RESUMO
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and cirrhosis. NAFLD is mediated by changes in lipid metabolism and known risk factors include obesity, metabolic syndrome, and diabetes. The aim of this study was to better understand differences in the lipid composition of individuals with NAFLD compared to controls, by performing direct infusion lipidomics on serum biospecimens from a cohort study of adults in Mexico. METHODS: A nested case-control study was conducted with a sample of 98 NAFLD cases and 100 healthy controls who are participating in an on-going, longitudinal study in Mexico. NAFLD cases were clinically confirmed using elevated liver enzyme tests and liver ultrasound or liver ultrasound elastography, after excluding alcohol abuse, and 100 controls were identified as having at least two consecutive normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (< 40 U/L) results in a 6-month period, and a normal liver ultrasound elastography result in January 2018. Samples were analyzed on the Sciex Lipidyzer Platform and quantified with normalization to serum volume. As many as 1100 lipid species can be identified using the Lipidyzer targeted multiple-reaction monitoring list. The association between serum lipids and NAFLD was investigated using analysis of covariance, random forest analysis, and by generating receiver operator characteristic (ROC) curves. RESULTS: NAFLD cases had differences in total amounts of serum cholesterol esters, lysophosphatidylcholines, sphingomyelins, and triacylglycerols (TAGs), however, other lipid subclasses were similar to controls. Analysis of individual TAG species revealed increased incorporation of saturated fatty acyl tails in serum of NAFLD cases. After adjusting for age, sex, body mass index, and PNPLA3 genotype, a combined panel of ten lipids predicted case or control status better than an area under the ROC curve of 0.83. CONCLUSIONS: These preliminary results indicate that the serum lipidome differs in patients with NAFLD, compared to healthy controls, and suggest that assessing the desaturation state of TAGs or a specific lipid panel may be useful clinical tools for the diagnosis of NAFLD.
Assuntos
Colesterol/sangue , Lisofosfatidilcolinas/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Esfingomielinas/sangue , Triglicerídeos/sangue , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Lipidômica , Masculino , México , Pessoa de Meia-Idade , Curva ROCRESUMO
A higher level of physical activity (PA) is associated with decreased risk of mortality, dementia, and depression, yet the mechanisms involved are not well understood, and little evidence exists for Mexican Americans. With data from the Sacramento Area Latino Study on Aging (1998-2007), we used Cox proportional hazards regression to separately evaluate associations of baseline PA level with mortality, dementia/cognitive impairment without dementia (CIND), and depressive symptoms, and we estimated the mediating effects of inflammatory markers in additive hazard models. A low level of PA (<35 metabolic equivalent of task-hours/week) was associated with increased mortality (hazard ratio (HR) = 1.50, 95% confidence interval (CI): 1.20, 1.88), dementia/CIND (HR = 1.37, 95% CI: 0.96, 1.96), and depressive symptoms (HR = 1.23, 95% CI: 1.00, 1.52). A low PA level added 512 (95% CI: -34, 1,058) cases of dementia/CIND per 100,000 person-years at risk (direct effect), while, through a mediating path, interleukin 6 (IL-6) added another 49 (95% CI: 5, 94) cases, or 9% of the total effect. For mortality, 8%-10% of the PA total effect was mediated through IL-6, tumor necrosis factor α (TNF-α), or TNF-α receptors. None of the inflammatory markers mediated the association between PA and depressive symptoms. Our results suggest that antiinflammation (especially as assessed by IL-6 and TNF-α levels) may partly explain how PA protects against dementia/CIND and mortality.
