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J Blangero

Publications and source records attributed to J Blangero.

At least 109 records · Page 6Linked to original sources
PubMed1999

Genetic analysis of susceptibility to infection with Ascaris lumbricoides.

Epidemiologic studies of helminthic infections have shown that susceptibility to these parasites frequently aggregates in families, suggesting the possible involvement of genetic factors. This paper presents a genetic epidemiologic analysis of Ascaris lumbricoides infection in the Jirel population of eastern Nepal. A total of 1,261 individuals belonging to a single pedigree were assessed for intensity of Ascaris infection at two time points. Following an initial assessment in which all individuals were treated with albendazole, a follow-up examination was performed one year later to evaluate reinfection patterns. Three measures of worm burden were analyzed, including eggs per gram of feces, direct worm counts, and worm biomass (weight). For all traits, variance component analysis of the familial data provided unequivocal evidence for a strong genetic component accounting for between 30% and 50% of the variation in worm burden. Shared environmental (i.e., common household) effects account for between 3% and 13% of the total phenotypic variance.

Adolescent↗
PubMed1999

Potential effects of ethnicity in genetic and environmental sources of variability in the stature, mass, and body mass index of children.

We examined sources of variability in stature, body mass, and body mass index (BMI) in families of black and white elementary schoolchildren from Philadelphia, Pennsylvania. The sample consisted of 445 black and 379 white children, 7-13 years old, and their parents (total n = 2016). The sample was distributed among 596 nuclear families, each representing an independent pedigree. Maximum-likelihood-based variance decomposition methods were used to simultaneously estimate ethnic group-specific effects of genes, sex, age by sex, and unmeasured environmental factors on stature, body mass, and BMI. Likelihood ratio tests were performed to assess the significance of h2 estimates and differences in sigma g and sigma e between black and white families. Genes account for moderate proportions of the phenotypic variance (h2) of these traits in black and white children. In black and white children, respectively, h2 estimates were 0.37 and 0.53 for stature, 0.37 and 0.31 for body mass, and 0.38 and 0.24 for BMI (p < 0.0005). Although the differences in h2 between ethnic groups were not significant (stature, p = 0.23; body mass, p = 0.49; BMI, p = 0.14), black children exhibited a significantly greater total residual phenotypic standard deviation (sigma e and sigma g) in body mass and BMI and a significantly greater sigma e for stature compared with white children. The larger residual phenotypic variance in the black sample is likely due to exposure to unmeasured environmental factors that are not accounted for in this model. Given that sigma g for stature is not significantly different between ethnic groups, the slightly lower estimates in black children are due to the increased contribution of the environment to the phenotypic variance in this trait.

Adolescent↗
PubMed1998

Anxiety proneness linked to epistatic loci in genome scan of human personality traits.

A genome-wide scan between normal human personality traits and a set of genetic markers at an average interval of 13 centimorgans was carried out in 758 pairs of siblings in 177 nuclear families of alcoholics. Personality traits were measured by the Tridimensional Personality Questionnaire. We detected significant linkage between the trait Harm Avoidance, a measure of anxiety proneness, and a locus on chromosome 8p21-23 that explained 38% of the trait variance. There was significant evidence of epistasis between the locus on 8p and others on chromosomes 18p, 20p, and 21q. These oligogenic interactions explained most of the variance in Harm Avoidance. There was suggestive evidence of epistasis in other personality traits. These results confirm the important influence of epistasis on human personality suggested by twin and adoption studies.

Anxiety↗
PubMed1998

A paired sibling analysis of the beta-3 adrenergic receptor and obesity in Mexican Americans.

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.

Adult↗
PubMed1998

Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara.

