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
Objective: Low HDL-C (high-density lipoprotein cholesterol) is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Our purpose was to identify genetic variants associated with HDL-C levels and cardiovascular risk in the Mexican population. Approach and Results: A genome-wide association studies for HDL-C levels in 2335 Mexicans, identified four loci associated with genome-wide significance: CETP, ABCA1, LIPC, and SIDT2. The SIDT2 missense Val636Ile variant was associated with HDL-C levels and was replicated in 3 independent cohorts (P=5.9×10−18 in the conjoint analysis). The SIDT2/Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C (low-density lipoprotein cholesterol) and ApoB levels, and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant affects function. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism. Conclusions: This is the first genome-wide association study for HDL-C levels seeking associations with coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans.
Assuntos
HDL-Colesterol/sangue , Doença da Artéria Coronariana/genética , Hiperlipoproteinemia Tipo II/genética , Proteínas de Transporte de Nucleotídeos/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idade de Início , Animais , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células HEK293 , Fatores de Risco de Doenças Cardíacas , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Masculino , Análise da Randomização Mendeliana , México/epidemiologia , Camundongos , Pessoa de Meia-Idade , Proteínas de Transporte de Nucleotídeos/metabolismo , Fenótipo , Medição de RiscoRESUMO
Childhood obesity is associated with a number of metabolic abnormalities leading to increased cardiovascular risk. Metabolites can be useful as early biomarkers and new targets to promote early intervention beginning in school age. Thus, we aimed to identify metabolomic profiles associated with obesity and obesity-related metabolic traits. We used data from the Obesity Research Study for Mexican children (ORSMEC) in Mexico City and included a case control (n = 1120), cross-sectional (n = 554) and a longitudinal study (n = 301) of 6-12-year-old children. Forty-two metabolites were measured using electrospray MS/MS and multivariate regression models were used to test associations of metabolomic profiles with anthropometric, clinical and biochemical parameters. Principal component analysis showed a serum amino acid signature composed of arginine, leucine/isoleucine, phenylalanine, tyrosine, valine and proline significantly associated with obesity (OR = 1.57; 95%CI 1.45-1.69, P = 3.84 × 10-31) and serum triglycerides (TG) (ß = 0.067, P = 4.5 × 10-21). These associations were validated in the cross-sectional study (P < 0.0001). In the longitudinal cohort, the amino acid signature was associated with serum TG and with the risk of hypertriglyceridemia after 2 years (OR = 1.19; 95%CI 1.03-1.39, P = 0.016). This study shows that an amino acid signature significantly associated with childhood obesity, is an independent risk factor of future hypertriglyceridemia in children.
Assuntos
Aminoácidos/metabolismo , Biomarcadores/metabolismo , Hipertrigliceridemia/diagnóstico , Metaboloma , Obesidade Infantil/complicações , Aminoácidos/análise , Antropometria , Estudos de Casos e Controles , Criança , Estudos Transversais , Feminino , Humanos , Hipertrigliceridemia/epidemiologia , Hipertrigliceridemia/etiologia , Hipertrigliceridemia/metabolismo , Estudos Longitudinais , Masculino , México/epidemiologia , Fatores de RiscoRESUMO
Obesity is a major public health concern in Mexico and worldwide. Although the estimated heritability is high, common variants identified by genome-wide association studies explain only a small proportion of this heritability. A combination of linkage and association strategies could be a more robust and powerful approach to identify other obesity-susceptibility variants. We thus sought to identify novel genetic variants associated with obesity-related traits in the Mexican population by combining these methods. We performed a genome-wide linkage scan for body mass index (BMI) and other obesity-related phenotypes in 16 Mexican families using the Sequential Oligogenic Linkage Analysis Routines Program. Associated single-nucleotide polymorphisms (SNPs) were tested for associations in an independent cohort. Two suggestive BMI-linkage peaks (logarithm of odds ⩾1.5) were observed at chromosomal regions 11q13 and 13q22. Only rs614080 in the 11q13 region was significantly associated with BMI and related traits in these families. This association was also significant in an independent cohort of Mexican adults. Moreover, this variant was significantly associated with GSTP1 gene expression levels in adipose tissue. In conclusion, the rs614080 SNP near the GSTP1 gene was significantly associated with BMI and GSTP1 expression levels in the Mexican population.
