension Associated Treatment Study, we examined whether variants in 35 candidate genes might modulate BP response to four different antihypertensive medications, including an angiotensin-converting enzyme inhibitor (lisinopril), a calcium channel blocker (amlodipine), and an a-adrenergic blocker (doxazosin) as compared with a thiazide diuretic (chlorthalidone) after 6 months of follow-up. Several suggestive gene by treatment interactions were identified. For example, among participants with two minor alleles of renin rs6681776, diastolic BP response was much improved on doxazosin compared with chlorthalidone (on average -9.49 mm Hg vs -1.70 mm Hg) (P=0.007). Although several suggestive loci were identified, none of the findings passed significance criteria after correction for multiple testing. Given the impact of hypertension and its sequelae in this population, this research highlights the potential for genetic factors to contribute to BP response to treatment. Continued concerted research efforts focused on genetics are needed to improve treatment response in this high-risk group.
Assuntos
Anti-Hipertensivos/uso terapêutico , Negro ou Afro-Americano/genética , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Hipertensão/tratamento farmacológico , Hipertensão/genética , Variantes Farmacogenômicos , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Idoso , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Diuréticos/uso terapêutico , Método Duplo-Cego , Feminino , Predisposição Genética para Doença , Humanos , Hipertensão/etnologia , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , América do Norte/epidemiologia , Farmacogenética , Fenótipo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/genética , Resultado do TratamentoRESUMO
Lipid traits (total, low-density and high-density lipoprotein cholesterol, and triglycerides) are risk factors for cardiovascular disease. DNA methylation is not only an inherited but also modifiable epigenetic mark that has been related to cardiovascular risk factors. Our aim was to identify loci showing differential DNA methylation related to serum lipid levels. Blood DNA methylation was assessed using the Illumina Human Methylation 450 BeadChip. A two-stage epigenome-wide association study was performed, with a discovery sample in the REGICOR study (n = 645) and validation in the Framingham Offspring Study (n = 2,542). Fourteen CpG sites located in nine genes (SREBF1, SREBF2, PHOSPHO1, SYNGAP1, ABCG1, CPT1A, MYLIP, TXNIP and SLC7A11) and 2 intergenic regions showed differential methylation in association with lipid traits. Six of these genes and 1 intergenic region were new discoveries showing differential methylation related to total cholesterol (SREBF2), HDL-cholesterol (PHOSPHO1, SYNGAP1 and an intergenic region in chromosome 2) and triglycerides (MYLIP, TXNIP and SLC7A11). These CpGs explained 0.7%, 9.5% and 18.9% of the variability of total cholesterol, HDL cholesterol and triglycerides in the Framingham Offspring Study, respectively. The expression of the genes SREBF2 and SREBF1 was inversely associated with methylation of their corresponding CpGs (P-value = 0.0042 and 0.0045, respectively) in participants of the GOLDN study (n = 98). In turn, SREBF1 expression was directly associated with HDL cholesterol (P-value = 0.0429). Genetic variants in SREBF1, PHOSPHO1, ABCG1 and CPT1A were also associated with lipid profile. Further research is warranted to functionally validate these new loci and assess the causality of new and established associations between these differentially methylated loci and lipid metabolism.
Assuntos
Doenças Cardiovasculares/genética , Ilhas de CpG , Metilação de DNA , Epigênese Genética , Loci Gênicos , Metabolismo dos Lipídeos/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Colesterol/sangue , Colesterol/química , Colesterol/metabolismo , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Análise de Sequência de DNA , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Triglicerídeos/sangue , Triglicerídeos/genética , Triglicerídeos/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Ativadoras de ras GTPase/genética , Proteínas Ativadoras de ras GTPase/metabolismoRESUMO
The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.