Assuntos
Demência/epidemiologia , Depressão/epidemiologia , Exercício Físico/psicologia , Inflamação/psicologia , Americanos Mexicanos/estatística & dados numéricos , Mortalidade , Idoso , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , California/epidemiologia , Cognição , Estudos de Coortes , Demência/sangue , Demência/prevenção & controle , Depressão/sangue , Depressão/prevenção & controle , Feminino , Humanos , Inflamação/sangue , Inflamação/epidemiologia , Interleucina-6/sangue , Masculino , Americanos Mexicanos/psicologia , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangueRESUMO
Influenza is responsible for up to 500,000 deaths every year, and antigenic variability represents much of its epidemiological burden. To visualize antigenic differences across many viral strains, antigenic cartography methods use multidimensional scaling on binding assay data to map influenza antigenicity onto a low-dimensional space. Analysis of such assay data ideally leads to natural clustering of influenza strains of similar antigenicity that correlate with sequence evolution. To understand the dynamics of these antigenic groups, we present a framework that jointly models genetic and antigenic evolution by combining multidimensional scaling of binding assay data, Bayesian phylogenetic machinery and nonparametric clustering methods. We propose a phylogenetic Chinese restaurant process that extends the current process to incorporate the phylogenetic dependency structure between strains in the modeling of antigenic clusters. With this method, we are able to use the genetic information to better understand the evolution of antigenicity throughout epidemics, as shown in applications of this model to H1N1 influenza. Copyright © 2017 John Wiley & Sons, Ltd.
Assuntos
Antígenos Virais/genética , Antígenos Virais/imunologia , Influenza Humana/virologia , Modelos Genéticos , Modelos Imunológicos , Teorema de Bayes , Bioestatística , Análise por Conglomerados , Evolução Molecular , Humanos , Vírus da Influenza A Subtipo H1N1/classificação , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/epidemiologia , Funções Verossimilhança , Epidemiologia Molecular , Filogenia , Estatísticas não Paramétricas , Processos EstocásticosRESUMO
Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican-Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans.
Assuntos
Hipercolesterolemia/genética , Hipertrigliceridemia/genética , Indígenas Norte-Americanos/genética , Obesidade/genética , Adulto , Apolipoproteína A-V , Apolipoproteínas A/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 8/genética , Dislipidemias/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Lipase Lipoproteica/genética , Modelos Logísticos , Masculino , México/etnologia , Pessoa de Meia-Idade , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Polimorfismo de Nucleotídeo Único , Proteínas Quinases/genética , População Branca/genética , Adulto JovemRESUMO
BACKGROUND: The Mexican population and others with Amerindian heritage exhibit a substantial predisposition to dyslipidemias and coronary heart disease. Yet, these populations remain underinvestigated by genomic studies, and to date, no genome-wide association (GWA) studies have been reported for lipids in these rapidly expanding populations. METHODS AND FINDINGS: We performed a two-stage GWA study for hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) in Mexicans (n=4361), and identified a novel Mexican-specific genome-wide significant locus for serum triglycerides (TGs) near the Niemann-Pick type C1 protein gene (p=2.43×10(-08)). Furthermore, three European loci for TGs (APOA5, GCKR and LPL), and four loci for HDL-C (ABCA1, CETP, LIPC and LOC55908) reached genome-wide significance in Mexicans. We used cross-ethnic mapping to narrow three European TG GWA loci, APOA5, MLXIPL, and CILP2 that were wide and contained multiple candidate variants in the European scan. At the APOA5 locus, this reduced the most likely susceptibility variants to one, rs964184. Importantly, our functional analysis demonstrated a direct link between rs964184 and postprandial serum apoAV protein levels, supporting rs964184 as the causative variant underlying the European and Mexican GWA signal. Overall, 52 of the 100 reported associations from European lipid GWA meta-analysis generalised to Mexicans. However, in 82 of the 100 European GWA loci, a different variant other than the European lead/best-proxy variant had the strongest regional evidence of association in Mexicans. CONCLUSIONS: This first Mexican GWA study of lipids identified a novel GWA locus for high TG levels; used the interpopulation heterogeneity to significantly restrict three previously known European GWA signals, and surveyed whether the European lipid GWA SNPs extend to the Mexican population.
