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D R Reed

Publications and source records attributed to D R Reed.

At least 19 recordsLinked to original sources
PubMed2004

Polymorphisms in the taste receptor gene (Tas1r3) region are associated with saccharin preference in 30 mouse strains.

The results of recent studies suggest that the mouse Sac (saccharin preference) locus is identical to the Tas1r3 (taste receptor) gene. The goal of this study was to identify Tas1r3 sequence variants associated with saccharin preference in a large number of inbred mouse strains. Initially, we sequenced approximately 6.7 kb of the Tas1r3 gene and its flanking regions from six inbred mouse strains with high and low saccharin preference, including the strains in which the Sac alleles were described originally (C57BL/6J, Sac(b); DBA/2J, Sac(d)). Of the 89 sequence variants detected among these six strains, eight polymorphic sites were significantly associated with preferences for 1.6 mm saccharin. Next, each of these eight variant sites were genotyped in 24 additional mouse strains. Analysis of the genotype-phenotype associations in all 30 strains showed the strongest association with saccharin preference at three sites: nucleotide (nt) -791 (3 bp insertion/deletion), nt +135 (Ser45Ser), and nt +179 (Ile60Thr). We measured Tas1r3 gene expression, transcript size, and T1R3 immunoreactivity in the taste tissue of two inbred mouse strains with different Tas1r3 haplotypes and saccharin preferences. The results of these experiments suggest that the polymorphisms associated with saccharin preference do not act by blocking gene expression, changing alternative splicing, or interfering with protein translation in taste tissue. The amino acid substitution (Ile60Thr) may influence the ability of the protein to form dimers or bind sweeteners. Here, we present data for future studies directed to experimentally confirm the function of these polymorphisms and highlight some of the difficulties of identifying specific DNA sequence variants that underlie quantitative trait loci.

Animals↗
PubMed2001

A genome-wide scan suggests a locus on chromosome 1q21-q23 contributes to normal variation in plasma cholesterol concentration.

To identify genes that influence plasma cholesterol, triglyceride, and high-density and low-density lipoproteins concentrations we conducted a genome-wide scan using 354 polymorphic markers spaced at 10-cM intervals in 75 obese but otherwise normal human families. The results of the genome scan using sibling pair analysis of quantitative phenotypes suggested that 1q21-q23 contains a locus that influences plasma cholesterol concentration. Chromosome 12 gave evidence of linkage to plasma triglyceride concentration (D12SPAH) and chromosomes 3, 6, 7, 10, 11, 17, and 20 yielded additional evidence of linkage for lipid phenotypes at lower levels of statistical significance. Allele sharing for markers near prominent candidate genes was either very weakly related or unrelated to sibling similarity for lipid concentrations. Together these results suggest that genes with important roles in regulating normal cholesterol and triglyceride concentrations do not coincide with the location of previously known candidate genes.

Adult↗
PubMed2001

High-resolution genetic mapping of the saccharin preference locus (Sac) and the putative sweet taste receptor (T1R1) gene (Gpr70) to mouse distal Chromosome 4.

The Sac (saccharin preference) locus affecting mouse behavioral and neural responsiveness to sweeteners has been mapped to distal Chr 4. A putative sweet taste receptor, T1R1, has been recently cloned, and the gene encoding it, Gpr70, has also been mapped to mouse distal Chr 4. To assess Gpr70 as a candidate gene for Sac, we compared the Gpr70 sequences of C57BL/6ByJ and 129P3/J mouse strains with different alleles of Sac. Using Gpr70 sequence variation between the C57BL/6ByJ and 129P3/J strains, we conducted a high-resolution analysis of the chromosomal localization of the Gpr70 and Sac loci in the F2 hybrids and 129.B6-Sac partially congenic mice originating from these two strains. The Gpr70 gene maps proximal to Sac, which demonstrates that they are different loci.

Animals↗
PubMed2001

Nutrient preference and diet-induced adiposity in C57BL/6ByJ and 129P3/J mice.

