RESUMO
When activated, thrombin activatable fibrinolysis inhibitor (TAFI) inhibits fibrinolysis by modifying fibrin, depressing its plasminogen binding potential. Polymorphisms in the TAFI structural gene (CPB2) have been associated with variation in TAFI levels, but the potential occurrence of influential quantitative trait loci (QTLs) located elsewhere in the genome has been explored only in families ascertained in part through probands affected by thrombosis. We report the results of the first genome-wide linkage screen for QTLs that influence TAFI phenotypes. Data are from 635 subjects from 21 randomly ascertained Mexican American families participating in the San Antonio Family Heart Study. Potential QTLs were localized through a genome-wide multipoint linkage scan using 417 highly informative autosomal short tandem repeat markers spaced at approximately 10-cM intervals. We observed a maximum multipoint LOD score of 3.09 on chromosome 13q, the region of the TAFI structural gene. A suggestive linkage signal (LOD = 2.04) also was observed in this region, but may be an artifact. In addition, weak evidence for linkage occurred on chromosomes 17p and 9q. Our results suggest that polymorphisms in the TAFI structural gene or its nearby regulatory elements may contribute strongly to TAFI level variation in the general population, although several genes in other regions of the genome may also influence variation in this phenotype. Our findings support those of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project, which identified a potential TAFI QTL on chromosome 13q in a genome-wide linkage scan in Spanish thrombophilia families.
Assuntos
Carboxipeptidase B2/genética , Cromossomos Humanos Par 13/genética , Americanos Mexicanos/genética , Locos de Características Quantitativas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carboxipeptidase B2/sangue , Carboxipeptidase B2/fisiologia , Feminino , Ligação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Low bone mineral density (BMD) is a predictor of cardiovascular mortality, suggesting that osteoporosis and cardiovascular disease may share common risk factors. We assessed the relationship between BMD and intimal medial thickening (IMT) of the common carotid artery, a marker of sub-clinical atherosclerosis, in 471 women examined as part of the San Antonio Family Osteoporosis Study, a population-based study of osteoporosis risk conducted in Mexican American families. Because of the documented role of vitamin D metabolism in bone metabolism and its possible role in cardiovascular function, we further evaluated whether allelic variation at the vitamin D receptor locus (VDR) influenced joint variation in BMD and IMT. The association of BMD with IMT depended on age, with low BMD being correlated with high IMT in older women, but with low IMT in younger women [age by IMT interaction effects significant at the spine (P = 0.042), radius ultradistal (P = 0.010), and hip (P = 0.006)]. In all women, the VDR BsmI BB genotype was associated with significantly higher forearm BMD (P = 0.005 for both radius ultradistal and midpoint), higher IMT (P = 0.05), and higher spine BMD in older women (P = 0.06), but not with hip BMD. The association of the VDR genotype with IMT was independent of its association with BMD. Although a functional consequence of the BsmI polymorphism on vitamin D metabolism has not been established, these findings support a possible biological relationship among VDR, bone metabolism, and atherosclerosis. We conclude that VDR polymorphisms may be one of multiple factors influencing the joint risk of atherosclerosis and osteoporosis.
Assuntos
Arteriosclerose/genética , Densidade Óssea/genética , Americanos Mexicanos/genética , Osteoporose Pós-Menopausa/genética , Polimorfismo Genético , Receptores de Calcitriol/genética , Adulto , Arteriosclerose/etnologia , Arteriosclerose/patologia , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/etnologia , Osteoporose Pós-Menopausa/patologia , Pós-Menopausa , Pré-Menopausa , Receptores de Calcitriol/metabolismo , Fatores de Risco , Texas/epidemiologia , Túnica Íntima/diagnóstico por imagem , Túnica Íntima/patologia , Túnica Média/diagnóstico por imagem , Túnica Média/patologia , UltrassonografiaRESUMO
OBJECTIVE: We conducted a whole-genome, multipoint linkage screen to localize a previously reported major locus accounting for 56% to 67% of the additive genetic effects on covariate-adjusted plasma HDL cholesterol (HDL-C) levels in Mexican Americans from the San Antonio Family Heart Study (SAFHS). METHODS AND RESULTS: After using complex segregation analysis to recover the major locus in 472 SAFHS participants from 10 genotyped families, we incorporated covariates required to detect that major locus, including plasma levels of triglycerides and apolipoprotein A-I, in a maximum-likelihood-based variance-components linkage screen. Only chromosome 16 exhibited convincing evidence for a quantitative trait locus (QTL), with a peak multipoint log of the odds (LOD)=3.73 (P=0.000034). Subsequent penetrance model-based linkage analysis, incorporating genotypes at the marker locus nearest the multipoint peak (D16S518) into the segregation model, detected linkage with the previously detected major locus (LOD=2.73, P=0.000642). Initial estimates place this QTL within a 15-cM region of chromosome 16q near the structural loci for lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP). CONCLUSIONS: A QTL influencing plasma levels of HDL-C in Mexican Americans from San Antonio maps to a region of human chromosome 16q near LCAT and CETP.