Assuntos
Apolipoproteínas A/genética , Loci Gênicos/genética , Hipertrigliceridemia/genética , Hipoalfalipoproteinemias/genética , Indígenas Norte-Americanos/genética , Triglicerídeos/genética , Apolipoproteína A-V , Apolipoproteínas A/sangue , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hipertrigliceridemia/etnologia , Hipoalfalipoproteinemias/etnologia , Desequilíbrio de Ligação , Proteínas de Membrana/genética , Proteínas de Membrana Transportadoras , México , Polimorfismo de Nucleotídeo Único/genética , Triglicerídeos/sangue , População Branca/genéticaRESUMO
Atherosclerotic cardiovascular disease (ASCVD) affects more than 1 in 3 American adults. Hypercholesterolemia is a major treatable risk factor for ASCVD, yet many individuals fail to reach target levels of LDL-cholesterol (LDL-C) through the use of statins and lifestyle changes. The E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP; also known as IDOL) is a recently identified regulator of the LDL receptor (LDLR) pathway. Genome-wide association studies (GWASs) in populations of mixed European descent have identified noncoding variants in the MYLIP region as being associated with LDL-C levels, but no underlying functional variants were pinpointed. In order to fine-map actual susceptibility variants, we studied a population demographically distinct from the discovery population to ensure a different pattern of linkage disequilibrium. Our analysis revealed that in a Mexican population, the nonsynonymous SNP rs9370867, which encodes the N342S amino acid substitution, is an underlying functional variant that was associated with high total cholesterol and accounted for one of the previous significant GWAS signals. Functional characterization showed that the Asn-encoding allele was associated with more potent LDLR degradation and decreased LDL uptake. Mutagenesis of residue 342 failed to affect intrinsic MYLIP E3 ligase activity, but it was critical for LDLR targeting. Our findings suggest that modulation of MYLIP activity can affect LDL-C levels and that pharmacologic inhibition of MYLIP activity might be a useful strategy in the treatment of dyslipidemia and ASCVD.
Assuntos
Colesterol/metabolismo , Polimorfismo Genético , Receptores de LDL/genética , Ubiquitina-Proteína Ligases/genética , Dislipidemias/metabolismo , Variação Genética , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Desequilíbrio de Ligação , México , Mutagênese , Mutação , Receptores de LDL/metabolismo , Fatores de Risco , Análise de Sequência de DNA , Ubiquitina-Proteína Ligases/metabolismoRESUMO
BACKGROUND: Although epidemiological studies have demonstrated an increased predisposition to low high-density lipoprotein cholesterol and high triglyceride levels in the Mexican population, Mexicans have not been included in any of the previously reported genome-wide association studies for lipids. METHODS AND RESULTS: We investigated 6 single-nucleotide polymorphisms associated with triglycerides, 7 with high-density lipoprotein cholesterol, and 1 with both triglycerides and high-density lipoprotein cholesterol in recent Caucasian genome-wide association studies in Mexican familial combined hyperlipidemia families and hypertriglyceridemia case-control study samples. These variants were within or near the genes ABCA1, ANGPTL3, APOA5, APOB, CETP, GALNT2, GCKR, LCAT, LIPC, LPL (2), MMAB-MVK, TRIB1, and XKR6-AMAC1L2. We performed a combined analysis of the family-based and case-control studies (n=2298) using the Z method to combine statistics. Ten of the single-nucleotide polymorphisms were nominally significant and 5 were significant after Bonferroni correction (P=2.20 x 10(-3) to 2.6 x 10(-11)) for the number of tests performed (APOA5, CETP, GCKR, and GALNT2). Interestingly, our strongest signal was obtained for triglycerides with the minor allele of rs964184 (P=2.6 x 10(-11)) in the APOA1/C3/A4/A5 gene cluster region that is significantly more common in Mexicans (27%) than in whites (12%). CONCLUSIONS: It is important to confirm whether known loci have a consistent effect across ethnic groups. We show replication of 5 Caucasian genome-wide association studies lipid associations in Mexicans. The remaining loci will require a comprehensive investigation to exclude or verify their significance in Mexicans. We also demonstrate that rs964184 has a large effect (odds ratio, 1.74) and is more frequent in the Mexican population, and thus it may contribute to the high predisposition to dyslipidemias in Mexicans.