Assuntos
Predisposição Genética para Doença , Glutationa S-Transferase pi/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Característica Quantitativa Herdável , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Cromossomos Humanos Par 11/química , Família , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla , Humanos , Padrões de Herança , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/patologiaRESUMO
It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 x 10(-11)) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , HDL-Colesterol/sangue , Indígenas Norte-Americanos/genética , Seleção Genética , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/fisiologia , Adulto , Alelos , HDL-Colesterol/genética , Feminino , Frequência do Gene , Genética Populacional , Estudo de Associação Genômica Ampla , Geografia , Haplótipos , Humanos , Desequilíbrio de Ligação , MasculinoRESUMO
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
Common polymorphisms in the fat mass and obesity-associated gene (FTO) have shown strong association with obesity in several populations. In the present study, we explored the association of FTO gene polymorphisms with obesity and other biochemical parameters in the Mexican population. We also assessed FTO gene expression levels in adipose tissue of obese and nonobese individuals. The study comprised 788 unrelated Mexican-Mestizo individuals and 31 subcutaneous fat tissue biopsies from lean and obese women. FTO single-nucleotide polymorphisms (SNPs) rs9939609, rs1421085, and rs17817449 were associated with obesity, particularly with class III obesity, under both additive and dominant models (P = 0.0000004 and 0.000008, respectively). These associations remained significant after adjusting for admixture (P = 0.000003 and 0.00009, respectively). Moreover, risk alleles showed a nominal association with lower insulin levels and homeostasis model assessment of B-cell function (HOMA-B), and with higher homeostasis model assessment of insulin sensitivity (HOMA-S) only in nonobese individuals (P (dom) = 0.031, 0.023, and 0.049, respectively). FTO mRNA levels were significantly higher in subcutaneous fat tissue of class III obese individuals than in lean individuals (P = 0.043). Risk alleles were significantly associated with higher FTO expression in the class III obesity group (P = 0.047). In conclusion, FTO is a major risk factor for obesity (particularly class III) in the Mexican-Mestizo population, and is upregulated in subcutaneous fat tissue of obese individuals.
Assuntos
Obesidade/etnologia , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Adulto , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , RNA Mensageiro/análise , Medição de Risco , Fatores de Risco , Gordura Subcutânea/química , Regulação para CimaRESUMO
Low serum HDL-cholesterol (HDL-C) is a major risk factor for coronary artery disease. We performed targeted genotyping of a 12.4 Mb linked region on 16q to test for association with low HDL-C by using a regional-tag SNP strategy. We identified one SNP, rs2548861, in the WW-domain-containing oxidoreductase (WWOX) gene with region-wide significance for low HDL-C in dyslipidemic families of Mexican and European descent and in low-HDL-C cases and controls of European descent (p = 6.9 x 10(-7)). We extended our investigation to the population level by using two independent unascertained population-based Finnish cohorts, the cross-sectional METSIM cohort of 4,463 males and the prospective Young Finns cohort of 2,265 subjects. The combined analysis provided p = 4 x 10(-4) to 2 x 10(-5). Importantly, in the prospective cohort, we observed a significant longitudinal association of rs2548861 with HDL-C levels obtained at four different time points over 21 years (p = 0.003), and the T risk allele explained 1.5% of the variance in HDL-C levels. The rs2548861 resides in a highly conserved region in intron 8 of WWOX. Results from our in vitro reporter assay and electrophoretic mobility-shift assay demonstrate that this region functions as a cis-regulatory element whose associated rs2548861 SNP has a specific allelic effect and that the region forms an allele-specific DNA-nuclear-factor complex. In conclusion, analyses of 9,798 subjects show significant association between HDL-C and a WWOX variant with an allele-specific cis-regulatory function.