Assuntos
HDL-Colesterol/sangue , Cromossomos Humanos Par 16/genética , Americanos Mexicanos/genética , Locos de Características Quantitativas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína A-I/sangue , Marcadores Genéticos/genética , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Genoma Humano , Genótipo , Humanos , Escore Lod , Masculino , Americanos Mexicanos/estatística & dados numéricos , Pessoa de Meia-Idade , Fenótipo , Texas/epidemiologia , Triglicerídeos/sangueRESUMO
The genetic mechanisms that control variation in blood pressure level are largely unknown. One of the first steps in understanding those mechanisms is the localization of the genes that have a significant effect on blood pressure. We performed genome scans of systolic (SBP) and diastolic blood pressure (DBP) on a population-based sample of families in the San Antonio Family Heart Study. A likelihood-based Mendelian model incorporating genotype-specific effects of sex, age, age(2), BMI, and blood pressure (SBP or DBP, as appropriate) as covariates was used to perform two-point lodscore (Z) linkage on 399 polymorphic markers. Results showed that the genotype-specific covariate effects were highly significant for both SBP and DBP. Linkage results showed that a quantitative trait locus (QTL) influencing DBP was significantly linked to D2S1790 (Z = 3.92, theta = 0.00) and showed suggestive linkage to D8S373 (Z = 1.92, theta = 0.00). A QTL influencing SBP showed suggestive linkage to D21S1440 (Z = 2.82, theta = 0.00) and D18S844 (Z = 2.09, theta = 0.11). Without the genotype-specific effects in the model, the linkage to D2S1790 was not even suggestive (Z = 1.33, theta = 0.09); thus genotype-specific modeling was crucial in detecting this linkage. A comparison with linkage studies based in other populations showed that the significant linkage to D2S1790 has been replicated at the same marker in the Quebec Family Study. The replicated significant linkage at D2S1790 may begin to establish the locations of the genes that significantly affect blood pressure across several human ethnic groups.
Assuntos
Pressão Sanguínea/genética , Genética Populacional , Americanos Mexicanos/genética , Adulto , Diástole , Feminino , Ligação Genética , Genoma Humano , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Modelos Estatísticos , Reação em Cadeia da Polimerase , SístoleRESUMO
Pulse pressure, a measure of aortic stiffness, is a strong predictor of cardiovascular mortality. To locate genes that affect pulse pressure, we performed genetic analysis on randomly ascertained families in the San Antonio Family Heart Study. Pulse pressure was defined as the difference between systolic and diastolic blood pressures. Likelihood methods were used to construct a model that had both single-locus and polygenic components for 46 families (1308 individuals). The single-locus component included sex-specific and genotype-specific effects of both age and body mass index. Using this model, we then performed 2-point linkage analysis in 10 families (440 individuals) that were among the largest of the 46 families and that had been genotyped for 399 polymorphic markers. The model that contained only the polygenic component and simple effects of the covariates showed pulse pressure heritability of 0.21. When the single-locus component was added, the sex-specific and genotype-specific effects of age and body mass index were highly significant (P<0.002). The full model accounted for 73% of the total variation of pulse pressure. Linkage analysis using this model with each marker revealed 4 markers with lod scores >1.9, which is the Lander-Kruglyak suggestive linkage standard. D21S1440 had a lod score of 2.78 with a recombination fraction (theta) of 0.02. D7S1799 had a lod score of 2.04 (theta=0.01), D8S1100 had a lod score of 1.98 (theta=0.08), and D18S844 had a lod score of 1.95 (theta=0.11). These results are highly correlated with results involving systolic blood pressure, indicating that pulse pressure may not be genetically distinct from systolic blood pressure.
