Biomedical subjects

R E Ferrell

Publications and source records attributed to R E Ferrell.

At least 37 records · Page 2Linked to original sources

PubMed2002

Does age, sex, or ACE genotype affect glucose and insulin responses to strength training?

The purpose of the present study was to determine whether age, sex, or angiotensin I-converting enzyme (ACE) genotype influences the effects of strength training (ST) on glucose homeostasis. Nineteen sedentary young (age = 20-30 yr) men (n = 10) and women (n = 9) were studied and compared with 21 sedentary older (age = 65-75 yr) men (n = 12) and women (n = 9) before and after a 6-mo total body ST program. Fasting insulin concentrations were reduced in young men and in older men with ST (P < 0.05 in both). In addition, total insulin area under the curve decreased by 21% in young men (P < 0.05), and there was a trend for a decrease (11%) in older men (P = 0.06). No improvements in insulin responses were observed in young or older women. The ACE deletion/deletion genotype group had the lowest fasting insulin and insulin areas under the oral glucose tolerance test (OGTT) curve before training (all P < 0.05), but those with at least one insertion allele had a trend for a greater reduction in total insulin area than deletion homozygotes (P = 0.07). These results indicate that ST has a more favorable effect on insulin response to an OGTT in men than in women and offer some support for the hypothesis that ACE genotype may influence insulin responses to ST.

Adult↗

PubMed2001

A model for gene therapy of human hereditary lymphedema.

Primary human lymphedema (Milroy's disease), characterized by a chronic and disfiguring swelling of the extremities, is associated with heterozygous inactivating missense mutations of the gene encoding vascular endothelial growth factor C/D receptor (VEGFR-3). Here, we describe a mouse model and a possible treatment for primary lymphedema. Like the human patients, the lymphedema (Chy) mice have an inactivating Vegfr3 mutation in their germ line, and swelling of the limbs because of hypoplastic cutaneous, but not visceral, lymphatic vessels. Neuropilin (NRP)-2 bound VEGF-C and was expressed in the visceral, but not in the cutaneous, lymphatic endothelia, suggesting that it may participate in the pathogenesis of lymphedema. By using virus-mediated VEGF-C gene therapy, we were able to generate functional lymphatic vessels in the lymphedema mice. Our results suggest that growth factor gene therapy is applicable to human lymphedema and provide a paradigm for other diseases associated with mutant receptors.

Adenoviridae↗

PubMed2001

Solid-state 2H MAS NMR studies of TNT absorption in soil and clays.

The binding of TNT to a soil and soil components is studied with 2H MAS NMR. This NMR technique clearly shows different interactions for deuterated TNT with soil, quartz, and clays. Basically, this NMR method relies on the well-defined 2H MAS NMR characteristics of a deuterated methyl group attached to an aromatic ring. Stationary rings and rings executing 2- or 3-fold jump motions all yield different NMR spectra. The technique has good sensitivity; these studies were conducted at a TNT loading of 22 mmol/kg. For the soil sample studied, TNT showed binding similar to a TNT/K10-montmorillonite sample.

Absorption↗

PubMed2001

Truncating mutations in FOXC2 cause multiple lymphedema syndromes.

Hereditary lymphedemas are developmental disorders of the lymphatics resulting in edema of the extremities due to altered lymphatic flow. One such disorder, the lymphedema-distichiasis syndrome, has been reported to be caused by mutations in the forkhead transcription factor, FOXC2. We sequenced the FOXC2 gene in 86 lymphedema families to identify mutations. Eleven families were identified with mutations predicted to disrupt the DNA binding domain and/or C-terminal alpha-helices essential for transcription activation by FOXC2. Broad phenotypic heterogeneity was observed within these families. The phenotypes observed overlapped four phenotypically defined lymphedema syndromes. FOXC2 appears to be the primary cause of lymphedema-distichiasis syndrome and is also a cause of lymphedema in families displaying phenotypes attributed to other lymphedema syndromes. Our data demonstrates that the phenotypic classification of autosomal dominant lymphedema does not reflect the underlying genetic causation of these disorders.