Assuntos
Negro ou Afro-Americano/genética , Predisposição Genética para Doença , Proteínas do Tecido Nervoso/genética , Receptores Nicotínicos/genética , Tabagismo/etnologia , Tabagismo/genética , População Branca/genética , Adulto , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
This study investigates the association of CRP (C-reactive protein) single-nucleotide polymorphisms (SNPs) with plasma CRP levels and radiographic severity in African Americans with early and established rheumatoid arthritis (RA). Using a cross-sectional case-only design, CRP SNPs were genotyped in two independent sets of African Americans with RA: Consortium for the Longitudinal Evaluation of African Americans with RA (CLEAR 1) and CLEAR 2. Radiographic data and CRP measurements were available for 294 individuals from CLEAR 1 (median (interquartile range (IQR) 25-75) disease duration of 1 (0.6-1.6) year) and in 407 persons from CLEAR 2 (median (IQR 25-75) disease duration of 8.9 (3.5-17.7) years). In CLEAR 1, in adjusted models, the minor allele of rs2808630 was associated with total radiographic score (incident rate ratio 0.37 (95% confidence interval (CI) 0.19-0.74), P-value=0.0051). In CLEAR 2, the minor allele of rs3093062 was associated with increased plasma CRP levels (P-value=0.002). For each rs3093062 minor allele, the plasma CRP increased by 1.51 (95% CI 1.15-1.95) mg dl(-1) when all the other covariates remained constant. These findings have important implications for assessment of the risk of joint damage in African Americans with RA.
Assuntos
Artrite Reumatoide/etnologia , Artrite Reumatoide/genética , Negro ou Afro-Americano/genética , Proteína C-Reativa/genética , Adulto , Idoso , Alelos , Artrite Reumatoide/diagnóstico por imagem , Estudos Transversais , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/etiologia , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RadiografiaRESUMO
One in six people worldwide will experience a stroke in his/her lifetime. While people in Africa carry a disproportionately higher burden of poor stroke outcomes, compared to the rest of the world, the exact contribution of genomic factors to this disparity is unknown. Despite noteworthy research into stroke genomics, studies exploring the genetic contribution to stroke among populations of African ancestry in the United States are few. Furthermore, genomics data in populations living in Africa are lacking. The wide genomic variation of African populations offers a unique opportunity to identify genomic variants with causal relationships to stroke across different ethnic groups. The Stroke Investigative Research and Educational Network (SIREN), a component of the Human Health and Heredity in Africa (H3Africa) Consortium, aims to explore genomic and environmental risk factors for stroke in populations of African ancestry in West Africa and the United States. In this article, we review the literature on the genomics of stroke with particular emphasis on populations of African origin.
Assuntos
População Negra/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/terapia , África , Humanos , Fatores de RiscoRESUMO
Methotrexate (MTX) has emerged as first-line therapy for early moderate-to-severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 Treatment of Early Aggressive Rheumatoid Arthritis Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P<0.003), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 genes CYP20A1 and CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2. The selected markers explained a consistently higher proportion of variation in toxicity than efficacy. These findings could inform future development of personalized therapeutic approaches.
Assuntos
Antirreumáticos/toxicidade , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Variação Genética , Metotrexato/toxicidade , Metotrexato/uso terapêutico , Antirreumáticos/administração & dosagem , Artrite Reumatoide/genética , Biomarcadores/análise , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Análise Multivariada , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Regressão , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Interação Gene-Ambiente , Síndrome do QT Longo/genética , Farmacogenética , Polimorfismo de Nucleotídeo Único/genética , Característica Quantitativa Herdável , Simulação por Computador , Estudos Transversais , Eletrocardiografia , Estudo de Associação Genômica Ampla , Humanos , Modelos Lineares , Cadeias de Markov , População Branca/genéticaRESUMO
Autophagy is a catabolic pathway utilized to maintain a balance among the synthesis, degradation, and recycling of cellular components, thereby playing a role in cell growth, development, and homeostasis. Previous studies revealed that a conditional knockout of essential member(s) of autophagy in a variety of tissues causes changes in structure and function of these tissues. Acinar cell-specific expression of knocked-in Cre recombinase through control of aquaporin 5 (Aqp5) promoter/enhancer (Aqp5-Cre) allows us to specifically inactivate Atg5, a protein necessary for autophagy, in salivary acinar cells of Atg5(f/f);Aqp5-Cre mice. There was no difference in apoptotic or proliferation levels in salivary glands of Atg5/Cre mice from each genotype. However, H&E staining and electron microscopy studies revealed modestly enlarged acinar cells and accumulated secretory granules in salivary glands of Atg5(f/f);Aqp5-Cre mice. Salivary flow rates and amylase contents of Atg5/Cre mice indicated that acinar-specific inactivation of ATG5 did not alter carbachol-evoked saliva and amylase secretion. Conversely, autophagy intersected with salivary morphological and secretory manifestations induced by isoproterenol administration. These results identified a role for autophagy as a homeostasis control in salivary glands. Collectively, Atg5(f/f);Aqp5-Cre mice would be a useful tool to enhance our understanding of autophagy in adaptive responses following targeted head and neck radiation or Sjögren syndrome.
