RESUMO
BACKGROUND/OBJECTIVES: Although newer approaches have identified several metabolites associated with obesity, there is paucity of such information in paediatric populations, especially among Mexican-Americans (MAs) who are at high risk of obesity. Therefore, we performed a global serum metabolite screening in MA children to identify biomarkers of childhood obesity. METHODS: We selected 15 normal-weight, 13 overweight and 14 obese MA children (6-17 years) and performed global serum metabolite screening using ultra-performance liquid chromatography/quadruple orthogonal acceleration time of flight tandem micro mass spectrometer. Metabolite values were analysed to assess mean differences among groups using one-way analysis of variance, to test for linear trend across groups and to examine Pearson's correlations between them and seven cardiometabolic traits (CMTs): body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, homeostasis model of assessment-insulin resistance, triglycerides and high-density lipoprotein cholesterol. RESULTS: We identified 14 metabolites exhibiting differences between groups as well as linear trend across groups with nominal statistical significance. After adjustment for multiple testing, mean differences and linear trends across groups remained significant (P < 5.9 × 10(-5) ) for L-thyronine, bradykinin and naringenin. Of the examined metabolite-CMT trait pairs, all metabolites except for 2-methylbutyroylcarnitine were nominally associated with two or more CMTs, some exhibiting significance even after accounting for multiple testing (P < 3.6 × 10(-3) ). CONCLUSIONS: To our knowledge, this study - albeit pilot in nature - is the first study to identify these metabolites as novel biomarkers of childhood obesity and its correlates. These findings signify the need for future systematic investigations of metabolic pathways underlying childhood obesity.
Assuntos
Resistência à Insulina , Americanos Mexicanos , Obesidade Infantil/sangue , Adolescente , Biomarcadores/sangue , Pressão Sanguínea , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Quimiocina CCL2/sangue , Criança , HDL-Colesterol/sangue , Citocinas/sangue , Feminino , Humanos , Insulina/sangue , Interleucina-6/sangue , Leptina/sangue , Lipídeos/sangue , Masculino , Obesidade Infantil/etnologia , Obesidade Infantil/prevenção & controle , Valores de Referência , Fatores de Risco , Fator de Necrose Tumoral alfa/sangue , Estados Unidos/epidemiologia , Circunferência da CinturaRESUMO
AIMS: We aimed to determine the genetic and environmental correlation between various anthropometric indexes and incident Type 2 diabetes with a focus on waist circumference. METHODS: We used the data on extended Mexican-American families (808 subjects, 7617.92 person-years follow-up) from the San Antonio Family Heart Study and estimated the genetic and environmental correlations of 16 anthropometric indexes with the genetic liability of incident Type 2 diabetes. We performed bivariate trait analyses using the solar software package. RESULTS: All 16 anthropometric indexes were significantly heritable (range of heritabilities 0.24-0.99). Thirteen indexes were found to have significant environmental correlation with the liability of incident Type 2 diabetes. In contrast, only anthropometric indexes consisting of waist circumference (waist circumference, waist-hip ratio and waist-height ratio) were significantly genetically correlated (genetic correlation coefficients: 0.45, 0.55 and 0.44, respectively) with the liability of incident Type 2 diabetes. We did not observe such a correlation for BMI. CONCLUSIONS: Waist circumference as a predictor of future Type 2 diabetes is supported by the finding that they share common genetic influences.
Assuntos
Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/genética , Resistência à Insulina , Americanos Mexicanos/genética , Americanos Mexicanos/estatística & dados numéricos , Circunferência da Cintura , Adulto , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/prevenção & controle , Feminino , Seguimentos , Humanos , Resistência à Insulina/etnologia , Resistência à Insulina/genética , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Estudos Prospectivos , Valores de Referência , Fatores de Risco , Estados Unidos/epidemiologia , Circunferência da Cintura/etnologia , Circunferência da Cintura/genéticaRESUMO
BACKGROUND AND PURPOSE: We hypothesized that the P-selectin (SELP) gene, localized to a region on chromosome 1q24, pleiotropically contributes to increased blood pressure and cerebral atrophy. We tested this hypothesis by performing genetic correlation analyses for 13 mRNA gene expression measures from P-selectin and 11 other genes located in 1q24 region and three magnetic resonance imaging derived indices of cerebral integrity. METHODS: The subject pool consisted of 369 (219F; aged 28-85, average = 47.1 ± 12.7 years) normally aging, community-dwelling members of large extended Mexican-American families. Genetic correlation analysis decomposed phenotypic correlation coefficients into genetic and environmental components among 13 leukocyte-based mRNA gene expressions and three whole-brain and regional measurements of cerebral integrity: cortical gray matter thickness, fractional anisotropy of cerebral white matter, and the volume of hyperintensive WM lesions. RESULTS: From the 13 gene expressions, significant phenotypic correlations were only found for the P- and L-selectin expression levels. Increases in P-selectin expression levels tracked with decline in cerebral integrity while the opposite trend was observed for L-selectin expression. The correlations for the P-selectin expression were driven by shared genetic factors, while the correlations with L-selectin expression were due to shared environmental effects. CONCLUSION: This study demonstrated that P-selectin expression shared a significant variance with measurements of cerebral integrity and posits elevated P-selectin expression levels as a potential risk factor of hypertension-related cerebral atrophy.