Elevated hemoglobin concentrations have been reported for high-altitude sojourners and Andean high-altitude natives since early in the 20th century. Thus, reports that have appeared since the 1970s describing relatively low hemoglobin concentration among Tibetan high-altitude natives were unexpected. These suggested a hypothesis of population differences in hematological response to high-altitude hypoxia. A case of quantitatively different responses to one environmental stress would offer an opportunity to study the broad evolutionary question of the origin of adaptations. However, many factors may confound population comparisons. The present study was designed to test the null hypothesis of no difference in mean hemoglobin concentration of Tibetan and Aymara native residents at 3,800-4,065 meters by using healthy samples that were screened for iron deficiency, abnormal hemoglobins, and thalassemias, recruited and assessed using the same techniques. The hypothesis was rejected, because Tibetan males had a significantly lower mean hemoglobin concentration of 15.6 gm/dl compared with 19.2 gm/dl for Aymara males, and Tibetan females had a mean hemoglobin concentration of 14.2 gm/dl compared with 17.8 gm/dl for Aymara females. The Tibetan hemoglobin distribution closely resembled that from a comparable, sea-level sample from the United States, whereas the Aymara distribution was shifted toward 3-4 gm/dl higher values. Genetic factors accounted for a very high proportion of the phenotypic variance in hemoglobin concentration in both samples (0.86 in the Tibetan sample and 0.87 in the Aymara sample). The presence of significant genetic variance means that there is the potential for natural selection and genetic adaptation of hemoglobin concentration in Tibetan and Aymara high-altitude populations.

Adaptation, Physiological↗
PubMed1998

Identification of a new SCN5A mutation, D1840G, associated with the long QT syndrome. Mutations in brief no. 153. Online.

The long QT syndrome (LQT) is an inherited cardiac disorder that can cause sudden cardiac death among apparently healthy young individuals due to malignant ventricular arrhythmias. LQT was found to be caused by mutations in four genes LTQ1, LQT2, LQT3 and LQT5, and linkage was reported for an additional locus, LQT4, on chromosome 4q25-27. We have studied a large (n=131) LQT-affected Jewish kindred and identified tight linkage between the LQT-affected status and LQT3 (lod score 6.13, with an estimated recombination fraction of zero). We identified a new point-mutation, A to G substitution at nucleotide 5519 of the SCN5A gene, changing the aspartate 1840 to glycine, D1840G. This is a non-conservative change of an amino acid completely conserved in sodium channels from Molusca to human. The mutation was identified in all affected individuals (n=23), and not identified in all the unaffected family members (n=40), and not in 200 chromosomes of healthy control individuals. The mutation was identified in 3/12 individuals with equivocal phenotype, thus, providing an accurate dignostic tool for all family members. This mutation is currently being used in a cellular electrophysiological model, to characterize the function of the mutated sodium channel in this syndrome.

Amino Acid Substitution↗
PubMed1998

Variant in sulfonylurea receptor-1 gene is associated with high insulin concentrations in non-diabetic Mexican Americans: SUR-1 gene variant and hyperinsulinemia.

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.

ATP-Binding Cassette Transporters↗
PubMed1998

Quantitative trait loci analysis of human event-related brain potentials: P3 voltage.

The P3 event-related brain potential (ERP) is a positive-going voltage change of scalp-recorded electroencephalographic activity that occurs between 300-500 ms after stimulus onset. It is elicited when a stimulus is perceived, memory operations are engaged, and attentional resources are allocated toward its processing. Because this ERP component reflects fundamental cognitive processing, it has found wide utility as an assessment of human mental function in basic and clinical studies. In particular, P3 attributes are heritable and have demonstrated considerable promise as a means to identify individuals at genetic risk for alcoholism. We have conducted a quantitative linkage analysis on a large sample from families with a high density of affected individuals. The analyses suggest that several regions of the human genome contain genetic loci related to the generation of the P3 component of the ERP, which are possible candidate loci underlying the functional organization of human neuroelectric activity.

Alcoholism↗
PubMed1998

Attitudes towards helminthic infection in the Jirel population of eastern Nepal.

Intestinal worm infections, including roundworm, hookworm, and whipworm, are major international health concerns, affecting approximately one fourth of the world's population. Many intervention schemes have been attempted to control these infections in heavily exposed populations, but success has been limited because individuals are readily reinfected upon renewed exposure. Few data are available concerning people's health beliefs about soil-transmitted helminthic infections in such populations. The purpose of this study was to assess health beliefs about common helminthiasis in a population experiencing moderate to high rates of infection. The focal population for the study was the Jirel population, a tribal group distributed across nine villages in the Jiri Region of Dolakha District, eastern Nepal. The results indicate that beliefs about the types, causes, and treatments of helminthic infections have been developed and reinforced by experience and empirical evidence. People's frequent inability to confirm the efficacy of drug therapy by observing worms in stools has led to dissatisfaction with biomedical approaches. Carefully planned education programs are required to alter prevailing attitudes and improve control of soil-transmitted helminthiasis in the region.