Adolescent↗

PubMed2001

The 5-HTTPRS/L polymorphism and aggressive behavior in Alzheimer disease.

BACKGROUND: Aggressive behavior in Alzheimer disease (AD) has been linked to dysfunction of serotonin neurotransmission. Homozygosity for the long variant (*L) of an identified biallelic polymorphism of the serotonin transporter promoter region (5-HTTPR) is associated with increased expression of the transporter protein and increased speed of response to serotonin reuptake inhibitor treatment. OBJECTIVE: To determine whether the *L/*L genotype and the *L allele are associated with an increased risk of aggressive symptoms in patients with AD. DESIGN: Case-control study. SETTING: University hospital geriatric psychiatry inpatient program and Alzheimer disease research center. SUBJECTS: Fifty-eight patients with AD with a history of aggressive behavior and 79 never-aggressive patients with AD with comparable severity of cognitive impairment. MAIN OUTCOME MEASURES: The 5-HTTPR genotype and allele frequency. RESULTS: The *L/*L genotype was significantly associated with aggression in patients with AD (odds ratio, 2.8; 95% confidence interval, 1.2-6.5). Similar results were obtained for *L allele frequency. CONCLUSION: The 5-HTTPR*L allele and *L/*L genotype may predispose patients with AD to develop aggressive behavior.

Aged↗

PubMed2001

Ancestral proportions and admixture dynamics in geographically defined African Americans living in South Carolina.

We analyzed admixture in samples of six different African-American populations from South Carolina: Gullah-speaking Sea Islanders in coastal South Carolina, residents of four counties in the "Low Country" (Berkeley, Charleston, Colleton, and Dorchester), and persons living in the city of Columbia, located in central South Carolina. We used a battery of highly informative autosomal, mtDNA, and Y-chromosome markers. Two of the autosomal markers (FY and AT3) are linked and lie 22 cM apart on chromosome 1. The results of this study indicate, in accordance with previous historical, cultural, and anthropological evidence, a very low level of European admixture in the Gullah Sea Islanders (m = 3.5 +/- 0.9%). The proportion of European admixture is higher in the Low Country (m ranging between 9. 9 +/- 1.8% and 14.0 +/- 1.9%), and is highest in Columbia (m = 17.7 +/- 3.1%). A sex-biased European gene flow and a small Native American contribution to the African-American gene pool are also evident in these data. We studied the pattern of pairwise allelic associations between the FY locus and the nine other autosomal markers in our samples. In the combined sample from the Low Country (N = 548), a high level of linkage disequilibrium was observed between the linked markers, FY and AT3. Additionally, significant associations were also detected between FY and 4 of the 8 unlinked markers, suggesting the existence of significant genetic structure in this population. A continuous gene flow model of admixture could explain the observed pattern of genetic structure. A test conditioning on the overall admixture of each individual showed association of ancestry between the two linked markers (FY and AT3), but not between any of the unlinked markers, as theory predicts. Thus, even in the presence of genetic structure due to continuous gene flow or some other factor, it is possible to differentiate associations due to linkage from spurious associations due to genetic structure.

Africa↗

PubMed2001

Chimpanzee apolipoprotein H (beta2-glycoprotein I): report on the gene structure, a common polymorphism, and a high prevalence of antiphospholipid antibodies.