RESUMO
Multiple genetic and environmental factors influence the risk for both major depression and alcohol/substance use disorders. In addition, there is evidence that these illnesses share genetic factors. Although, the heritability of these illnesses is well established, relatively few studies have focused on ethnic minority populations. Here, we document the prevalence, heritability, and genetic correlations between major depression and alcohol and drug disorders in a large, community-ascertained sample of Mexican-American families. A total of 1,122 Mexican-American individuals from 71 extended pedigrees participated in the study. All subjects received in-person psychiatric interviews. Heritability, genetic, and environmental correlations were estimated using SOLAR. Thirty-five percent of the sample met criteria for DSM-IV lifetime major depression, 34% met lifetime criteria for alcohol use disorders, and 8% met criteria for lifetime drug use disorders. The heritability for major depression was estimated to be h(2) = 0.393 (P = 3.7 × 10(-6)). Heritability estimates were higher for recurrent depression (h(2) = 0.463, P = 4.0 × 10(-6)) and early onset depression (h(2) = 0.485, P = 8.5 × 10(-5)). While the genetic correlation between major depression and alcohol use disorders was significant (ρ(g) = 0.58, P = 7 × 10(-3)), the environmental correlation between these traits was not significant. Although, there is evidence for increased rates of depression and substance use in US-born individuals of Mexican ancestry, our findings indicate that genetic control over major depression and alcohol/substance use disorders in the Mexican-American population is similar to that reported in other populations.
Assuntos
Alcoolismo/genética , Depressão/genética , Americanos Mexicanos/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alcoolismo/etnologia , Depressão/etnologia , Família/psicologia , Feminino , Predisposição Genética para Doença , Humanos , Padrões de Herança , Entrevista Psicológica , Masculino , Transtornos Mentais/epidemiologia , Americanos Mexicanos/etnologia , Americanos Mexicanos/psicologia , Pessoa de Meia-Idade , Prevalência , Escalas de Graduação Psiquiátrica , Fatores de Risco , Transtornos Relacionados ao Uso de Substâncias/etnologiaRESUMO
Albuminuria, a hallmark of diabetic nephropathy, has been shown to be significantly heritable in multiple studies. Therefore, the identification of genes that affect susceptibility to albuminuria may lead to novel avenues of intervention. Current evidence suggests that the podocyte and slit diaphragm play a key role in controlling the selective sieve of the glomerular filtration barrier, and podocyte-specific genes have been identified that are necessary for maintaining its integrity. We therefore investigated the role of gene variants of tight junction protein (TJP1) which encodes another slit diaphragm-associated protein zona occludens 1 as risk factors for albuminuria in the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), which consists of extended Mexican-American families with a high prevalence of type 2 diabetes. Albuminuria, defined as an albumin (mg/dl) to creatinine (mg/dl) ratio (ACR) of 0.03, which is approximately equivalent to a urinary albumin excretion (UAE) >30 mg/day, was present in a total of 14.9% of participants, and 31% had type 2 diabetes. The TJP1 exons, flanking intronic sequence, and putative proximal promoter regions were investigated in this population. Twentynine polymorphisms, including 7 nonsynonymous SNPs, were identified and genotyped in all subjects of this study for association analysis. Three sets of correlated SNPs, which include 3 exonic SNPs, were nominally associated with ACR (p value range 0.007-0.049); however, the association with the discrete trait albuminuria was not significant (p value range 0.094-0.338). We conclude that these variants in TJP1 do not appear to be major determinants for albuminuria in the SAFDGS; however, they may play a minor role in its severity in this Mexican-American population. Further examination of the TJP1 gene region in this and other cohorts will be useful to determine whether ZO-1 plays a significant role in glomerular permselectivity.