Assuntos
HDL-Colesterol/genética , Dislipidemias/genética , Estudo de Associação Genômica Ampla , Triglicerídeos/genética , População Branca/genética , Alelos , Estudos de Casos e Controles , HDL-Colesterol/sangue , Família , Frequência do Gene , Variação Genética , Genética Populacional , Genótipo , Humanos , Hipertrigliceridemia/genética , Americanos Mexicanos/genética , México , Razão de Chances , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangueRESUMO
BACKGROUND AND PURPOSE: Although the Mexican population has a high predisposition to dyslipidemias and premature coronary artery disease, this population is underinvestigated for the genetic factors conferring the high susceptibility. This study attempted to determine these genetic factors. METHODS AND RESULTS: First, we investigated apolipoprotein B (apoB) levels in Mexican extended families with familial combined hyperlipidemia using a two-step testing strategy. In the screening step, we screened 5721 single-nucleotide polymorphisms (SNPs) for linkage signals with apoB. In the test step, we analyzed the 130 SNPs residing in regions of suggestive linkage signals for association with apoB. We identified significant associations with two SNPs (ie, rs1424032 [P=6.07x10(-6)] and rs1349411 [P=2.72x10(-4)]) that surpassed the significance level for the number of tests performed in the test step (P<3.84x10(-4)). Second, these SNPs were tested for replication in Mexican hyperlipidemic case-control samples. The same risk alleles as in the families with familial combined hyperlipidemia were significantly associated (P<0.05) with apoB in the case-control samples. The rs1349411 resides near the apoB messenger RNA editing enzyme (APOBEC1) involved in the processing of APOB messenger RNA in the small intestine. The rs1424032 resides in a highly conserved noncoding region predicted to function as a regulatory element. CONCLUSIONS: We identified two novel variants, rs1349411 and rs1424032, for serum apoB levels in Mexicans.
Assuntos
Indígena Americano ou Nativo do Alasca/genética , Apolipoproteínas B/genética , Citidina Desaminase/genética , Hiperlipidemia Familiar Combinada/genética , Hiperlipidemias/genética , Polimorfismo de Nucleotídeo Único , Desaminase APOBEC-1 , Adulto , Apolipoproteínas B/metabolismo , Estudos de Casos e Controles , Citidina Desaminase/metabolismo , Feminino , Frequência do Gene , Ligação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Hiperlipidemia Familiar Combinada/sangue , Hiperlipidemia Familiar Combinada/etnologia , Hiperlipidemias/sangue , Hiperlipidemias/etnologia , Masculino , México/epidemiologia , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Fenótipo , RNA Mensageiro/metabolismo , Fatores de RiscoRESUMO
This paper introduces a likelihood method of estimating ethnic admixture that uses individuals, pedigrees, or a combination of individuals and pedigrees. For each founder of a pedigree, admixture proportions are calculated by conditioning on the pedigree-wide genotypes at all ancestry-informative markers. These estimates are then propagated down the pedigree to the nonfounders by a simple averaging process. The large-sample standard errors of the founders' proportions can be similarly transformed into standard errors for the admixture proportions of the descendants. These standard errors are smaller than the corresponding standard errors when each individual is treated independently. Both hard and soft information on a founder's ancestry can be accommodated in this scheme, which has been implemented in the genetic software package Mendel. The utility of the method is demonstrated on simulated data and a real data example involving Mexican families of mixed Amerindian and Spanish ancestry.
Assuntos
Etnicidade/genética , Funções Verossimilhança , Linhagem , Simulação por Computador , Marcadores Genéticos , Genótipo , Humanos , México/etnologia , SoftwareRESUMO
Background: most of the studies of HIV-1 infection in South America have been limited to Brazil and little is known about the viral variants that are causing disease else where in the continent. Aim: to determine the characteristics of the viral variants present in Chile as well as patterns of viral transmission. Material and methods: viral sequences were obtained from 21 HIV-1 infected people from Santiago, Chile who were infected either via sexual contact or intravenous drug use. Cloned sequences obtained from both the third variable and conserved regions of the envelope as well as the viral protease were evaluated. Results: we found only clade B subtype viruses in Santiago. An evaluation of the envelope gene revealed no evidence that the sequences were monophyletic by risk group. A number of the protease sequences were predicted to encode amino acid substitutions commonly found during selection for protease inhibitor resistance. Conclusions: the HIV-1 strains studied in Chile, belong to the subtype B. There is no molecular evidence of separate introductions of the virus into the different risk groups. A number of substitutions in the protease gene that may confer resistance to protease inhibitors were found in patients with no previous exposure to this class of drugs