Assuntos
HDL-Colesterol/biossíntese , Oxirredutases/genética , Oxirredutases/fisiologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/fisiologia , Adolescente , Adulto , Idoso , Alelos , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Finlândia , Genética Populacional , Humanos , Masculino , México , Pessoa de Meia-Idade , Polimorfismo Genético , Oxidorredutase com Domínios WWRESUMO
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
OBJECTIVE: The ATP-binding cassette transporter A1 (ABCA1) R230C variant is associated with low HDL cholesterol levels, obesity, and the metabolic syndrome in Mexican-Mestizos. Because a pivotal role for ABCA1 in pancreatic beta-cell function was recently observed in the mouse model, we assessed the association of this variant with type 2 diabetes in this population. RESEARCH DESIGN AND METHODS: The initial group included 446 unrelated Mexican individuals: 244 with type 2 diabetes aged 20-69 years (121 with onset 50 years. An independent study group included 242 type 2 diabetic case subjects and 225 control subjects with similar characteristics. RESULTS: R230C/C230C genotypes were significantly more frequent in type 2 diabetic individuals (24.6%) than in control subjects (11.4%) in the initial study group (OR 2.501; P = 0.001). After stratifying by age at diagnosis, the association was significant only in the early-onset group (age at diagnosis
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Diabetes Mellitus Tipo 2/genética , Variação Genética , Transportador 1 de Cassete de Ligação de ATP , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Genótipo , Humanos , México , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Valores de ReferênciaRESUMO
Hepatic nuclear factor-4alpha (HNF-4alpha), a transcription factor involved in the regulation of serum lipid and glucose levels, has recently been associated with type 2 diabetes. The HNF-4alpha gene (HNF4A) resides on chromosome 20q12-q13.1, which, in addition to type 2 diabetes, has also previously been linked to high triglycerides in Finnish familial combined hyperlipidemia (FCHL) families. FCHL, characterized by elevated levels of serum total cholesterol, triglycerides, or both, is a common dyslipidemia observed in up to 20% of patients with premature coronary heart disease. Considering the clear phenotypic overlap between type 2 diabetes and FCHL, both predisposing to high serum triglycerides and glucose intolerance, we tested this gene for association in dyslipidemic families originating from two distinct populations, Finnish and Mexican, and comprising 1,447 subjects. Our data show that common HNF4A variants and haplotypes are associated with elevated serum lipid levels and the metabolic syndrome (P = 0.008-0.04), as well as with elevated glucose parameters (P = 0.008-0.03), using family-based association analysis. Importantly, both Finnish and Mexican families shared two common lipid-associated HNF4A haplotypes (P = 0.005 for total cholesterol and 0.006 for triglycerides). In conclusion, we show for the first time that common HNF4A variants are associated with high serum lipid levels and the metabolic syndrome.
Assuntos
Variação Genética , Fator 4 Nuclear de Hepatócito/genética , Hiperlipidemias/sangue , Síndrome Metabólica/genética , Apolipoproteínas B/sangue , Apolipoproteínas B/genética , Colesterol/sangue , Diabetes Mellitus Tipo 2/genética , Finlândia , Frequência do Gene , Humanos , Hiperlipidemias/genética , México , Fenótipo , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangueRESUMO
The etiology of Alzheimer's disease (AD) is complex. To date, molecular genetic studies in several families affected with AD have identified three genes associated with highly penetrant early-onset AD: Presenilin 1 (PSEN1), Presenilin 2 (PSEN2) and beta-amyloid precursor protein (APP); and one gene (apolipoprotein E) associated with late-onset AD. Molecular analysis of the PSEN1 gene was performed by direct sequencing of genomic DNA. The possible founder effect was investigated analyzing two highly polymorphic microsatellite markers flanking the PSEN1 gene. Twelve unrelated Mexican families with early-onset AD were analyzed. The Ala431Glu mutation in exon 12 of PSEN1 was found in nine (75%) of these families, which segregated showing autosomal dominant inheritance. Because all families bearing the mutation are from the State of Jalisco (located in Western Mexico), a founder effect was hypothesized. Microsatellite haplotype analysis suggested a common ancestor in these nine kindreds. In conclusion, the Ala431Glu mutation is a prevalent cause of early-onset familial Alzheimer's disease in families from the State of Jalisco, Mexico. Genetic evidence supports that it is a founder mutation descending from a single common ancestor. These findings have important implications for prompt diagnosis and genetic counseling for Mexican patients with familial AD from Jalisco.