Purified carbohydrates and fats are usually palatable to humans and other animals, and their consumption often induces weight gain and accumulation of fat. In this study, we examined consumption of complex carbohydrates (cornstarch and Polycose) and fats (soybean oil and margarine) in mice from two inbred strains, C57BL/6ByJ and 129P3/J. At lower concentrations of liquid nutrients tested using two-bottle tests, when the amounts consumed had negligible energy content, the C57BL/6ByJ mice had higher acceptance of Polycose and soybean oil. This was probably due to strain differences in chemosensory perception of Polycose and oil. At higher concentrations, the mice consumed a substantial part of their daily energy from the macronutrient sources, however, there were no or only small strain differences in nutrient consumption. These small differences were probably due to strain variation in body size. The two strains also did not differ in chow intake. Despite similar energy intakes, access to the nutrients resulted in greater body weight (BW) gain in the C57BL/6ByJ mice than in the 129P3/J mice. The diet-induced weight gain was examined in detail in groups of 2-month-old C57BL/6ByJ and 129P3/J mice given ether chow, or chow and margarine to eat. Access to margarine did not increase total energy consumption of either strain. It increased BW and adiposity of the C57BL/6ByJ mice, but only after they reached the age of approximately 3 months. There were no differences in BW and adiposity between control and margarine-exposed 129P3/J mice. The results suggest that diet-induced adiposity in the B6 mice depends on age and does not depend on hyperphagia.

Animals↗
PubMed2001

Hydrogen-deuterium exchange at non-labile sites: a new reaction facet with broad implications for structural and dynamic determinations.

Hydrogen-deuterium exchange at non-labile sites is reported. The conjugate bases of isophthalic acid (m-C6H4(CO2H)2), 2-oxoglutaric acid (HO2CCOCH2CH2CO2H), and 2-methylisophthalic acid (2-CH3-1,3-C6H4(CO2H)2) undergo scrambling with 1, 2, and 3 carbon-centered hydrogens under a variety of conditions. Likewise, protonated 2-(m-methoxyphenyl)-ethylamine ((m-CH3OC6H4)CH2CH2NH2) undergoes up to 5 H/D exchanges upon gentle activation whereas the conjugate acid of 2-phenylethylamine (C6H5CH2CH2NH2) requires the presence of ammonia-d3 in order to be pushed to undergo up to 8 H/D exchanges. The very act of electrospraying ions can result in extensive movement of deuterium to carbon centers and, in some cases, could not be prevented. These findings offer great promise for future exploitation but also suggest that the interpretation of many H/D exchange experiments using mass spectrometry as the analytical tool could be in error.

Carboxylic Acids↗
PubMed2001

Leptin resistance is associated with extreme obesity and aggregates in families.

OBJECTIVE: To examine the determinants of plasma leptin levels and leptin resistance in a sample of extremely obese subjects and their relatives. DESIGN AND METHOD: We obtained plasma leptin values on 968 individuals from 218 families having both extremely obese and average weight members for obesity related variables. Multivariate regression analyses were used to identify predictors of both plasma leptin concentration and an index of leptin resistance. Family correlations and heritabilities were computed for plasma leptin and indices of leptin resistance. RESULTS: Body mass index and sex predicted 63% of the variance in plasma leptin. Extremely obese subjects were most likely and average weight subjects least likely to be leptin resistant. Both leptin and leptin resistance aggregated within families. CONCLUSION: Leptin resistance is strongly associated with extreme obesity and appears to be a heritable trait. The determination of its genetic causes will aid in understanding the role of leptin in common forms of human obesity.

Adult↗
PubMed2001

Positional cloning of the mouse saccharin preference (Sac) locus.