Adolescent↗
PubMed1998

Multipoint quantitative-trait linkage analysis in general pedigrees.

Multipoint linkage analysis of quantitative-trait loci (QTLs) has previously been restricted to sibships and small pedigrees. In this article, we show how variance-component linkage methods can be used in pedigrees of arbitrary size and complexity, and we develop a general framework for multipoint identity-by-descent (IBD) probability calculations. We extend the sib-pair multipoint mapping approach of Fulker et al. to general relative pairs. This multipoint IBD method uses the proportion of alleles shared identical by descent at genotyped loci to estimate IBD sharing at arbitrary points along a chromosome for each relative pair. We have derived correlations in IBD sharing as a function of chromosomal distance for relative pairs in general pedigrees and provide a simple framework whereby these correlations can be easily obtained for any relative pair related by a single line of descent or by multiple independent lines of descent. Once calculated, the multipoint relative-pair IBDs can be utilized in variance-component linkage analysis, which considers the likelihood of the entire pedigree jointly. Examples are given that use simulated data, demonstrating both the accuracy of QTL localization and the increase in power provided by multipoint analysis with 5-, 10-, and 20-cM marker maps. The general pedigree variance component and IBD estimation methods have been implemented in the SOLAR (Sequential Oligogenic Linkage Analysis Routines) computer package.

Computer Simulation↗
PubMed1998

Evidence for at least two major loci influencing human fatness.

The genetics of human fatness has been the subject of many recent studies, motivated by the increased morbidity and mortality associated with obesity, as well as the increasing prevalence of overweight and obesity. The body-mass index (BMI) and fat mass (FM), measured by underwater weighing, were assessed for 1,630 individuals from approximately 300 families from phase 1 of the Quebec Family Study. The two phenotypes are highly correlated ( approximately .8) in adults, and previous segregation analysis revealed evidence for a recessive major gene for each trait. In our study, we utilized bivariate segregation analysis to determine the source(s) of phenotypic correlation-namely, a pleiotropic major gene, shared familial factors/polygenes, or shared nontransmitted environmental factors. Analysis was performed by use of the Pedigree Analysis Package, with extensions to the bivariate case. Tests of hypotheses provided evidence for two pleiotropic recessive loci, together accounting for 64% and 47% of the variance in BMI and FM, respectively. Under the model, all sources of phenotypic correlation were significant: 73% of the covariance was attributed to the pleiotropic major loci, 8% to residual familial effects, and 19% to nontransmitted environmental factors. The high degree of genetic identity between the two traits is not surprising, since the BMI often is used as a surrogate for FM; however, simultaneous analysis of both phenotypes enabled the detection of a second major locus, which apparently does not affect extreme overweight (as does the primary major locus) but which affects variation in the "normal" range.

Adipose Tissue↗
PubMed1998

An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians.

Genetic factors influence the development of type II diabetes mellitus, but genetic loci for the most common forms of diabetes have not been identified. A genomic scan was conducted to identify loci linked to diabetes and body-mass index (BMI) in Pima Indians, a Native American population with a high prevalence of type II diabetes. Among 264 nuclear families containing 966 siblings, 516 autosomal markers with a median distance between adjacent markers of 6.4 cM were genotyped. Variance-components methods were used to test for linkage with an age-adjusted diabetes score and with BMI. In multipoint analyses, the strongest evidence for linkage with age-adjusted diabetes (LOD = 1.7) was on chromosome 11q, in the region that was also linked most strongly with BMI (LOD = 3.6). Bivariate linkage analyses strongly rejected both the null hypothesis of no linkage with either trait and the null hypothesis of no contribution of the locus to the covariation among the two traits. Sib-pair analyses suggest additional potential diabetes-susceptibility loci on chromosomes 1q and 7q.