Assuntos
Doenças Cardiovasculares/genética , Ligação Genética , Americanos Mexicanos/genética , Pulso Arterial , Adolescente , Envelhecimento/genética , Pressão Sanguínea , Índice de Massa Corporal , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Feminino , Marcadores Genéticos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Característica Quantitativa Herdável , Fatores Sexuais , Texas/epidemiologiaRESUMO
Recent changes in lifestyle have led to a global epidemic of obesity. To determine the associations of these changes with cardiovascular disease (CVD) risk, the authors correlated changes in CVD risk factors with changes in weight and physical activity in a population-based sample of 539 Mexican Americans in the San Antonio Heart Study in 1992-1999 who were examined twice approximately 5 years apart. Average weight change during that interval was 2.7 kg. While change in physical activity (expressed as percent change) was associated modestly only with change in low density lipoprotein cholesterol median diameter (p = 0.017), weight change was strongly and positively associated with unfavorable changes in lipid and lipoprotein traits, insulin levels, and blood pressure, explaining 2-10% of the variation in the risk factor changes during the interval. The unfavorable associations with weight gain tended to be more pronounced in lean compared with obese individuals and in men compared with women. However, the associations were significant for most CVD risk factors in all groups. In Mexican Americans, a population at high risk for obesity, weight change was positively correlated with metabolic variables associated with risk of CVD. Therefore, increasing adiposity in this population may tend to slow, or even reverse, the decline in CVD morbidity and mortality.
Assuntos
Peso Corporal , Doenças Cardiovasculares/epidemiologia , Americanos Mexicanos/estatística & dados numéricos , Esforço Físico , Adulto , Análise de Variância , Glicemia/análise , Índice de Massa Corporal , Doenças Cardiovasculares/sangue , Feminino , Humanos , Modelos Lineares , Lipídeos/sangue , Masculino , Fatores de Risco , Distribuição por Sexo , Texas/epidemiologia , Fatores de Tempo , População Urbana/estatística & dados numéricosRESUMO
OBJECTIVE: To investigate whether the region of chromosome 11 (11q13) containing the genes UCP2 and UCP3 could be excluded for linkage with a variety of obesity-related phenotypes in humans. DESIGN: Exclusion mapping using a variance component approach in extended pedigrees. SUBJECTS: Four-hundred and fifty eight individuals (195 females, 263 males) distributed in 10 Mexican American families of probands randomly ascertained with respect to any disease state and who are participating in the San Antonio Family Heart Study. Ages range from 18 to 87 (mean age 35 y). MEASUREMENTS: Serum leptin levels, fat mass (FM), body mass index (BMI), and waist circumference. RESULTS: We were able to exclude the chromosomal region containing UCP2/UCP3 as having an effect on this set of obesity-related phenotypes at relative effect sizes of 10% or greater (P-values<0.05). CONCLUSIONS: These results suggest that variation in these genes is unlikely to have a substantial effect on the expression of obesity-related phenotypes in the Mexican American population.
Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Par 11 , Proteínas de Membrana Transportadoras , Americanos Mexicanos/genética , Proteínas Mitocondriais , Obesidade/genética , Proteínas/genética , População Branca/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antropometria , Mapeamento Cromossômico , Feminino , Humanos , Canais Iônicos , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Texas , Proteína Desacopladora 2 , Proteína Desacopladora 3RESUMO
Hyperinsulinemia predicts the development of type 2 diabetes, and family studies suggest that insulin levels are regulated in part by genes. We conducted a genome-wide scan to detect genes influencing variation in fasting serum insulin concentrations in 391 nondiabetic individuals from 10 large multigenerational families. Approximately 380 microsatellite markers with an average spacing of 10 cM were genotyped in all study subjects. Insulin concentrations measured by radioimmunoassay were transformed by their natural logarithms before analysis. In multipoint analysis, peak evidence for linkage occurred on chromosome 3p approximately 109 cM from pter in the region of 3p14.2-p14.1. The multipoint logarithm of odds (LOD) score was 3.07, occurring in the region flanked by markers D3S1600 and D3S1285 (P value by simulation <0.0001). In a two-point analysis, LOD scores ranged from 0.75 to 2.52 for the nine markers typed in the region spanning 88-143 cM from pter. The fasting insulin resistance index was highly correlated with fasting insulin concentrations in this sample and also provided strong evidence for linkage to this region (LOD = 2.99). There was no evidence in our genome-wide scan for linkage of insulin levels to any other chromosome. These results provide evidence that a gene-influencing variation in insulin concentrations exists on chromosome 3p. Possible candidate genes in this region include GBE1 and ACOX2, which encode enzymes involved in glycogen and fatty acid metabolism, respectively.