Differences in sweetener intake among inbred strains of mice are partially determined by allelic variation of the saccharin preference (Sac) locus. Genetic and physical mapping limited a critical genomic interval containing Sac to a 194 kb DNA fragment. Sequencing and annotation of this region identified a gene (Tas1r3) encoding the third member of the T1R family of putative taste receptors, T1R3. Introgression by serial backcrossing of the 194 kb chromosomal fragment containing the Tas1r3 allele from the high-sweetener-preferring C57BL/6ByJ strain onto the genetic background of the low-sweetener-preferring 129P3/J strain rescued its low-sweetener-preference phenotype. Polymorphisms of Tas1r3 that are likely to have functional significance were identified using analysis of genomic sequences and sweetener-preference phenotypes of genealogically distant mouse strains. Tas1r3 has two common haplotypes, consisting of six single nucleotide polymorphisms: one haplotype was found in mouse strains with elevated sweetener preference and the other in strains relatively indifferent to sweeteners. This study provides compelling evidence that Tas1r3 is equivalent to the Sac locus and that the T1R3 receptor responds to sweeteners.

Alleles↗
PubMed2000

X-linkage does not account for the absence of father-son similarity in plasma uric acid concentrations.

Plasma uric acid concentration aggregates in families, and this similarity has been suggested to be due, in part, to multiple shared genes. Men have higher plasma uric acid concentrations than women and are affected with gout nine times more frequently. Rare forms of hyperuricemia and gout are due to mutations of X-linked genes (HPRT1 and PRPS1). Given these observations, we tested the hypothesis that normal variation in plasma uric acid levels would display a pattern of familial similarity consistent with X-linkage in 892 individuals from 196 obese but otherwise healthy families. As predicted by X-linked inheritance, fathers and sons showed no resemblance in plasma uric acid concentration (r = 0.013, NS), while all other pairings showed moderate-to-strong familial resemblance (ranging from 0.167, P < 0.01, parent-offspring to 0.415, sister-sister, P < 0.01). We then tested the hypothesis that loci along the X chromosome would influence plasma uric acid concentration. We conducted both single-point and multipoint linkage analyses using 17 X-linked markers spaced at approximately 9 cm intervals to determine whether allele sharing among sibs was related to sib similarity in plasma uric acid concentrations (n = 1,100 sib pairs). We found no regions of the X chromosome that cosegregated with plasma uric acid concentrations (P > 0.05). We conclude that variation in genes on the X chromosome contribute little to normal variation in plasma uric acid concentrations.

Adolescent↗
PubMed2000

Experimental determination of the alpha and beta C--H bond dissociation energies in naphthalene.

The acidities of the two different sites in naphthalene (1alpha and 1beta) and the electron affinities of the alpha- and beta-naphthyl radicals were measured using a Fourier transform mass spectrometer. Both carbon-hydrogen bond dissociation energies for naphthalene also were obtained, in this case via the application of a thermodynamic cycle. The final results are DeltaH(o)acid (1alpha) = 394.2+/-1.2 kcal mol(-1), DeltaH(o)acid (1beta) = 395.5+/-1.3 kcal mol(-1), EA(alpha) = 31.6+/-0.5 kcal mol(-1), EA(beta) = 31.6+/-0.5 kcal mol(-1), BDE(1alpha) = 112.2+/-1.3 kcal mol(-1) and BDE(1alpha) = 111.9+/-1.4 kcal mol(-1), and they are compared to benzene and phenyl radical as well as ab initio and density functional theory (B3LYP) calculations.

Environmental Pollutants↗
PubMed2000

Resemblance for body mass index in families of obese African American and European American women.

OBJECTIVE: We determined the levels of resemblance in body mass index (BMI) in large samples of families selected through obese African American and European American women. RESEARCH METHODS AND PROCEDURES: We examined correlations among relatives in 1,185 European American and African American families ascertained through age-matched obese women (BMI > or = 30 kg/m2). A subset of 801 families were ascertained through extremely obese women (BMI > or = 40 kg/m2). RESULTS: Parent-offspring and sibling correlations ranged from 0.19 to 0.15, suggesting a moderate level of heritability in both groups. Mean BMI values for female relatives were lower for European Americans than for African Americans even though probands were matched, perhaps because the European American relatives regress to a lower population mean. We found significantly higher family correlations for height in European Americans, suggesting greater environmental variability among African Americans for factors affecting growth and physical development. DISCUSSION: Our results suggest a similar level of heritability of BMI in families of obese African American and European American women. Other genetic studies will be needed to determine the extent to which the same or different genes and environmental conditions contribute to an overall similar heritability in the two racial groups.

