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J Blangero

Publications and source records attributed to J Blangero.

At least 145 records · Page 8Linked to original sources
PubMed1996

Evidence for linkage of regions on chromosomes 6 and 11 to plasma glucose concentrations in Mexican Americans.

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.

Blood Glucose↗
PubMed1996

Genetic analysis of the IRS. Pleiotropic effects of genes influencing insulin levels on lipoprotein and obesity measures.

Insulin resistance is part of a metabolic syndrome that also includes non-insulin-dependent diabetes mellitus, dyslipidemia, obesity, and hypertension. It has been hypothesized that insulin resistance represents the primary physiological defect underlying this syndrome. Since insulin resistance is at least partially genetically determined, we hypothesized that genes influencing insulin resistance would have pleiotropic effects on a number of other traits, including triglyceride (TG) and HDL cholesterol levels, body mass index (BMI) and body fat distribution, and blood pressure levels. To investigate this hypothesis, we analyzed data obtained from individuals in 41 families enrolled in the San Antonio Family Heart Study. Statistical methods that take advantage of the relatedness among individuals were used to differentiate between genetic and nongenetic (ie, environmental) contributions to phenotypic variation between traits. Serum levels of fasting and 2-hour insulin (measured in 767 and 743 nondiabetic family members, respectively) were used as a measure of insulin resistance. The genetic correlations were high between insulin levels (both fasting and 2-hour) and each of the following: BMI, HDL level, waist-to-hip ratio, and subscapular-to-triceps ratio, indicating that the same gene, or set of genes, influences each pair of traits. In contrast, the genetic correlations of insulin levels with systolic and diastolic blood pressures were low. We have previously shown that a single diallelic locus accounts for 31% of the phenotypic variation in 2-hour insulin levels in this population. We conducted a bivariate segregation analysis to see if the common genetic effects on insulin and these other traits could be attributable to this single locus. These results indicated a significant effect of the 2-hour insulin locus on fasting insulin levels (P = .02) and BMI (P = .05), with the "high" insulin allele associated with higher levels of fasting insulin but lower levels of BMI. There was no detectable effect of this locus on HDL level, TG level, subscapular-to-triceps ratio, or blood pressure. Overall, these results suggest that a common set of genes influencing insulin levels also influences other insulin resistance syndrome-related traits, although for the most part this pleiotropy is not attributable to the 2-hour insulin level major locus.

Adult↗
PubMed1996

Triiodothyronine exerts a major pleiotropic effect on reverse cholesterol transport phenotypes.

The thyroid hormone triiodothyronine (T3) is known to be a potent mediator of APOA1 gene expression. With the use of multivariate quantitative genetic analysis, we have assessed the magnitude of shared effects of T3 on plasma concentrations of apolipoprotein AI (apo AI) and three related phenotypes: HDL-C, apo AII, and LpAI (which is a concentration of apo AI that contains HDL particles). Maximum likelihood techniques were used to simultaneously estimate mean effects and variance components in large, extended Mexican American families living in San Antonio, Tex. We found that T3 accounted for 16%, 23%, 21%, and 37% of the additive genetic variance in HDL-C, apo AI, apo AII, and LpAI, respectively, while explaining virtually none of the random environmental variance in these phenotypes. T3 also has a pronounced effect on the pairwise genetic correlations among the four phenotypes: After the pleiotropic effects of T3 concentrations are controlled for, the genetic correlations are reduced by 6% in the case of HDL-C and apo AI and 97% for apo AII and LpAI. Thus, genes that influence T3 have a significant effect on HDL-C, apo AI, apo AII, and LpAI and also on the correlations among these phenotypes.

Adolescent↗
PubMed1996

Effects of a major gene for apolipoprotein A-I concentration are thyroid hormone dependent in Mexican Americans.

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.

Adult↗
PubMed1996

Genetic basis of variation in carotid artery wall thickness.

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.

Cardiovascular Diseases↗
PubMed1996

Genetic and environmental correlations among hormone levels and measures of body fat accumulation and topography.

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.