Assuntos
Albuminúria/genética , Proteínas de Membrana/genética , Fosfoproteínas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Éxons , Frequência do Gene , Genoma Humano , Hispânico ou Latino/genética , Humanos , Íntrons , Pessoa de Meia-Idade , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Texas , Proteína da Zônula de Oclusão-1RESUMO
AIMS/HYPOTHESIS: The aim of this study was to examine whether genetic variation in ADIPOQ, ADIPOR1 and ADIPOR2 may contribute to increased susceptibility to components of the insulin resistance syndrome (IRS). MATERIALS AND METHODS: We genotyped single-nucleotide polymorphisms (SNPs) in ADIPOQ, ADIPOR1 and ADIPOR2 in Mexican American subjects (N=439) and performed an association analysis of IRS-related traits. RESULTS: Of the eight SNPs examined in the ADIPOQ gene, rs4632532 and rs182052 exhibited significant associations with BMI (p=0.029 and p=0.032), fasting specific insulin (p=0.023 and p=0.026), sum of skin folds (SS) (p=0.0089 and p=0.0084) and homeostasis model assessment of insulin sensitivity (HOMA-%S) (p=0.015 and p=0.016). Two other SNPs, rs266729 and rs2241767, were significantly associated with SS (p=0.036 and p=0.013). SNP rs7539542 of ADIPOR1 was significantly associated with BMI, SS and waist circumference (p=0.025, p=0.047 and p=0.0062). Fourteen of the ADIPOR2 SNPs were found to be significantly (p<0.05) associated with fasting plasma triglyceride concentrations. Four of these SNPs (rs10848569, rs929434, rs3809266 and rs12342) were in high pairwise linkage disequilibrium (r (2)=0.99) and were strongly associated with fasting triglyceride levels (p=0.00029, p=0.00016, p=0.00027 and p=0.00021). Adjusting for the effects of BMI and HOMA-%S on triglyceride concentrations increased significance to p=0.000060 for SNP rs929434. Bayesian quantitative trait nucleotide analysis was used to examine all possible models of gene action. Again, SNP rs929434 provided the strongest statistical evidence of an effect on triglyceride concentrations. CONCLUSIONS/INTERPRETATION: These results provide evidence for association of SNPs in ADIPOQ and its receptors with multiple IRS-related phenotypes. Specifically, several genetic variants in ADIPOR2 were strongly associated with decreased triglyceride levels.
Assuntos
Adiponectina/genética , Variação Genética , Resistência à Insulina/genética , Americanos Mexicanos/genética , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/genética , Idoso , Teorema de Bayes , Índice de Massa Corporal , Feminino , Genótipo , Humanos , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Fenótipo , TexasRESUMO
If CC chemokine receptor 5 (CCR5)-dependent mechanisms at the time of initial virus exposure are important determinants of virus entry and disease outcome, then the polymorphisms in CCR5 that influence risk of transmission and disease progression should be similar; this hypothesis was tested in a cohort of 649 Argentinean children exposed perinatally to human immunodeficiency virus type 1 (HIV-1). Two lines of evidence support this hypothesis. First, CCR5 haplotype pairs associated with enhanced risk of transmission were the chief predictors of a faster disease course. Second, some of the haplotype pairs associated with altered rates of transmission and disease progression in children were similar to those that we previously found influenced outcome in European American adults. This concordance suggests that CCR5 haplotypes may serve as genetic rheostats that influence events occurring shortly after initial virus exposure, dictating not only virus entry but, by extension, also the extent of early viral replication.