Assuntos
Cromossomos Humanos Par 3/genética , Ligação Genética , Insulina/sangue , Americanos Mexicanos/genética , Adulto , Jejum/sangue , Feminino , Genótipo , Humanos , Resistência à Insulina/genética , Escore Lod , Masculino , Repetições de Microssatélites , Concentração OsmolarRESUMO
We previously reported that our genome-scanning initiative had detected a highly significant linkage (log odds ratio = 4.95; P = 9 x 10(-7)) between a quantitative trait locus (QTL) on chromosome 2 and leptin levels in Mexican American families. We now have typed additional microsatellite markers in this region, increasing this log odds ratio score to 7.46 (P = 2 x 10(-9)). This region of chromosome 2 contains a strong positional candidate gene, POMC. The POMC gene codes for POMC, the prohormone from which alphaMSH, ACTH, and beta-endorphin are derived. Studies by others have shown that POMC-derived products are involved in the regulation of appetite and obesity. We have used polymorphisms in POMC to map its location within the 95% confidence interval of the peak for the linkage signal for the QTL. We also constructed POMC haplotypes using these polymorphisms and have found a significant association with normal variation in leptin levels (P = 0.001). We conclude that variation in POMC is associated with normal variation in serum leptin levels, providing further evidence that POMC may be the leptin QTL previously identified in Mexican American families.
Assuntos
Polimorfismo Genético , Pró-Opiomelanocortina/genética , Proteínas/metabolismo , Mapeamento Cromossômico , Cromossomos Humanos Par 2 , Feminino , Genótipo , Hispânico ou Latino/genética , Humanos , Leptina , Escore Lod , Masculino , México/etnologia , Reação em Cadeia da PolimeraseRESUMO
There is a strong familial predisposition to type 2 diabetes, hypertension, and cardiovascular disease. The authors evaluated the association between a family history of these diseases and a large panel of cardiovascular risk factors in 1,431 Mexican American subjects who were enrolled in the San Antonio Family Heart Study in San Antonio, Texas. The baseline phase of the study covered 1992-1996. Diabetes and hypertension were diagnosed according to standard clinical criteria, while cardiovascular disease was defined as a history of heart attack or heart surgery. The prevalence of diabetes, hypertension, and cardiovascular disease in this population was 15%, 12%, and 3%, respectively. For each unaffected subject, the authors computed a family history score based on the presence or absence of disease in parents and older siblings, and correlations between cardiovascular risk factors and family history scores were estimated by using likelihood-based variance component methods. Diabetes family history score was significantly correlated with a broad panel of cardiovascular risk factors, including glucose and insulin, obesity, blood pressure, triglycerides, and total cholesterol. Hypertension family history score was significantly correlated with glucose, blood pressure, body mass index, waist circumference, total cholesterol, and triglycerides. These results support the idea that genes that confer a risk for diabetes, and to a lesser extent hypertension, adversely alter the cardiovascular risk profile long before the manifestation of clinical disease.
Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Complicações do Diabetes , Hipertensão/complicações , Americanos Mexicanos/estatística & dados numéricos , Adulto , Distribuição por Idade , Doenças Cardiovasculares/sangue , Diabetes Mellitus/sangue , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/genética , Feminino , Humanos , Hipertensão/sangue , Hipertensão/epidemiologia , Hipertensão/genética , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Prevalência , Risco , Fatores de Risco , Distribuição por Sexo , Texas/epidemiologiaRESUMO
The beta3 adrenergic receptor, located on chromosome 8, is a regulator of energy expenditure and lipolysis. A missense mutation in this gene, characterized by the replacement of tryptophan by arginine at codon 64 (Trp64Arg), is associated with obesity in some studies. We examined the effect of this variant on obesity in Mexican Americans, using a paired sibling design to minimize variability due to genetic background and a previously identified major susceptibility locus for obesity. We identified 45 sib-pairs that were concordant (identical by descent) for a locus on chromosome 2 which we have shown previously to be tightly linked to obesity in this population. The Trp64Arg variant, detected by PCR-restriction fragment length polymorphism analysis, was present in one sibling within each of the 45 sib-pairs. Presence of the variant was associated with significantly higher values in body mass index (P = 0.04), fat mass (P = 0.04), and waist circumference (P = 0.05). We conclude that the Trp64Arg variant is associated with obesity in this Mexican American population. The paired sibling design probably enhanced our ability to detect the effects of this variant by allowing us to account for variation attributable to another obesity susceptibility locus and to background genes.