Assuntos
Aquaporina 5/fisiologia , Autofagia/fisiologia , Integrases/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Glândulas Salivares/fisiologia , Células Acinares/efeitos dos fármacos , Células Acinares/enzimologia , Envelhecimento/fisiologia , Amilases/metabolismo , Animais , Apoptose , Aquaporina 5/genética , Autofagia/genética , Proteína 5 Relacionada à Autofagia , Caspase 3/metabolismo , Proliferação de Células , Técnicas de Introdução de Genes , Técnicas de Inativação de Genes , Homeostase/efeitos dos fármacos , Hipertrofia , Integrases/genética , Isoproterenol/farmacologia , Masculino , Camundongos , Camundongos Knockout , Antígeno Nuclear de Célula em Proliferação/metabolismo , Saliva/enzimologia , Saliva/metabolismo , Glândulas Salivares/citologia , Glândulas Salivares/enzimologia , Glândulas Salivares/crescimento & desenvolvimento , Vesículas Secretórias/metabolismo , Deleção de Sequência , Estresse Fisiológico/fisiologia , Proteínas Ubiquitinadas/metabolismoRESUMO
BACKGROUND AND AIMS: In vitro studies suggest that low density lipoprotein receptor-related protein 1 (LRP1) plays a role in the secondary uptake of chylomicrons. In addition, in vivo studies using LRP-1 knockout mice show these animals exhibit delayed chylomicron clearance. Whether this is true in humans is unknown. We aimed to determine whether genetic variants in LRP-1 are associated with postprandial chylomicron uptake in humans given an oral fat challenge. METHODS AND RESULTS: As many as 817 men and women (mean age +/- standard deviation = 48.4 +/- 16.4 years) forming the study population for the Genetics of Lipid Lowering Drugs Network (GOLDN) study ingested an oral fat load of 700 kilocalories per m² of body surface area at 83% fat, after an 8-h fast. Chylomicrons were measured by nuclear resonance spectroscopy (NMR) at fasting, and 3.5 and 6 h after the meal. 26 Single nucleotide polymorphisms (SNPs) in the LRP-1 gene were genotyped on the Affymetrix 6.0 array. Chylomicrons were, as expected, zero at fasting. Mixed linear models adjusted for age, sex, study site and pedigree tested for associations between LRP-1 SNPs and changes in chylomicron concentrations 3.5-6 h. A gene-based test across all 26 SNPs was conducted which corrected for the linkage disequilibrium (LD) between SNPs. 11 LRP-1 SNPs were significantly associated with the change in chylomicron concentration correction for multiple testing (Q < 0.05). The subsequent gene-based test, was also significant (P = 0.01). CONCLUSION: These results require replication but strongly indicate the role of LRP1 in postprandial lipoprotein uptake and/or clearance.