Assuntos
Infecções por HIV/transmissão , HIV-1 , Transmissão Vertical de Doenças Infecciosas , Receptores CCR5/genética , Síndrome da Imunodeficiência Adquirida/transmissão , Argentina , Estudos de Coortes , Progressão da Doença , Feminino , Variação Genética , Genótipo , Infecções por HIV/genética , Infecções por HIV/virologia , Haplótipos , Humanos , Lactente , Gravidez , Complicações Infecciosas na Gravidez/virologiaRESUMO
Insulin resistance and hyperinsulinemia are strong correlates of obesity and type 2 diabetes, but little is known about their genetic determinants. Using data on nondiabetics from Mexican American families and a multipoint linkage approach, we scanned the genome and identified a major locus near marker D6S403 for fasting "true" insulin levels (LOD score 4.1, empirical P<.0001), which do not crossreact with insulin precursors. Insulin resistance, as assessed by the homeostasis model using fasting glucose and specific insulin (FSI) values, was also strongly linked (LOD score 3.5, empirical P<.0001) with this region. Two other regions across the genome were found to be suggestively linked to FSI: a location on chromosome 2q, near marker D2S141, and another location on chromosome 6q, near marker D6S264. Since several insulin-resistance syndrome (IRS)-related phenotypes were mapped independently to the regions on chromosome 6q, we conducted bivariate multipoint linkage analyses to map the correlated IRS phenotypes. These analyses implicated the same chromosomal region near marker D6S403 (6q22-q23) as harboring a major gene with strong pleiotropic effects on obesity and on lipid measures, including leptin concentrations (e.g., LOD(eq) for traits-specific insulin and leptin was 4.7). A positional candidate gene for insulin resistance in this chromosomal region is the plasma cell-membrane glycoprotein PC-1 (6q22-q23). The genetic location on chromosome 6q, near marker D6S264 (6q25.2-q26), was also identified by the bivariate analysis as exerting significant pleiotropic influences on IRS-related phenotypes (e.g., LOD(eq) for traits-specific insulin and leptin was 4.1). This chromosomal region harbors positional candidate genes, such as the insulin-like growth factor 2 receptor (IGF2R, 6q26) and acetyl-CoA acetyltransferase 2 (ACAT2, 6q25.3-q26). In sum, we found substantial evidence for susceptibility loci on chromosome 6q that influence insulin concentrations and other IRS-related phenotypes in Mexican Americans.
Assuntos
Cromossomos Humanos Par 6/genética , Hispânico ou Latino/genética , Resistência à Insulina/genética , Insulina/sangue , Obesidade/genética , Adulto , Glicemia/análise , Índice de Massa Corporal , Mapeamento Cromossômico , Diabetes Mellitus/genética , Jejum , Feminino , Marcadores Genéticos/genética , Predisposição Genética para Doença/genética , Humanos , Resistência à Insulina/fisiologia , Leptina/sangue , Escore Lod , Masculino , México/etnologia , Obesidade/sangue , Obesidade/fisiopatologia , Fenótipo , Dobras Cutâneas , Texas , Triglicerídeos/sangueRESUMO
Acanthosis nigricans (AN) is a skin condition associated with hyperinsulinemia and insulin resistance and has been shown to be a risk factor for type 2 diabetes. The influence of genetic factors on AN and the basis of its association with type 2 diabetes and its risk factors are unknown. Using data from 397 participants from two Mexican American family studies, we investigated the heritability of AN and its genetic correlation with other diabetes risk factors. AN was examined as both a continuous trait and a dichotomous trait by means of a previously described validated scale. The results indicated that the heritability (h2) for AN, when examined as a continuous trait, was high (0.58+/-0.10) and statistically significant (P<0.001). The h2 for AN as a dichotomous trait was estimated to be moderate (0.23+/-0.05) and was also significant (P=0.018). The additive genetic correlations between AN (either as a continuous trait or a dichotomous trait) and type 2 diabetes and its risk factors, including body mass index and fasting insulin, were high or moderately high and statistically significant. The random environmental correlations, by contrast, were low and statistically insignificant. These data suggest that genes that influence AN have pleiotropic effects on diabetes and its risk factors.