Assuntos
Arginina/genética , Americanos Mexicanos , Obesidade/genética , Receptores Adrenérgicos beta/genética , Triptofano/genética , Adulto , Variação Genética , Humanos , Receptores Adrenérgicos beta 3RESUMO
Essential hypertension has been linked to a highly polymorphic marker at the angiotensinogen locus, and association with a polymorphism in this locus has been found in some populations. We tested the hypothesis that these same polymorphic markers are linked to essential hypertension in Mexican Americans. The data comprised all the affected relative pairs in 46 extended families chosen at random from a low-income barrio in San Antonio. Specifically, we searched for linkage by testing for excessive marker alleles shared identical by descent (IBD) among hypertensive relative pairs. When women taking oral contraceptives or hormones were excluded, the affected relative pairs shared a significant excess of alleles IBD for the highly heterozygous GT repeat polymorphism (P=.038) and were marginally significant for the M235T variant (P=.079), which has a much lower heterozygosity (0.43 versus 0.85 for the GT repeat). We also assayed plasma levels of angiotensinogen and, using likelihood methods, found no significant association (P=.43) between plasma levels of angiotensinogen and M235T genotypes. These results support the linkage of essential hypertension to the angiotensinogen locus but do not indicate a specific role for the M235T variant.
Assuntos
Angiotensinogênio/genética , Mapeamento Cromossômico , Ligação Genética/genética , Hipertensão/genética , Americanos Mexicanos/genética , Adulto , Índice de Massa Corporal , Repetições de Dinucleotídeos/genética , Feminino , Variação Genética , Genótipo , Humanos , Hipertensão/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genéticaRESUMO
The purpose of this study was to investigate the genetic control of various HDL measures and to determine the proportion of genetic variance explained by shared genes (ie, pleiotropy) and the proportion unique to each trait. The data used were drawn from large, randomly ascertained pedigrees of Mexican Americans participating in the San Antonio Family Heart Study. Data were available for 655 individuals (258 men and 397 women) in 26 families. We performed a multivariate quantitative genetic analysis to simultaneously estimate both the additive genetic and random environmental correlations among seven HDL phenotypes. These seven HDL phenotypes can be divided into two categories: measures of concentration and estimates of particle size. Concentration was measured for apo A-I, apo A-II, esterified cholesterol, and unesterified cholesterol, and particle size was estimated for apo A-I, apo A-II, and esterified cholesterol. The heritabilities (h2) for each of the seven traits were significantly greater than zero (P<.05) and ranged from 0.2 to 0.6. When considered in a pairwise fashion, all combinations of these traits showed marked genetic correlations (rho(G)=0.33 to 0.87) and all were significantly greater than zero (P<.05), indicative of pleiotropic effects. However, we found substantial unique genetic variance for each of these traits even after accounting for the effects shared in common with all the remaining measures. We conclude that the genetic variation in these HDL phenotypes is a result of the action of common as well as unique genes.
Assuntos
Lipoproteínas HDL/genética , Fenótipo , Adulto , Apolipoproteína A-I/análise , Apolipoproteína A-II/análise , Colesterol/sangue , Ésteres do Colesterol/sangue , HDL-Colesterol/sangue , HDL-Colesterol/genética , Feminino , Hispânico ou Latino , Humanos , Lipoproteínas HDL/sangue , Masculino , México/etnologia , Tamanho da PartículaRESUMO
Dehydroepiandrosterone sulfate (DHEAS) is an adrenal steroid which has been inversely associated with development of atherosclerosis. We estimated heritability of serum DHEAS levels in 564 related Mexican Americans. We found a significant heritability for DHEAS (h2 = 0.39, p < 0.001). Measures of alcohol consumption, reproductive status, body composition, and HDL3 levels showed significant relationships with serum DHEAS levels. Sex and age were significantly associated with the mean, but not the genetic variance, of DHEAS levels. The results of this study demonstrate a significant genetic influence on steroid concentration and help to quantify the factors contributing to cardiovascular disease risk in Mexican Americans.