Adipose Tissue↗
PubMed1996

Evidence for a major gene for type II diabetes and linkage analyses with selected candidate genes in Mexican-Americans.

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).

Alleles↗
PubMed1996

Genetic analysis of serum alanine transaminase activity in normal and hepatitis C virus-infected chimpanzees: an application of research-oriented genetic management.

The hepatic enzyme alanine transaminase (ALT) is a diagnostic marker for liver damage but has a considerable degree of normal variation. We used complex segregation analysis to determine whether evidence exists for major genic determination of normal ALT values in an important animal model, the chimpanzee (Pan troglodytes). Normal ALT values were available for 212 chimpanzees. Available genealogical data allowed assignment of 165 animals to a total of 19 pedigrees; 47 animals were treated as independent. A major gene explaining 60% of the phenotypic variance in normal alanine transaminase (ALT) activity was detected by complex segregation analysis. The allele for high ALT activity had a frequency of 0.20. Polygenes accounted for an additional 20% of the variation. The observation that 80% of the total phenotypic variance is attributable to genetic factors has important implications for studies that use ALT activity in assessments. Genetic analysis of change in ALT activity after inoculation with hepatitis C virus (HCV) in a subset of animals indicated that approximately 30% of the variation in response may also be attributable to genetic factors and that the estimated major locus genotypes differ in their responses. This suggests that genetic components can exert substantial influences on experimental parameters in hepatitis research.

Alanine Transaminase↗
PubMed1996

Quantitative variation in obesity-related traits and insulin precursors linked to the OB gene region on human chromosome 7.

Despite the evidence that human obesity has strong genetic determinants, efforts at identifying specific genes that influence human obesity have largely been unsuccessful. Using the sibship data obtained from 32 low income Mexican American pedigrees ascertained on a type II diabetic proband and a multipoint variance-components method, we tested for linkage between various obesity-related traits plus associated metabolic traits and 15 markers on human chromosome 7. We found evidence for linkage between markers in the OB gene region and various traits, as follows: D7S514 and extremity skinfolds (LOD = 3.1), human carboxypeptidase A1 (HCPA1) and 32,33-split proinsulin level (LOD = 4.2), and HCPA1 and proinsulin level (LOD = 3.2). A putative susceptibility locus linked to the marker D7S514 explained 56% of the total phenotypic variation in extremity skinfolds. Variation at the HCPA1 locus explained 64% of phenotypic variation in proinsulin level and approximately 73% of phenotypic variation in split proinsulin concentration, respectively. Weaker evidence for linkage to several other obesity-related traits (e.g., waist circumference, body-mass index, fat mass by bioimpedance, etc.) was observed for a genetic location, which is approximately 15 cM telomeric to OB. In conclusion, our study reveals that the OB region plays a significant role in determining the phenotypic variation of both insulin precursors and obesity-related traits, at least in Mexican Americans.

Adult↗
PubMed1995

Plasma HDL cholesterol, triglycerides, and adiposity. A quantitative genetic test of the conjoint trait hypothesis in the San Antonio Family Heart Study.

BACKGROUND: The conjoint trait hypothesis proposes that combined low HDL cholesterol (HDL-C) and high triglyceride (TG) levels represent a single, inherited phenotype that adiposity may influence in an unspecified manner. We conducted formal statistical genetic tests of the conjoint trait hypothesis and the relation of the conjoint trait to adiposity using data for 569 subjects in 25 pedigrees from the San Antonio Family Heart Study. METHODS AND RESULTS: We conducted multivariate genetic analyses to detect the effects of genes and environmental factors on variation in plasma concentrations of HDL-C and TG, fat mass (as percent body weight [FM%], determined by bioelectric impedance), and body mass index (BMI). We used maximum-likelihood methods to simultaneously estimate the phenotypic means and SDs, heritabilities (h2), effects of sex, age-by-sex, eight dietary and medical covariates, and genetic and environmental correlations. Likelihood ratio tests disclosed significant heritabilities (P < .001) for all traits (h2HDL-C = 0.55, h2TG = 0.53, h2FM% = 0.37, h2BMI = 0.44) but significant genetic correlations (P < .001), indicating pleiotropy, between two trait pairs only: HDL-C and TG (PG = -0.52) and fat mass and BMI (PG = 0.86). We obtained significant environmental correlations between all trait pairs except HDL-C and BMI (P > .05). CONCLUSIONS: Both shared genes (pleiotropy) and shared environmental factors contribute to the commonly observed inverse phenotypic association between plasma levels of HDL-C and TG. Rather than low HDL-C and high TG being a single, genetically transmissible entity, it is the inverse relation between these two phenotypes throughout their normal ranges of variation as well as at the extremes that is influenced by shared genes and shared environments. However, common environmental factors, not shared genes, account for reported associations of plasma HDL-C and TG levels with measures of adiposity.