Assuntos
Acantose Nigricans/genética , Diabetes Mellitus Tipo 2/genética , Americanos Mexicanos/genética , Acantose Nigricans/complicações , Adulto , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/etiologia , Feminino , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Fatores de Risco , TexasRESUMO
Although several genetic forms of rare or syndromic hypertriglyceridemia have been reported, little is known about the specific chromosomal regions across the genome harboring susceptibility genes for common forms of hypertriglyceridemia. Therefore, we conducted a genomewide scan for susceptibility genes influencing plasma triglyceride (TG) levels in a Mexican American population. We used both phenotypic and genotypic data from 418 individuals distributed across 27 low-income, extended Mexican American families. For the analyses, TG values were log transformed (ln TG). We used a variance-components technique to conduct multipoint linkage analyses for localizing susceptibility genes that determine variation in TG levels. We used an approximately 10-15-cM map, which was made on the basis of information from 295 microsatellite markers. After accounting for the effects of sex and sex-specific age terms, we found significant evidence for linkage (LOD = 3.88) of ln TG levels to a genetic location between the markers GABRB3 and D15S165 on chromosome 15q. This putative locus explains 39.7+/-7% (P=.000012) of total phenotypic variation in ln TG levels. Suggestive evidence was found for linkage of ln TG levels to two different locations on chromosome 7, which are approximately 85 cM apart from each other. Also, there is some evidence for linkage of high-density lipoprotein cholesterol concentrations to a genetic location near one of the regions on chromosome 7. In conclusion, we found strong evidence for linkage of ln TG levels to a genetic location on chromosome 15q in a Mexican American population, which is prone to disease conditions such as type 2 diabetes and the insulin-resistance syndrome that are associated with hypertriglyceridemia. This putative locus appears to have a major influence on ln TG variation.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 15/genética , Predisposição Genética para Doença/genética , Hipertrigliceridemia/genética , Americanos Mexicanos/genética , Triglicerídeos/sangue , Adulto , HDL-Colesterol/sangue , Cromossomos Humanos Par 7/genética , Doença das Coronárias/complicações , Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Feminino , Genótipo , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/complicações , Resistência à Insulina/genética , Escore Lod , Masculino , Repetições de Microssatélites/genética , Herança Multifatorial , Fenótipo , Pobreza , Receptores de GABA-A/genéticaRESUMO
Since little is known about chromosomal locations harboring type 2 diabetes-susceptibility genes, we conducted a genomewide scan for such genes in a Mexican American population. We used data from 27 low-income extended Mexican American pedigrees consisting of 440 individuals for whom genotypic data are available for 379 markers. We used a variance-components technique to conduct multipoint linkage analyses for two phenotypes: type 2 diabetes (a discrete trait) and age at onset of diabetes (a truncated quantitative trait). For the multipoint analyses, a subset of 295 markers was selected on the basis of optimal spacing and informativeness. We found significant evidence that a susceptibility locus near the marker D10S587 on chromosome 10q influences age at onset of diabetes (LOD score 3.75) and is also linked with type 2 diabetes itself (LOD score 2.88). This susceptibility locus explains 63.8%+/-9.9% (P=. 000016) of the total phenotypic variation in age at onset of diabetes and 65.7%+/-10.9% (P=.000135) of the total variation in liability to type 2 diabetes. Weaker evidence was found for linkage of diabetes and of age at onset to regions on chromosomes 3p, 4q, and 9p. In conclusion, our strongest evidence for linkage to both age at onset of diabetes and type 2 diabetes itself in the Mexican American population was for a region on chromosome 10q.
Assuntos
Cromossomos Humanos Par 10/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Hispânico ou Latino/genética , Escore Lod , Fatores Etários , Idade de Início , Mapeamento Cromossômico , Intervalo Livre de Doença , Feminino , Genótipo , Humanos , Masculino , México/etnologia , Repetições de Microssatélites/genética , Linhagem , Penetrância , Característica Quantitativa Herdável , Fatores Sexuais , Estados Unidos/epidemiologiaRESUMO
Since there have not been any studies that quantify the influence of genetic factors on gallbladder disease (GBD) in humans using information from families, we utilized pedigree data to explore the genetic control of variation in liability to GBD. Using an extension of a variance components approach, we performed genetic analyses of GBD using information from 32 low-income Mexican-American families with two slightly different general models incorporating several sex-specific GBD risk factors. After evaluating the relative magnitudes of the covariate effects from these two models, we identified a parsimonious model including only significant predictors of GBD. According to this model, heritability for GBD was high (h2 = 0.44+/-0.18), after accounting for the significant effects of age, leptin in both sexes, total cholesterol, and HDL cholesterol in males only. We have shown quantitatively that variation in GBD is under strong genetic control. However, there are two major limitations to our findings: (1) since GBD was defined by a self-reported clinical history rather than an ultrasound examination, the prevalence of GBD could have been underestimated; and (2) since our design did not allow for shared environmental effects, our estimate of heritability may have been inflated.