Apolipoprotein H (apoH, protein; APOH, gene) is a 50-kDa glycoprotein that binds to negatively charged substrates, including phospholipids. ApoH is a main target antigen for the binding of antiphospholipid antibodies that are associated with thrombotic events. We have previously characterized the structural organization of the human APOH gene. Because of the significant structural homology between the human and chimpanzee genomes, we have employed oligonucleotides from the human APOH gene sequence to amplify chimpanzee DNA covering the entire transcribed region together with flanking sequence in the 5' region. As in humans, the chimpanzee APOH gene consists of eight exons and seven introns and encodes for a 326-amino-acid protein. The deduced amino acid and nucleotide sequence show 99.4% and 99.6% similarity between human and chimpanzee APOH, respectively. Using isoelectric focusing (IEF) and immunoblotting, we screened 155 chimpanzees (128 unrelated captured parents and 27 captive-born offspring) for the apoH protein polymorphism. The most common IEF pattern in chimpanzees was identical to a previously described APOH*3 allele in humans. In addition, an anodally shifted pattern was observed in chimpanzees with an allele frequency of 0.168, and the corresponding allele was designated as APOH*4. DNA sequencing of APOH*4 carriers revealed a missense mutation in exon 6 (A-->G) at codon 210, which replaces the amino acid lysine by glutamic acid. This mutation does not affect the binding of apoH to cardiolipin as revealed by cardiolipin/enzyme-linked immunosorbent assay (ELISA). We also evaluated the prevalence of anti-apoH antibodies in chimpanzee plasma by using human-apoH-based ELISA and the association of the Lys210Glu mutation with the occurrence of anti-apoH antibodies. The prevalence of anti-apoH antibodies in chimpanzees (64%) was found to be unusually high compared with that found in humans. However, the Lys210Glu mutation showed no association with the occurrence of anti-apoH antibodies. The prevalence of anti-apoH antibodies in chimpanzees may serve as a useful animal model for the human antiphospholipid syndrome, where these antibodies are associated with clinical manifestations.

Alleles↗

PubMed2001

Age-related maculopathy: an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions.

PURPOSE: We seek to identify genetic loci that contribute to age-related maculopathy susceptibility. METHODS: Families consisting of at least two siblings affected by age-related maculopathy were ascertained using eye care records and fundus photographs. Additional family members were used to increase the power to detect linkage. Microsatellite genotyping was conducted by the National Heart, Lung and Blood Institute Mammalian Genotyping Service and the National Institutes of Health Center for Inherited Disease Research. Linkage analyses were conducted with parametric (autosomal dominant; heterogeneity lod score) and nonparametric methods (S(all) statistic) using three diagnostic models. False-positive rates were determined from simulations using actual pedigrees and genotyping data. RESULTS: Under our least stringent diagnostic model, model C, 860 affected individuals from 391 families (452 sib pairs) were genotyped. Sixty-five percent of the affected individuals had evidence of exudative disease. Four regions, 1q31, 9p13, 10q26, and 17q25, showed multipoint heterogeneity lod scores or S(all) scores of 2.0 or greater (under at least one model). Under our most stringent diagnostic model, model A, the 1q31 heterogeneity lod score was 2.46 between D1S1660 and D1S1647. Under model C, the 17q25 heterogeneity lod score at D17S928 was 3.16. Using a threshold of 1.5, additional loci on chromosomes 2 and 12 were identified. CONCLUSIONS: The locus on chromosome 1q31 independently confirms a report by Klein and associates mapping an age-related maculopathy susceptibility gene to this region. Simulations indicate that the 1q31 and 17q25 loci are unlikely to be false positives. There was no evidence that other known macular or retinal dystrophy candidate gene regions are major contributors to the genetics of age-related maculopathy.

Aged↗

PubMed2001

Role of angiotensin converting enzyme genotype in sodium sensitivity in older hypertensives.

BACKGROUND: Individuals differ in their blood pressure (BP) response to changes in dietary sodium (Na+) intake. It is possible that differences in BP responses to dietary Na+ are influenced by genes. METHODS: A total of 35 older (62.9 +/- 1.2 years) hypertensive subjects had their mean arterial blood pressure (MABP) determined after 8 days of low (20 mmol/day) and high (200 mmol/day) Na+ intake. The insertion/ deletion polymorphism of the angiotensin converting enzyme (ACE) gene was genotyped with standard polymerase chain reaction methods. RESULTS: Of the 35 subjects, 24 were classified as sodium-sensitive (> or = 5 mm Hg increase in MABP in response to the increase in dietary Na+) and 11 were classified as sodium-resistant (<5 mm Hg increase in MABP). Those homozygous for the insertion allele of the ACE gene (insertion/insertion [II]; n = 8) had lower (P = .04) MABP responses to the increase in dietary Na+ (0 +/- 3 mm Hg) compared to heterozygotes (insertion/deletion [ID]; n = 20) (9 +/- 2 mm Hg; P = .0001) and those homozygous for the deletion allele (deletion/deletion [DD]; n = 7) (9 +/- 3 mm Hg; P = .05). The prevalence of sodium sensitivity was higher (P = .0083) in DD (71%) and ID (83%) compared to II (25%) genotype groups. CONCLUSIONS: Based on these data in older hypertensive individuals, we conclude that the ACE gene ID and DD genotypes are associated with an increase in BP during a high Na+ diet, which is consistent with the phenotypic characteristic of sodium sensitivity.