Analysis of Variance↗
PubMed1998

Amplitude of visual P3 event-related potential as a phenotypic marker for a predisposition to alcoholism: preliminary results from the COGA Project. Collaborative Study on the Genetics of Alcoholism.

Recent data collected at six identical electrophysiological laboratories from the large national multisite Collaborative Study on the Genetics of Alcoholism provide evidence for considering the P3 amplitude of the event-related potential as a phenotypic marker for the risk of alcoholism. The distribution of P3 amplitude to target stimuli at the Pz electrode in individuals 16 years of age and over from 163 randomly ascertained control families (n = 687) was compared with those from 219 densely affected alcoholic families (n = 1276) in which three directly interviewed first-degree relatives met both DSM-III-R and Feighner criteria at the definite level for alcohol dependence (stage II). The control sample did not exclude individuals with psychiatric illness or alcoholism to obtain incidence rates of psychiatric disorders similar to those of the general population. P3 amplitude data from control families was converted to Z-scores, and a P3 amplitude beyond 2 SD's below the mean was considered an "abnormal trait." When age- and sex-matched distributions of P3 amplitude were compared, members of densely affected stage II families were more likely to manifest low P3 amplitudes (2 SD below the mean) than members of control families, comparing affected and unaffected offspring, and all individuals; all comparisons of these distributions between groups were significant (p < 0.00001). P3 amplitude means were also significantly lower in stage II family members, compared with control family members for all comparisons, namely probands, affected and unaffected individuals (p < 0.0001), and offspring (p < 0.01). Furthermore, affected individuals from stage II families, but not control families, had significantly lower P3 amplitudes than unaffected individuals (p < 0.001). Affected males from stage II families had significantly lower P3 amplitudes than affected females (p < 0.001). Recent linkage analyses indicate that visual P3 amplitude provides a biological phenotypic marker that has genetic underpinnings.

Adolescent↗
PubMed1997

Serum leptin levels are independently correlated with two measures of HDL.

Leptin is the peptide product of the OB gene, which is associated with obesity in some strains of mice. Because dyslipidemias are frequently associated with obesity, we have begun to characterize the pathways connecting these related traits. In this investigation we tested for correlation of HDL phenotype measures with leptin concentrations using data from 1159 participants in the San Antonio Family Heart Study, a study of risk factors for cardiovascular disease in Mexican Americans living in and around San Antonio, Texas. In a subset of 288 unrelated individuals, we tested for correlation of leptin with nine different measures of HDL phenotype and found that only three were significantly related. However, stepwise regression analysis suggested that only two measures, HDL triglyceride concentrations (HDL-TG) and the proportion of apo A-I on HDL particles larger than HDL3 (Large HDL-apo A-I), were independently correlated with leptin. Because obesity and HDL phenotypes are both under strong genetic control, we conducted a trivariate genetic analysis, using the entire data set, to test the hypothesis that the phenotypic correlations were due to the effects of shared genes (i.e., pleiotropy). Heritabilities for the three traits were estimated to be 0.47 for leptin, 0.46 for HDL-TG, and 0.46 for Large HDL-apo A-I. Results from the genetic analyses revealed that the phenotypic correlation of leptin with HDL-TG was nongenetic (i.e., shared environment), while the phenotypic correlation with Large HDL-apo A-I was due to pleiotropy (i.e., shared genes). These results confirmed the result derived from the subset of unrelated individuals that the two measures of HDL are independently correlated with leptin. To our knowledge, this is the first report of a relationship between leptin and any aspect of lipoprotein phenotype. A better understanding of the genes responsible for this relationship may provide a molecular explanation for the aggregation of atherogenic phenotypes, such as diabetes, obesity, and dyslipoproteinemia.

Adult↗
PubMed1997

Ventilation and hypoxic ventilatory response of Tibetan and Aymara high altitude natives.