Assuntos
Doenças da Vesícula Biliar/etnologia , Doenças da Vesícula Biliar/genética , População Branca/genética , Adulto , Distribuição por Idade , Idoso , HDL-Colesterol/sangue , Comorbidade , Diabetes Mellitus/epidemiologia , Feminino , Doenças da Vesícula Biliar/sangue , Variação Genética , Hispânico ou Latino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prevalência , Fatores de Risco , Distribuição por Sexo , Texas/epidemiologiaRESUMO
The high-affinity sulfonylurea receptor (SUR1) gene regulates insulin secretion and may play a role in type 2 diabetes. A silent variant in exon 31 of SUR1 (AGG-->AGA) was detected by single-strand conformational polymorphism and genotypes were determined for 396 Mexican American subjects (289 non-diabetic). The normal and mutant alleles were designated G and A, respectively. Among non-diabetics, those with the AA genotype had higher fasting insulin values than those with the AG and GG genotypes (113.4 pmol/l for AA vs 82.8 pmol/l for AG/GG, P=0.043). Similar results were observed for 2-h insulin (849.6 pmol/l for AA vs 498.6 pmol/l for AG/GG, P=0.0003) and for the proinsulin to specific insulin ratio (0.068 for AA vs 0.056 for AG/GG, P=0.030). Specific insulin levels also differed significantly across the three genotypic classes (P=0.021). No differences in fasting glucose, body mass index, or waist circumference according to genotype were noted. Two-hour glucose was modestly higher in individuals with the AA genotype. Since we have previously reported linkage between SUR1 and hyperglycemia, the present association between a SUR1 variant and hyperinsulinemia in normal individuals from a high diabetes risk ethnic group raises the possibility of primary insulin hypersecretion as an antecedent of type 2 diabetes in at least some individuals from this population.
Assuntos
Transportadores de Cassetes de Ligação de ATP , Hiperinsulinismo/etnologia , Insulina/sangue , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio/genética , Receptores de Droga/genética , Adulto , Glicemia/análise , Análise Mutacional de DNA , Diabetes Mellitus Tipo 2/etiologia , Feminino , Genótipo , Humanos , Masculino , Proteínas de Membrana/genética , Polimorfismo Genético/genética , Proinsulina/sangue , Receptores de Sulfonilureias , Estados Unidos/etnologiaRESUMO
The genetic factors involved in type II diabetes are still unknown. To address this problem, we are creating a 10 to 15 cM genetic map on 444 individuals from 32 Mexican American families ascertained on a type II diabetic proband. Using highly polymorphic microsatellite markers and a multipoint variance components method, we found evidence for linkage of plasma glucose concentration 2 hr after oral glucose administration to two regions on chromosome 11: beta-hemoglobin (HBB) and markers D11S899/D11S1324 near the sulfonylurea receptor (SUR) gene. Iod scores at these two loci were 2.77 and 3.37, respectively. The SUR gene region accounted for 44.7% of the phenotypic variance. Evidence for linkage to fasting glucose concentration was also observed for two loci on chromosome 6, one of which is identical to a proposed susceptibility locus for type I diabetes (D6S290). When diabetics were excluded from the analyses, all Iod scores became zero, suggesting that the observed linkages were with the trait diabetes rather than with normal variation in glucose levels. Results were similar whether all diabetics were included in the analyses or only those who were not under treatment with oral antidiabetic agents or insulin.
Assuntos
Glicemia/genética , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 6 , Americanos Mexicanos , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Ligação Genética , HumanosRESUMO
BACKGROUND AND PURPOSE: Other than the documented associations of risk factors and carotid artery wall thickness, the genetic basis of variation in carotid artery intimal-medial thickness (IMT) is unknown. The purpose of this study was to examine the extent to which variation in common carotid artery (CCA) IMT and internal carotid artery (ICA) IMT are under genetic control. METHODS: The sibship data used for this analysis were part of an epidemiological survey in Mexico City. The CCA and ICA analyses were based on 46 and 44 sibships of various sizes, respectively. The CCA and ICA IMTs were measured with carotid ultrasonography. Using a robust variance decomposition method, we performed genetic analyses of CCA IMT and ICA IMT measurements with models incorporating several cardiovascular risk factors (eg, lipids, diabetes, blood pressure, and smoking) as covariates. RESULTS: After accounting for the effects of covariates, we detected high heritabilities for CCA IMT (h2 = 0.92 +/- 0.05, P = .001) and ICA IMT (h2 = 0.86 +/- 0.13, P = .029). Genes accounted for 66.0% of the total variation in CCA IMT, whereas 27.7% of variation was attributable to covariates. For ICA IMT, genes explained a high proportion (74.9%) of total phenotypic variation. The covariates accounted for 11.5% of variation in ICA IMT. CONCLUSIONS: Our results suggest that substantial proportions of phenotypic variance in CCA IMT and ICA IMT are attributable to shared genetic factors.