Adolescent↗
PubMed2000

Reduced mortality associated with body mass index (BMI) in African Americans relative to Caucasians.

Although obesity is especially common in African-American women, the relationship between body mass index (BMI, kg/m2) and mortality primarily has been studied in Caucasians, and almost exclusively in average weight populations. In order to examine the relationship between race and mortality in a predominately overweight population, we assessed mortality in 6,602 parents of obese African-American and Caucasian subjects. Most parents of both races were overweight or obese: 87.8% of African-American mothers (mean BMI = 37.7) and 78.6% of Caucasian mothers (mean BMI = 34.9) had a BMI > or =27.3; 61.9% of African-American fathers (mean BMI = 31.5) and 63.6% of Caucasian fathers (mean BMI = 31.8) had a BMI > or =27.8. Even though African Americans had equivalent (fathers) or higher (mothers) average BMI and percentage overweight or obesity than Caucasians, unadjusted mortality rates were consistently lower in African Americans than in Caucasians. In a combined sample, income, age (linear, quadratic and cubic effects), gender, BMI (linear and quadratic), and race were significant predictors of mortality. Linear and quadratic effects of BMI were significant within race and in the combined sample, after controlling for the effects of all other predictor variables. Therefore, the mortality differences cannot be due to differences in age, income, BMI, or gender distributions. In addition, there was significant heterogeneity between races for all models examined, suggesting interactions between race and all other predictor variables. Moreover, there was a strong residual effect for race after accounting for the other variables. The highly selective and cross-sectional nature of this sample limits our ability to make specific BMI-associated risk estimates. However, the consistent differences between comparably ascertained racial groups sampled from the upper extreme of the BMI distribution provide support for a lower BMI-associated mortality rate in African Americans relative to Caucasians.

Adult↗
PubMed1999

Sequence variants in the 5' flanking region of the leptin gene are associated with obesity in women.

Few mutations have been found in the human leptin gene and the relationship between leptin gene sequence variation and human overweight is uncertain. To determine whether sequence variation within the leptin gene and its regulatory elements contribute to extreme obesity, we screened approximately 3 kb of the 5' flanking region and the three exons in 125 unrelated extremely obese (BMI > or = 40 kg/m2) and 86 average weight women (BMI < 27 kg/m2). Within the protein coding regions only one heterozygous silent mutation was found (codon 102; AAC/AAT). Within the 5' flanking region, six frequent sequence variants were detected (q > 0.10), and the allele frequencies of three of these variants differed between obese and average weight Caucasian women (+19, chi 2 = 4.46, p = 0.035; -1823, chi 2 = 4.36, p = 0.037; -2548, chi 2 = 5.73, p = 0.017). Nine infrequent sequence variants were detected (q < 0.05) but they did not occur more often among obese women compared with those of average-weight. For extremely obese women, three polymorphisms (+19, -188, and -633) predicted the degree of obesity. Allelic variants may influence the regulation of the leptin gene and thereby influence body weight, particularly among extremely obese women. However, given the low variability in coding regions and the high variability in the 5' flanking region, discerning the functional significance of each variant is likely to be difficult.

Adolescent↗
PubMed1999

Genome scan for human obesity and linkage to markers in 20q13.