Aged↗

PubMed2001

Molecular regulation of lymphangiogenesis and targets for tissue oedema.

New insight has recently been obtained into the molecular mechanisms regulating the function of lymphatic endothelial cells. Vascular endothelial growth factors-C and -D have been shown to stimulate lymphangiogenesis, and their receptor VEGFR-3 has been linked to human hereditary lymphoedema, although there is evidence that other genes are also involved. These data suggest that it may become possible to stimulate lymphatic growth and function and to treat tissue oedema involved in many diseases.

Animals↗

PubMed2001

The 5-HTTPR polymorphism confers liability to a combined phenotype of psychotic and aggressive behavior in Alzheimer disease.

BACKGROUND: Psychotic symptoms in subjects with Alzheimer disease (AD+psychosis, AD+P) are a marker for a distinct phenotype characterized by more rapid cognitive and functional decline and a liability to aggressive behaviors. We recently found that AD subjects homozygous for long alleles (l) of an insertion/deletion polymorphism in the promoter region of the serotonin transporter (5-HTTPR) had elevated rates of aggressive behavior. OBJECTIVE: To examine whether the 5-HTTPR ll genotype confers an increased risk of AD+P, and of the combined AD+P/aggressive phenotype. METHODS: The 5-HTTPR genotype was determined in 332 subjects diagnosed with possible or probable AD. All subjects received structured psychiatric assessments and were categorized with regard to their history of aggressive behaviors and psychotic symptoms. RESULTS: Consistent with other reports, AD+P was associated with a significant increased risk for aggressive behavior. AD+P and aggression were both significantly associated with 5-HTTPR ll genotype and with an increased l allele frequency. Subjects with the combined behavioral phenotype (AD+P and aggressive behavior) had the highest rate of ll genotype and highest l allele frequency. CONCLUSION: The 5-HTTPR l allele appears to confer risk for the combined AD+P/aggressive phenotype. Confirmation of this association in a similar behaviorally well-characterized independent sample is needed.

Aged↗

PubMed2001

Moderate physical activity is associated with higher bone mineral density in postmenopausal women.

OBJECTIVES: To determine the associations between different levels of habitual physical activity, hormone replacement therapy (HRT), and bone mineral density (BMD) in postmenopausal women. DESIGN: Cross-sectional. SETTING: Academic medical center. PARTICIPANTS: Twenty sedentary women, 20 active nonathletic women, and 23 endurance-trained athletes, all of whom were postmenopausal, with half of each group on and half not on HRT. MEASUREMENTS: BMD and body composition determined by dual energy x-ray absorptiometry, maximal oxygen consumption (VO2max), dietary history by questionnaire, and vitamin D receptor (VDR) genotyping on deoxyribonucleic acid. RESULTS: Body weight was higher in the active nonathletic than in the sedentary and athletic women. Body fat was lower and VO2max higher in the athletic women than in the sedentary and the active nonathletic women. Physical activity level was significantly associated with BMD in three of the five measurements taken (L1-L4 lumbar spine, trochanter, total body; all P < .05). These differences were also generally significant after adjusting for body weight. The association between physical activity status and BMD at the neck of the femur and Ward's triangle bordered on significance (P = .07-.09). At most sites, the active nonathletic women had higher BMD than did the sedentary and athletic women. HRT was significantly associated only with total body BMD (P < .05). The groups were similar in terms of dietary habits (protein, calcium, sodium, phosphorus intake); VDR genotypes; and family, smoking, and nutritional histories. CONCLUSION: Given the similarity of the groups with respect to other factors that affect BMD, it appears that prolonged low-to-moderate-intensity physical activity, but not the same number of years of higher-intensity training for competitive events, was independently associated with higher BMD.