Assuntos
Quilomícrons/metabolismo , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/metabolismo , Absorção Intestinal , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Refeições , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Quilomícrons/sangue , Feminino , Estudos de Associação Genética , Humanos , Desequilíbrio de Ligação , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Minnesota , Análise de Sequência com Séries de Oligonucleotídeos , Período Pós-Prandial , UtahRESUMO
OBJECTIVE: Low-density lipoprotein-related receptor protein 1 (LRP1) is a multi-functional endocytic receptor and signaling molecule that is expressed in adipose and the hypothalamus. Evidence for a role of LRP1 in adiposity is accumulating from animal and in vitro models, but data from human studies are limited. The study objectives were to evaluate (i) relationships between LRP1 genotype and anthropometric traits, and (ii) whether these relationships were modified by dietary fatty acids. DESIGN AND METHODS: We conducted race/ethnic-specific meta-analyses using data from 14 studies of US and European whites and 4 of African Americans to evaluate associations of dietary fatty acids and LRP1 genotypes with body mass index (BMI), waist circumference and hip circumference, as well as interactions between dietary fatty acids and LRP1 genotypes. Seven single-nucleotide polymorphisms (SNPs) of LRP1 were evaluated in whites (N up to 42 000) and twelve SNPs in African Americans (N up to 5800). RESULTS: After adjustment for age, sex and population substructure if relevant, for each one unit greater intake of percentage of energy from saturated fat (SFA), BMI was 0.104 kg m(-2) greater, waist was 0.305 cm larger and hip was 0.168 cm larger (all P<0.0001). Other fatty acids were not associated with outcomes. The association of SFA with outcomes varied by genotype at rs2306692 (genotyped in four studies of whites), where the magnitude of the association of SFA intake with each outcome was greater per additional copy of the T allele: 0.107 kg m(-2) greater for BMI (interaction P=0.0001), 0.267 cm for waist (interaction P=0.001) and 0.21 cm for hip (interaction P=0.001). No other significant interactions were observed. CONCLUSION: Dietary SFA and LRP1 genotype may interactively influence anthropometric traits. Further exploration of this, and other diet x genotype interactions, may improve understanding of interindividual variability in the relationships of dietary factors with anthropometric traits.
Assuntos
População Negra , Ácidos Graxos/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Obesidade/genética , Polimorfismo de Nucleotídeo Único , População Branca , Tecido Adiposo , Adulto , Idoso , Idoso de 80 Anos ou mais , População Negra/genética , Índice de Massa Corporal , Europa (Continente)/epidemiologia , Feminino , Frequência do Gene , Interação Gene-Ambiente , Predisposição Genética para Doença , Genótipo , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Fenótipo , Prevalência , Estados Unidos/epidemiologia , População Branca/genéticaRESUMO
Nearly one-third of adults in the United States have hypertension, which is associated with increased cardiovascular disease (CVD) morbidity and mortality. The goal of antihypertensive pharmacogenetic research is to enhance understanding of drug response based on the interaction of individual genetic architecture and antihypertensive therapy to improve blood pressure control and ultimately prevent CVD outcomes. In the context of the Genetics of Hypertension Associated Treatment study and using a case-only design, we examined whether single-nucleotide polymorphisms in RYR3 interact with four classes of antihypertensive drugs, particularly the calcium channel blocker amlodipine versus other classes, to modify the risk of coronary heart disease (CHD; fatal CHD and non-fatal myocardial infarction combined) and heart failure (HF) in high-risk hypertensive individuals. RYR3 mediates the mobilization of stored Ca(+2) in cardiac and skeletal muscle to initiate muscle contraction. There was suggestive evidence of pharmacogenetic effects on HF, the strongest of which was for rs877087, with the smallest P-value=0.0005 for the codominant model when comparing amlodipine versus all other treatments. There were no pharmacogenetic effects observed for CHD. The findings reported here for the case-only analysis of the antihypertensive pharmacogenetic effect of RYR3 among 3058 CHD cases and 1940 HF cases show that a hypertensive patient's genetic profile may help predict which medication(s) might better lower CVD risk.