Adipose Tissue↗
PubMed1995

Major gene with sex-specific effects influences fat mass in Mexican Americans.

Increased adiposity has repeatedly been identified as a major risk factor for a variety of chronic diseases. However, the question still remains whether the amount of adipose tissue itself is genetically mediated. To address this question, a segregation analysis, using maximum likelihood techniques as implemented in the computer program Pedigree Analysis Package (PAP), was performed on fat mass (kilograms of body fat) in a large sample of extended Mexican American families residing in San Antonio, TX. The only model not rejected was a Mendelian mixed model for fat mass, incorporating genotype x sex interaction. In males the major gene accounted for 37% of the total variance compared with 43% in females. In both sexes homozygous recessive individuals have a fat mass more than double that of individuals of the other two genotypes. It was possible to reject linkage of the anonymous major gene for fat mass with several candidate loci for obesity. However, tentative evidence of linkage was detected with markers on both chromosomes 2 and 11, thereby providing hypotheses for future testing.

Adolescent↗
PubMed1995

Simulation of a common oligogenic disease with quantitative risk factors. GAW9 problem 2: the answers.

For Problem 2, simulated family data were provided for a common oligogenic disease that was defined by imposing a threshold, T, on a quantitative trait, Q1. Every individual with a value of Q1 > T (where T = 87.5) was defined as affected. Participants were told that three other quantitative traits (Q2, Q3, and Q4) and an environmental factor (EF) also were thought to be associated with the disease as intervening variables, and that 12 candidate loci (C1 - C12) were postulated to influence traits associated with the disease. The tasks for GAW9 were to characterize the genetic and environmental contribution to Q1 (and the disease), Q2, Q3, and Q4, and to localize any single genes that had detectable effects.

Adolescent↗
PubMed1995

Genetic control of apolipoprotein A-I distribution among HDL subclasses.

We conducted genetic analyses to determine the components of variation for size distributions of apolipoprotein (apo) A-I among human plasma lipoproteins resolved on the basis of size. Analyses used data for 717 individuals in 26 pedigrees. Apo A-I distributions among lipoprotein size classes were measured by nondenaturing gradient gel electrophoresis (GGE) and immunoblotting procedures. Curves were fitted to apo A-I absorbance profiles to estimate fractional absorbance in each of five high-density lipoprotein (HDL) subclasses. Multivariate regression analyses revealed several covariates (sex, age, diabetes, and apo A-I concentrations) that were significantly associated with variation in one or more HDL subclasses. Female gender and elevated apo A-I concentrations were associated with increases in proportion of apo A-I in larger HDLs, while increasing age and diabetes were associated with decreases. The analyses showed significant heritabilities. h2, for each variable representing the different HDL subclasses. Both genetic and nongenetic effects on apo A-I size distributions were generally exerted across the range of lipoprotein sizes, as suggested by high genetic and environmental correlations between HDL subclass variables. Decomposition of total overall variance showed that unidentified environmental factors accounted for 48% of variation in apo A-I size distribution, while genetic factors explained about 36% and the identified covariates explained the remaining 16%. When considered separately, apo A-I concentration explained only 5% of the total variation in apo A-I size distribution, indicating that apo A-I concentration is a poor predictor of apo A-I size distribution. In summary, the data suggest that there are significant genetic and environmental effects on apo A-I size distribution in humans, and that they are general metabolic effects rather than effects on specific HDL subclasses.