Newcomers acclimatizing to high altitude and adult male Tibetan high altitude natives have increased ventilation relative to sea level natives at sea level. However, Andean and Rocky Mountain high altitude natives have an intermediate level of ventilation lower than that of newcomers and Tibetan high altitude natives although generally higher than that of sea level natives at sea level. Because the reason for the relative hypoventilation of some high altitude native populations was unknown, a study was designed to describe ventilation from adolescence through old age in samples of Tibetan and Andean high altitude natives and to estimate the relative genetic and environmental influences. This paper compares resting ventilation and hypoxic ventilatory response (HVR) of 320 Tibetans 9-82 years of age and 542 Bolivian Aymara 13-94 years of age, native residents at 3,800-4,065 m. Tibetan resting ventilation was roughly 1.5 times higher and Tibetan HVR was roughly double that of Aymara. Greater duration of hypoxia (older age) was not an important source of variation in resting ventilation or HVR in either sample. That is, contrary to previous studies, neither sample acquired hypoventilation in the age ranges under study. Within populations, greater severity of hypoxia (lower percent of oxygen saturation of arterial hemoglobin) was associated with slightly higher resting ventilation among Tibetans and lower resting ventilation and HVR among Aymara women, although the associations accounted for just 2-7% of the variation. Between populations, the Tibetan sample was more hypoxic and had higher resting ventilation and HVR. Other systematic environmental contrasts did not appear to elevate Tibetan or depress Aymara ventilation. There was more intrapopulation genetic variation in these traits in the Tibetan than the Aymara sample. Thirty-five percent of the Tibetan, but none of the Aymara, resting ventilation variance was due to genetic differences among individuals. Thirty-one percent of the Tibetan HVR, but just 21% of the Aymara, HVR variance was due to genetic differences among individuals. Thus there is greater potential for evolutionary change in these traits in the Tibetans. Presently, there are two different ventilation phenotypes among high altitude natives as compared with sea level populations at sea level: lifelong sustained high resting ventilation and a moderate HVR among Tibetans in contrast with a slightly elevated resting ventilation and a low HVR among Aymara.

Acclimatization↗
PubMed1997

Power of variance component linkage analysis to detect epistasis.

Variance component methods are now being used in linkage analysis to detect genes influencing complex diseases. These methods are easily extended to allow for simultaneous estimation of both the additive effects of multiple loci on phenotypic variation (conditional oligogenic analysis) and the additive interaction (epistatic) effects among loci. We performed linkage analyses on 200 of the simulated replicates in order to evaluate the power to detect the main effects of MG1 and MG2 on Q1 as well as their interaction effects. The power to detect the main effect of MG1 was moderately good, although the power to detect MG2 and the MG1 x MG2 interaction was poor.

Analysis of Variance↗
PubMed1997

Effects of genotype-by-sex interaction on quantitative trait linkage analysis.

Genotype-by-sex (G x S) interaction refers to the interaction of autosomal genes with male or female physiological "environments." G x S interaction has been demonstrated in quantitative genetic analysis of a variety of traits including serum lipid concentrations and anthropometrics, and the importance of considering sex-specific major gene effects in segregation analyses also has been demonstrated. The goal of this study was to examine the effects of G x S interaction on the power to detect linkage. Trait Q3 in GAW10 Problem 2 was analyzed because it was modeled to have G x S interaction at the major gene locus MG3. All 200 nuclear family and 200 extended pedigree replicates were first screened for the presence of G x S interaction in Q3 using a quantitative genetic method. More than half of both the nuclear family and extended pedigree replicates evidenced significant G x S interaction. Variance components linkage analysis was then performed using all markers on GAW10 chromosome 4 in all 200 nuclear family and 200 extended pedigree replicates. A peak lod score of 1.92 at the correct chromosomal location was obtained using the extended pedigree data and incorporating G x S interaction effects. Not incorporating G x S interaction lowered the peak lod score from the analyses of the extended pedigrees to 1.53. Incorporation of G x S interaction effects also increased the power to detect linkage in the nuclear family replicates, although the nuclear families had considerably less power than the extended pedigrees to detect linkage, whether or not G x S interaction was modeled. Incorporation of G x S interaction effects can increase the power to detect linkage, even when the G x S interaction effects are modest.

Environment↗