Assuntos
Anti-Hipertensivos/administração & dosagem , Doenças Cardiovasculares/genética , Hipertensão/tratamento farmacológico , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Adulto , Anlodipino/administração & dosagem , Pressão Sanguínea/genética , Bloqueadores dos Canais de Cálcio/administração & dosagem , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/fisiopatologia , Diuréticos/administração & dosagem , Feminino , Humanos , Hipertensão/complicações , Hipertensão/genética , Masculino , Polimorfismo de Nucleotídeo Único , Resultado do Tratamento , Estados UnidosRESUMO
As a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fenofibrate favorably modulates dyslipidemia and inflammation markers, which are associated with cardiovascular risk. To determine whether variation in the PPARα receptor gene was associated with lipid and inflammatory marker response, we conducted a 3-week trial of fenofibrate in 861 men and women. Mixed linear models that controlled for age and sex, as well as family pedigree and study center, were constructed using single-nucleotide polymorphisms (SNPs) in the PPARα gene as predictors and changes in fasting triglycerides (TGs), cholesterol and inflammatory markers as outcomes. Significant associations with low-density cholesterol and interleukin-2 (P<0.001) responses to fenofibrate were found. Although there were suggestive associations with tumor necrosis factor-alpha and TG responses (P<0.05), these did not survive the correction for multiple testing. We conclude that variants in the PPARα gene may contribute to future pharmacogenomic paradigms seeking to predict fenofibrate responders from both an anti-dyslipidemic and anti-inflammatory perspective.
Assuntos
LDL-Colesterol/genética , Fenofibrato/administração & dosagem , Lipídeos/genética , PPAR alfa/genética , Adulto , Idoso , LDL-Colesterol/sangue , Feminino , Estudos de Associação Genética , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue , Triglicerídeos/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
BACKGROUND AND AIMS: Metabolic syndrome (MetS) is a complex condition characterized by different phenotypes, according to the combinations of risk factors and is associated with cardiovascular abnormalities. Whether control of MetS components by treatment produces improvement in the associated cardiovascular abnormalities is unknown. We investigated whether partial control of components of MetS was associated with less echocardiographic abnormalities than the complete presentation of MetS based on measured components. METHODS AND RESULTS: We evaluated markers of echocardiographic preclinical cardiovascular disease in MetS (ATP III) defined by measured components or by history of treatment, in 1421 African-American and 1195 Caucasian non-diabetic HyperGEN participants, without prevalent cardiovascular disease or serum creatinine >2 mg/dL. Of 2616 subjects, 512 subjects had MetS by measured components and 328 by history. Hypertension was found in 16% of participants without MetS, 6% of those with MetS by history and 42% of those with MetS by measured components. Obesity and central fat distribution had similar prevalence in both MetS groups (both p < 0.0001 vs. No-MetS). Blood pressure was similar in MetS by history and No-MetS, and lower than in MetS by measured components (p < 0.0001). LV mass and midwall shortening, left atrial (LA) dimension and LA systolic force were similarly abnormal in both MetS groups (all p < 0.0001 vs. No-MetS) without difference between them. CONCLUSIONS: There is a little impact of control by treatment of single components of MetS (namely hypertension) on echocardiographic abnormalities. Lower blood pressure in participants with MetS by history was not associated with substantially reduced alterations in cardiac geometry and function.