Assuntos
Doença de Alzheimer/genética , Efeito Fundador , Predisposição Genética para Doença , Mutação de Sentido Incorreto , Presenilina-1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/etiologia , Apolipoproteínas E/genética , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Frequência do Gene , Testes Genéticos , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Polimorfismo GenéticoRESUMO
BACKGROUND: Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) are relatively common lipid disorders caused by mutations of the low-density lipoprotein receptor (LDLR) and apolipoprotein B (apoB) genes, respectively. A third locus on chromosome 1p34.1-p32 was recently linked to FH and the responsible gene has been identified [protein convertase subtilisin/kexin type 9 (PCSK9)]. METHODS: We assessed the contribution of the LDLR, apoB, and PCSK9 genes as cause of FH in Mexico. Forty six unrelated probands, as well as 68 affected and 60 healthy relatives, were included. RESULTS: All index cases were diagnosed as having heterozygous autosomal dominant FH. Seventeen of the 46 index cases had LDLR gene mutations, four of which were novel (Fs92ter108, C268R, Q718X, and Fs736ter743); and only one patient had an apoB mutation (R3500Q). We sequenced the PCSK9 gene in the remainder of the 28 probands with no identified LDLR or APOB gene defects; however, no PCSK9 mutations were found, including one large kindred with positive linkage to the 1p34.1-32 locus (multipoint LOD score of 3.3) and two small pedigrees. Linkage was excluded from these three loci in at least four kindreds suggesting that other yet uncharacterized genes are involved. CONCLUSIONS: Our results underline substantial genetic heterogeneity for FH in the Mexican population.
Assuntos
Apolipoproteínas B/genética , Cromossomos Humanos Par 1/genética , Heterogeneidade Genética , Hiperlipoproteinemia Tipo II/genética , Receptores de LDL/genética , Serina Endopeptidases/genética , Adulto , Apolipoproteína B-100 , Feminino , Humanos , Escore Lod , Masculino , México , Pessoa de Meia-Idade , Pró-Proteína Convertase 9 , Pró-Proteína Convertases , Locos de Características QuantitativasRESUMO
OBJECTIVE: To investigate the largely unknown genetic component of the common lipid disorder, familial combined hyperlipidemia (FCHL) in Mexicans, we analyzed the upstream transcription factor 1 (USF1) gene that was recently associated with FCHL and high triglycerides (TG) in Finns. We also analyzed the Mexican FCHL families for 26 microsatellite markers residing in the seven chromosomal regions on 2p25.1, 9p23, 10q11.23, 11q13, 16q24.1, 19q13, and 21q21, previously linked to FCHL in whites. METHODS AND RESULTS: We genotyped 314 individuals in 24 Mexican families for 13 SNPs spanning an 88-kb region, including USF1. The FCHL and TG traits showed significant evidence for association with 3 SNPs, hCV1459766, rs3737787, and rs2073658, and haplotype analyses further supported these findings (probability values of 0.05 to 0.0009 for SNPs and their haplotypes). Of these SNPs, hCV1459766 is located in the F11 receptor (F11R) gene, located next to USF1, making it difficult to exclude. Importantly, the association was restricted to a considerably smaller region than in the Finns (14 kb versus 46 kb), possibly because of a different underlying linkage disequilibrium structure. In addition, 1 of the 7 regions, 16q24.1, showed suggestive evidence for linkage (a lod score of 2.6) for total cholesterol in Mexicans. CONCLUSIONS: This study, the first to extensively investigate the genetic component of the common FCHL disorder in Mexicans, provides independent evidence for the role of USF1 in FCHL in an outbred population and links the 16q24.1 region to an FCHL-component trait in Mexicans.
Assuntos
Cromossomos Humanos Par 16 , Ligação Genética , Hiperlipidemia Familiar Combinada/etnologia , Hiperlipidemia Familiar Combinada/genética , Fatores Estimuladores Upstream/genética , Adulto , Idoso , Aterosclerose/etnologia , Aterosclerose/genética , Família , Feminino , Haplótipos , Humanos , Masculino , México/epidemiologia , Repetições de Microssatélites , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Coronary artery disease and diabetes mellitus are among the primary mortality and morbidity causes in Mexico. Genetic factors play a fundamental role in the development of these entities. In the past few years due to the recognition and study of families with monogenic forms of diabetes and dislipidemias associated with development of atherosclerosis, several genes and loci have been associated with these conditions through genetic linkage studies. These studies have provided evidence of the genetic heterogeneity that exists and the type of genes involved in different ethnic groups. The study of Mexican families with early-onset diabetes and combined familial hyperlipidemia showed the participation of different genetic loci associated with these conditions in the Mexican population. These findings show the value of gene mapping strategies in the identification of the genetic component in these entities in our population.