Adult↗
PubMed1995

A major locus influencing plasma high-density lipoprotein cholesterol levels in the San Antonio Family Heart Study. Segregation and linkage analyses.

To detect and measure the effects of a single locus on quantitative variation in plasma concentrations of HDL cholesterol (HDL-C), we conducted statistical genetic analyses on data from 526 Mexican American individuals in 25 randomly ascertained pedigrees. By using maximum-likelihood complex segregation analysis, we found evidence for a major locus with a codominant mixture model that included the phenotypic means, standard deviations, relative frequency of a low HDL-C allele, and heritability for plasma HDL-C levels, plus the effects of sex (genotype specific), age-by-sex, age2-by-sex, plasma concentrations of apolipoprotein (apo)AI and triglycerides (genotype specific), exogenous sex hormone use, and menopausal status under an unrestricted general model. Inclusion of the four covariates (in addition to the sex and age-by-sex effects) accounted for nearly 79% of the variance in total plasma HDL-C levels. Of the remaining 21% of the variance, the detected major locus accounted for approximately 55% in men and 21% in women; the total genetic contributions to the variance by genes were approximately 82% in men and 69% in women. Linkage analyses with penetrance parameter estimates from the segregation analysis excluded tight linkage between the detected major locus and markers for the following candidate loci: the apoAI/apoCIII genomic region (P < .05), apoB (P < .01), hepatic lipase (P < .001), lipoprotein lipase (P < .001), and the LDL receptor (P < .001). While not excluding the apoE locus (LOD = -0.348, P < .21), the analysis provided no support for tight linkage between it and the detected major locus.

Adolescent↗
PubMed1995

Evidence for a major gene affecting postchallenge insulin levels in Mexican-Americans.

Hyperinsulinemia, which is considered a hallmark of insulin resistance, precedes the development of non-insulin-dependent diabetes mellitus (NIDDM). Results of family and twin studies have shown that heredity influences insulin resistance and insulin levels. In Caucasian families ascertained through two or more NIDDM siblings, it has been reported that single genes with large effects, i.e., major genes, influence both fasting and 1-h postchallenge insulin levels. To determine whether a major gene affects 2-h postchallenge insulin levels in Mexican-Americans, we conducted segregation analyses using data collected on 527 pedigreed individuals from 27 families in San Antonio, TX. Probands for the families were randomly ascertained and all first-, second-, and third-degree relatives aged 16 years and older were invited to participate. Subjects received a 2-h oral glucose tolerance test, and diabetes was diagnosed according to World Health Organization criteria. We found that an autosomal dominant major gene best described the inheritance of 2-h insulin levels (ln-transformed) in these 27 families. Of the individuals in the population, 17% were homozygous for the 2-h low-insulin allele (back-transformed mean = 125 pmol/l) and 83% were heterozygous or homozygous for the 2-h high-insulin allele (back-transformed mean = 406 pmol/l). This major gene accounted for 31% of the variance in ln(2-h insulin levels) in this population. Using quantitative trait linkage analyses, we excluded tight linkage between this gene affecting 2-h insulin levels and three candidate loci for insulin levels: the insulin receptor gene, the low-density lipoprotein receptor gene, and the glucokinase gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Major gene for percent of oxygen saturation of arterial hemoglobin in Tibetan highlanders.

This report employs a statistical genetic approach to analyze quantitative oxygen transport variables in a high-altitude (4,850-5,450 m) native Tibetan population and demonstrates the presence of a major gene influencing % O2 saturation of arterial hemoglobin. This result suggests the hypothesis that individuals with the dominant allele for higher % O2 saturation have a selective advantage at high altitude. Studies of the biologically distinctive Himalayan and Andean populations have greatly influenced thinking about ongoing human evolution and adaptation; this is the first statistical evidence for a major gene enhancing oxygen transport in a high-altitude native population.

Adaptation, Physiological↗