Assuntos
Doenças Cardiovasculares/diagnóstico por imagem , Síndrome Metabólica/terapia , Negro ou Afro-Americano , Anti-Hipertensivos/uso terapêutico , Índice de Massa Corporal , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/terapia , HDL-Colesterol/sangue , Estudos Transversais , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Hipertensão/complicações , Hipolipemiantes/uso terapêutico , Resistência à Insulina , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/diagnóstico por imagem , Pessoa de Meia-Idade , Obesidade/complicações , Triglicerídeos/sangue , Ultrassonografia , População BrancaRESUMO
BACKGROUND AND AIMS: Adiponectin is an adipose-secreted protein that has been linked to changes in insulin sensitivity, high-density lipoprotein cholesterol levels, and inflammatory patterns. Although fenofibrate therapy can raise adiponectin levels, treatment response is heterogeneous and heritable, suggesting a role for genetic mediators. This is the first genome-wide association study of fenofibrate effects on circulating adiponectin. METHODS AND RESULTS: Plasma adiponectin was measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 793) before and after a 3-week daily treatment with 160 mg of fenofibrate. Associations between variants on the Affymetrix Genome-Wide Human SNP Array 6.0 and adiponectin were assessed using mixed linear models, adjusted for age, sex, site, and family. We observed a statistically significant (P = 5 × 10â»8) association between rs2384207 in 12q24, a region previously linked to several metabolic traits, and the fenofibrate-induced change in circulating adiponectin. Additionally, our genome-wide analysis of baseline adiponectin levels replicated the previously reported association with CDH13 and suggested novel associations with markers near the PCK1, ZBP1, TMEM18, and SCUBE1 genes. The findings from the single marker tests were corroborated in gene-based analyses. Biological pathway analyses suggested a borderline significant association between the EGF receptor signaling pathway and baseline adiponectin levels. CONCLUSIONS: We present preliminary evidence linking several biologically relevant genetic variants to adiponectin levels at baseline and in response to fenofibrate therapy. Our findings provide support for fine-mapping of the 12q24 region to investigate the shared biological mechanisms underlying levels of circulating adiponectin and susceptibility to metabolic disease.
Assuntos
Adiponectina/sangue , Caderinas/genética , Cromossomos Humanos Par 12 , Resistência a Medicamentos , Fenofibrato/farmacologia , Hipolipemiantes/farmacologia , Polimorfismo de Nucleotídeo Único , Adiponectina/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adulto , Caderinas/metabolismo , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Minnesota , Análise de Sequência com Séries de Oligonucleotídeos , Irmãos , UtahRESUMO
The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (ß = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.
Assuntos
Negro ou Afro-Americano/genética , Fumar/genética , Adulto , Idoso , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 15/genética , Feminino , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Proteoglicanas/genética , Receptores Nicotínicos/genética , Estatística como AssuntoRESUMO
RATIONALE: Left ventricular hypertrophy (LVH) is a heritable predictor of cardiovascular disease, particularly in blacks. OBJECTIVE: Determine the feasibility of combining evidence from two distinct but complementary experimental approaches to identify novel genetic predictors of increased LV mass. METHODS: Whole-exome sequencing (WES) was conducted in seven African-American sibling trios ascertained on high average familial LV mass indexed to height (LVMHT) using Illumina HiSeq technology. Identified missense or nonsense (MS/NS) mutations were examined for association with LVMHT using linear mixed models adjusted for age, sex, body weight, and familial relationship. To functionally assess WES findings, human induced pluripotent stem cell-derived cardiomyocytes (induced pluripotent stem cell-CM) were stimulated to induce hypertrophy; mRNA sequencing (RNA-seq) was used to determine gene expression differences associated with hypertrophy onset. Statistically significant findings under both experimental approaches identified LVH candidate genes. Candidate genes were further prioritized by seven supportive criteria that included additional association tests (two criteria), regional linkage evidence in the larger HyperGEN cohort (one criterion), and publically available gene and variant based annotations (four criteria). RESULTS: WES reads covered 91% of the target capture region (of size 37.2 MB) with an average coverage of 65×. WES identified 31,426 MS/NS mutations among the 21 individuals. A total of 295 MS/NS variants in 265 genes were associated with LVMHT with q-value <0.25. Of the 265 WES genes, 44 were differentially expressed (P < 0.05) in hypertrophied cells. Among the 44 candidate genes identified, 5, including HLA-B, HTT, MTSS1, SLC5A12, and THBS1, met 3 of 7 supporting criteria. THBS1 encodes an adhesive glycoprotein that promotes matrix preservation in pressure-overload LVH. THBS1 gene expression was 34% higher in hypertrophied cells (P = 0.0003) and a predicted conserved and damaging NS variant in exon 13 (A2099G) was significantly associated with LVHMT (P = 4 × 10(-6)). CONCLUSION: Combining evidence from cutting-edge genetic and cellular experiments can enable identification of novel LVH risk loci.