Assuntos
Doenças Cardiovasculares/genética , Sulfato de Desidroepiandrosterona/sangue , Variação Genética , Americanos Mexicanos , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etnologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Fatores de Risco , Fatores Sexuais , TexasRESUMO
BACKGROUND: The familial aggregation of coronary heart disease can be in large part accounted for by a clustering of cardiovascular disease risk factors. To elucidate the determinants of cardiovascular disease, many epidemiological studies have focused on the behavioral and lifestyle determinants of these risk factors, whereas others have examined whether specific candidate genes influence quantitative variation in these phenotypes. METHODS AND RESULTS: Among Mexican Americans from San Antonio (Tex), we quantified the relative contributions of both genetic and environmental influences to a large panel of cardiovascular risk factors, including serum levels of lipids, lipoproteins, glucose, hormones, adiposity, and blood pressure. Members of 42 extended families were studied, including 1236 first-, second-, and third-degree relatives of randomly ascertained probands and their spouses. In addition to the phenotypic assessments, information was obtained regarding usual dietary and physical activity patterns, medication use, smoking habits, alcohol consumption, and other lifestyle behaviors and medical factors. Maximum likelihood methods were used to partition the variance of each phenotype into components attributable to the measured covariates, additive genetic effects (heritability), household effects, and an unmeasured environmental residual. For the lipid and lipoprotein phenotypes, age, gender, and other environmental covariates accounted in general for < 15% of the total phenotypic variance, whereas genes accounted for 30% to 45% of the phenotypic variation. Similarly, genes accounted for 15% to 30% of the phenotypic variation in measures of glucose, hormones, adiposity, and blood pressure. CONCLUSIONS: These results highlight the importance of considering genetic factors in studies of risk factors for cardiovascular disease.
Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Americanos Mexicanos , Adulto , Fatores Etários , Idoso , Antropometria , Apolipoproteínas A/sangue , Glicemia , Pressão Sanguínea , Doenças Cardiovasculares/complicações , HDL-Colesterol/sangue , Sulfato de Desidroepiandrosterona/sangue , Complicações do Diabetes , Diabetes Mellitus/epidemiologia , Saúde da Família , Feminino , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Prevalência , Fatores de Risco , Fatores Sexuais , Globulina de Ligação a Hormônio Sexual/metabolismo , Texas/epidemiologiaRESUMO
Apolipoprotein A-I (apoA-I) is the principal protein component of HDL cholesterol. The thyroid hormone triiodothryonine (T3) is known to be a potent mediator of expression of the apoA-I structural gene (APOA1). Using complex segregation analysis, we detected a major gene influencing plasma concentration of apoA-I and examined its interaction with T3 serum level in Mexican Americans participating in the San Antonio Family Heart Study. Strong evidence for a major locus with two alleles (A and a) determining apoA-I level was obtained when interaction with T3 was allowed. The major gene appears not to be linked to the APOA1 structural locus. Genotypes differed significantly in their relationships to T3 level. The AA and Aa genotypes showed a positive relationship with T3 level, while the rarer aa homozygote showed a strong negative relationship with T3. The relative variance in apoA-I concentration due to this major gene varied from 56% to 18%, depending on T3 level. On average, the major gene accounts for 30% of apoA-I variation, and shared-household effects account for an additional 11%. These findings suggest that thyroid hormone has an important role in the genetic control of lipoprotein metabolism.