Obesity is a highly prevalent, multigenic trait that predicts increased morbidity and mortality. Here we report results from a genome scan based on 354 markers in 513 members of 92 nuclear families ascertained through extreme obesity and normal body weight. The average marker interval was approximately 10 cM. We examined four correlated obesity phenotypes, including the body-mass index (BMI) (both as a quantitative trait and as a discrete trait with a threshold of BMI > or /=30 kg/m2) and percentage of fat (both as a quantitative trait and as a discrete trait with a threshold of 40%) as assessed by bioelectrical impedance. In the initial stage of the genome scan, four markers in 20q gave positive evidence for linkage, which was consistent across most obesity phenotypes and analytic methods. After saturating 20q with additional markers (25 markers total) in an augmented sample of 713 members from 124 families, we found linkage to several markers in a region, 20q13, previously implicated in both human and animal studies. Three markers (D20S107, D20S211, and D20S149) in 20q13 had empirical P values (based on Monte Carlo simulations, which controlled for multiple testing) < or /=. 01 for single-point analysis. In addition, the parametric, affecteds-only analysis for D20S476 yielded a LOD score of 3.06 (P=. 00009), and the affected-sib-pair test yielded a LOD score of 3.17 (P=.000067). Multipoint analyses further strengthened and localized these findings. This region includes several plausible candidate genes for obesity. Our results suggest that one or more genes affecting obesity are located in 20q13.

Black People↗
PubMed1998

Dieting, exercise, or disordered eating does not account for extremes of body weight within families.

OBJECTIVE: Families having both members with obesity and thin members should contain substantial information for genetics studies, provided measured phenotype is an accurate indicator of genetic predisposition. We assessed the impact of potentially complicating behavioral factors on obesity phenotypes of family members selected for a long-term project to identify genes for human obesity. RESEARCH METHODS AND PROCEDURES: Ninety-nine Caucasian families were selected for study because they contained both extremely obese and average-weight family members. Family members (n=492) were queried about their diet and exercise habits, their psychiatric histories as they pertained to eating disorders, and for a subset of subjects (n=329), a lifetime dieting history and a lifetime maximum weight were recorded. RESULTS: Subjects with average body weights in these families did not appear to be maintaining their weight by dieting and <4% of the average-weight subjects had ever been obese in the past. DISCUSSION: Although dieting and other weight loss practices potentially could either mask or complicate the genotype-phenotype relationship, we found little evidence for this possibility in the families studied.

Adolescent↗
PubMed1998

Obesity related phenotypes in families selected for extreme obesity and leanness.

BACKGROUND: Obesity is a multigenic trait, and special methods and sampling designs are needed for gene identification. OBJECTIVE: To describe characteristics of families selected to increase information for genetic linkage studies of obesity. DESIGN: Families having extremely obese siblings with a lean parent and sibling. SUBJECTS: 594 members of 94 Caucasian families. MEASUREMENTS: Measured height and weight, bioelectric impedance, skinfolds, circumferences and questionnaires. RESULTS: Families have an extreme range of obesity phenotypes, which are bimodally distributed. The obese individuals are predominantly women with an onset of obesity early in life. Obesity onset age was negatively correlated with level of obesity, and onset ages were correlated among family members. Individual obesity measures were highly correlated. The extreme range of phenotypes within families increases family variability and presumably gene segregation. CONCLUSION: Sampling families through extremely obese sibling pairs with a lean parent and sibling results in families with an extreme range of obesity and leanness. The large within-family variance and early age of onset should make these families highly informative for gene mapping and gene identification studies.

Adolescent↗
PubMed1998

Estimates of the heights and weights of family members: accuracy of informant reports.

OBJECTIVE: Information about the accuracy of family informant estimates of height and weight should assist investigators in evaluating the costs and benefits of using this type of data in genetic study designs. DESIGN AND METHOD: To assess the accuracy of family informant estimates, 374 first-degree relatives from 94 Caucasian families, gave estimates about the heights and weights of their first degree relatives. These estimates were compared with measured heights and weights to determine their accuracy. RESULTS: Informant estimates were highly predictive of measured heights (r=0.95), and weights (r=0.94), but informants systematically overestimated heights (mean=1.4 cm) and underestimated weights of their family members (mean=4.1 kg). CONCLUSIONS: On average, height estimates were generally within 1% of the measured height and weight estimates were within 3-5% of the measured weight. Therefore, these proxy measures can provide useful data, when measured or self-reported heights and weights are not available.

Bias↗