Assuntos
Doenças Cardiovasculares/genética , Diabetes Mellitus/genética , Suscetibilidade a Doenças/epidemiologia , Adolescente , Adulto , Doenças Cardiovasculares/epidemiologia , Criança , Mapeamento Cromossômico , Diabetes Mellitus/epidemiologia , Família , Feminino , Ligação Genética , Humanos , Masculino , México/epidemiologiaRESUMO
La enfermedad arterial coronaria y la diabetes mellitus figuran entre las primeras causas de mortalidad y morbilidad en México. Factores genéticos juegan un papel fundamental en el desarrollo de estas entidades. A partir del reconocimiento y estudio de familias con formas monogénicas de diabetes y distintas dislipidemias asociadas al desarrollo de ateroesclerosis, se han identificado en los últimos años distintos genes y loci relacionados con estos padecimientos a través de estudios de mapeo genético. Estos estudios han evidenciado la heterogeneidad genética que existe en cuanto al tipo de genes involucrados en los distintos grupos étnicos. El estudio de familias mexicanas con diabetes de inicio temprano e hiperlipidemia familiar combinada mostró la participación de distintos loci génicos asociados a estas entidades en la población mexicana. Esto muestra la utilidad de las estrategias de mapeo para la identificación del componente genético de estas entidades en nuestra población.
Coronary artery disease and diabetes mellitus are among the primary mortality and morbidity causes in Mexico. Genetic factors play a fundamental role in the development of these entities. In the past few years due to the recognition and study of families with monogenic forms of diabetes and dislipidemias associated with development of atherosclerosis, several genes and loci have been associated with these conditions through genetic linkage studies. These studies have provided evidence of the genetic heterogeneity that exists and the type of genes involved in different ethnic groups. The study of Mexican families with early onset diabetes and combined familial hyperlipidemia showed the participation of different genetic loci associated with these conditions in the Mexican population. These findings show the value of gene mapping strategies in the identification of the genetic component in these entities in our population.
Assuntos
Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Doenças Cardiovasculares/genética , Diabetes Mellitus/genética , Suscetibilidade a Doenças/epidemiologia , Mapeamento Cromossômico , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus/epidemiologia , Família , Ligação Genética , México/epidemiologiaRESUMO
Autosomal recessive hypercholesterolemia (ARH) is characterized by elevated LDL serum levels, xanthomatosis, and premature coronary artery disease. Three loci have been described for this condition (1p35, 15q25-q26 and 13q). Recently, the responsible gene at the 1p35 locus, encoding an LDL receptor adaptor protein (ARH) has been identified. We studied a Mexican ARH family with two affected siblings. Sequence analysis of the ARH gene (1p35 locus) revealed that the affected siblings are homozygous for a novel mutation (IVS4+2T>G) affecting the donor splice site in intron 4, whereas both the parents and an unaffected sister are heterozygous for this mutation. The IVS4+2T>G mutation results in a major alternative transcript derived from a cryptic splice site, which carries an in-frame deletion of 78 nucleotides in the mature mRNA. The translation of this mRNA yields a mutant protein product (ARH-26) lacking 26 amino acids, resulting in the loss of beta-strands beta6 and beta7 from the PTB domain. This is the first case where a naturally occurring mutant with an altered PTB domain has been identified.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Genes Recessivos , Hipercolesterolemia/genética , Mutação , Sítios de Splice de RNA/genética , Adulto , Sequência de Aminoácidos , Consanguinidade , Feminino , Humanos , Hipercolesterolemia/fisiopatologia , Masculino , México , Dados de Sequência Molecular , Linhagem , Estrutura Terciária de Proteína , Xantomatose/genética , Xantomatose/fisiopatologiaRESUMO
Heterozygous familial hypercholesterolemia (FH) is a highly atherogenic genetic disorder leading to premature coronary heart disease (CHD), usually before 60 years of age. We studied an extended multigenerational kindred with FH linked to chromosome 1p32 in which atherosclerotic complications were either delayed or prevented in individuals with elevated HDL cholesterol (HDL-C) levels or hyperalphalipoproteinemia (HA). Premature CHD was observed in FH individuals without HA. The study of this family established that the HA trait in the family also followed an autosomal dominant mode of inheritance with a pattern of segregation independent from FH. We identified a locus on chromosome 6 linked to elevated HDL-C levels (HA) in this family. Haplotype analysis refined the localization to a 7.32-cM interval (73 to 80 cM from pter) flanked by markers D6S1280 and D6S1275. Parametric 2-point and multipoint analyses yielded maximum LOD scores of 3.05 and 3.17, respectively. This finding was confirmed with a nonparametric multipoint score of 3.78 (P=0.0009). We propose that this locus, linked to elevated HDL-C levels, confers protection against premature CHD within an FH context.