Assuntos
Apolipoproteína A-I/genética , Regulação da Expressão Gênica , Tri-Iodotironina/sangue , Adulto , Apolipoproteína A-I/sangue , Sequência de Bases , Feminino , Ligação Genética , Haplótipos , Humanos , Masculino , Americanos Mexicanos , Dados de Sequência MolecularRESUMO
We have carried out two independent family studies in low-income Mexican-Americans from San Antonio, Texas. In the first study, probands were ascertained at random without regard to any medical condition (658 examined individuals from 50 families), and in the second study, probands were subjects with type II diabetes identified in a prior epidemiological survey (523 examined individuals from 29 families). Pedigrees ranging in size from 2 to 45 family members (median 11) in the first study and from 2 to 50 family members (median 12) in the second study were examined. Diabetes was diagnosed according to World Health Organization criteria. In both sets of families, segregation analyses revealed support for a major gene with an autosomal dominant mode of inheritance influencing early age of onset of diabetes. Non-Mendelian inheritance was rejected in both data sets. Individuals with the early age of onset allele had a mean age of diabetes onset of 51 years in the first data set and 60 years in the second data set. In the first data set, the major gene accounted for approximately 70% of the phenotypic variance in age of onset of diabetes, and there were no residual family effects once the major gene effect was taken into account. In the second data set, the major gene accounted for approximately 50% of the phenotypic variance, and residual family effects were statistically significant. Linkage analyses were performed with 11 candidate genes, and tight linkage with diabetes was rejected for Rh blood group, glucose transporter 2, fatty acid-binding protein, tumor necrosis factor beta, glucokinase, and lipoprotein lipase. A logarithm of odds (LOD) score of 0.92 at a recombination fraction of 0.05 was observed for insulin receptor substrate 1. This LOD score corresponds to a chi2 of 4.24 (P = 0.039).
Assuntos
Diabetes Mellitus Tipo 2/genética , Americanos Mexicanos/genética , Alelos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Mapeamento Cromossômico , Cromossomos Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Suscetibilidade a Doenças , Família , Feminino , Genes Dominantes , Triagem de Portadores Genéticos , Ligação Genética , Marcadores Genéticos , Genótipo , Humanos , Escore Lod , Masculino , Modelos Genéticos , Núcleo Familiar , Linhagem , Probabilidade , Fatores de Risco , TexasRESUMO
Previous studies have shown that the inverse relationship between HDL cholesterol (HDL-C) and triglyceride (TG) levels, risk factors for cardiovascular disease, is due largely to the effects of shared genes. HDL-C and TG are also known to be related to endogenous sex hormone levels, however the nature of the relationships is unclear. The objective of this study is to ascertain the extent to which these relationships are determined by shared genes. We conducted a multivariate quantitative genetic analysis of HDL-C, TG, dehydroepiandrosterone sulfate (DHEAS) and sex hormone-binding globulin (SHBG) in 635 people from 27 pedigrees participating in the San Antonio Family Heart Study. Heritabilities (h2) and genetic and environmental correlations (rho G and rho E) were estimated simultaneously by maximum likelihood methods. All four traits showed significant (P < 0.05) heritabilities: h2HDL-C = 0.38, h2TG = 0.54, h2DHEAS = 0.43, h2SHBG = 0.26. Significant genetic correlations were detected between HDL and each of the other traits: rho G(HDL-TG) = -0.56, rho G(HDL-DHEAS) = 0.23 and rho G(HDL-SHBG) = -0.56. However, there were no significant genetic correlations between TG and either measure of sex hormones. Thus, at least three separate groups of genes influence HDL-C levels in Mexican Americans: one group that has pleiotropic effects on HDL and TG, one group influences both HDL-C and SHBG and a third influences both HDL-C and DHEAS.
Assuntos
Hormônios Esteroides Gonadais/sangue , Lipoproteínas/sangue , Lipoproteínas/genética , Americanos Mexicanos , Tecido Adiposo/anatomia & histologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , HDL-Colesterol/sangue , Sulfato de Desidroepiandrosterona/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Reprodução , Caracteres Sexuais , Globulina de Ligação a Hormônio Sexual/análise , Triglicerídeos/sangueRESUMO
In this study we partition the phenotypic correlations between body fat measures and serum levels of hormones with known, or suspected, lipolytic effects into their genetic and environmental components. Using variance decomposition techniques, we are able to estimate the pleiotropic effects of genes and/or shared environmental factors that give rise to the phenotypic correlations previously reported between these traits. We used data from a large sample of randomly ascertained Mexican-American families living in San Antonio, TX. Data were available for 582 individuals in 26 pedigrees. Levels of sex hormone-binding globulin, dehydroepiandrosterone sulfate, insulin, insulin-like growth factor I, total T4, and total T3 were assayed. The measures of body fat accumulation and topography included body mass index, subscapular/triceps ratio, and relative fat patterning index. The results of this analysis demonstrate that significant phenotypic correlations among these traits can arise from three underlying conditions: 1) entirely from shared genetic effects (pleiotropy), 2) entirely from shared random environmental effects, or 3) a combination of both effects. However, we also show that it is possible for significant genetic and environmental correlations to interact in such a way as to produce a phenotypic correlation that itself would not be considered significant.