Aged↗

PubMed2001

FABP2 genotype is associated with insulin sensitivity in older women.

This study determined whether sequence variations in genes related to glucose and insulin metabolism are associated with insulin sensitivity in postmenopausal women after accounting for habitual physical activity levels, body composition, and hormone-replacement therapy (HRT). Eighteen sedentary, 19 physically active, and 23 athletic postmenopausal white women underwent a frequently sampled intravenous glucose tolerance test to determine insulin sensitivity (S(I)) and dual-energy x-ray absorptiometry to determine body composition. After accounting for the effects of body composition, habitual physical activity levels, and HRT status, S(I) was 26% lower in subjects with the Thr54 fatty acid-binding protein 2 (FABP2) allele compared with Ala54 homozygotes (4.3 +/- 0.5 v 5.8 +/- 0.6 microU x 10(-4)/min/mL; P <.05). Angiotensin-converting enzyme genotype was not significantly associated with S(I). There were no significant associations between Gln27Glu beta(2)-adrenergic receptor or Pro12Ala peroxisome proliferator-activated receptor gamma variants and glucose or insulin kinetic parameters. It was concluded that FABP2 genotype influences insulin sensitivity independent of body composition, habitual physical activity levels, and HRT status in postmenopausal white women.

Absorptiometry, Photon↗

PubMed2001

Obesity gene variant and elite endurance performance.

beta2-adrenergic receptor (ADRB2) Gln27Glu genotype was determined in sedentary (n = 19), active (n = 20), and elite endurance athletic (n = 24) Caucasian postmenopausal women. Age was similar in all physical activity and ADRB2 genotype groups. ADRB2 genotypes were in Hardy-Weinberg equilibrium in sedentary and active women, but not in the athletes (chi(2) = 4.28, P <.05), due to the near absence of ADRB2 Glu27Glu homozygotes among the athletes. Weight tended to be higher in ADRB2 Glu27Glu women (63.5 +/- 1.8 v 57.7 +/- 1.7 and 60.0 +/- 1.8, P =.08), as did body mass index (BMI) (25.0 +/- 0.4 v 22.9 +/- 0.6 and 23.4 +/- 0.5 kg/m(2), P =.05), due to a higher fat mass in Glu27Glu women (24.1 +/- 1.0 v 18.1 +/- 1.4 and 20.1 +/- 1.4 kg, P <.05). Maximal O2 consumption was lower in ADRB2 Glu27Glu than in ADRB2 Glu27Gln and Gln27Gln genotype women (25.4 +/- 1.1 v 32.4 +/- 1.5 and 29.1 +/- 1.7 mL/kg/min, P <.05). We conclude that the Glu27Glu ADRB2 genotype may dissociate from and the Gln27Gln and Gln27Glu genotypes may associate with elite endurance performance in older women.

Aged↗

PubMed2001

Association of 8p23 deletions with poor survival in head and neck cancer.

OBJECTIVE: Allelic loss at 8p23 occurs frequently in head and neck squamous cell carcinoma. The objective of this study was to determine the prognostic importance of 8p23 loss. STUDY DESIGN AND SETTINGS: We tested 51 primary tumors and 19 lymph node metastases for loss of heterozygosity with 7 microsatellite polymorphisms at 8p23 and correlated the results with disease-free interval and disease-specific survival. RESULTS: The Kaplan-Meier analysis demonstrated statistically significant association of 8p23 allelic loss with both shorter disease-free interval and disease-specific survival. For the pN stage, the log-rank test indicated significance in correlation with the disease-free interval, whereas the pT stage showed a significant correlation with disease-specific survival. Multivariate analysis identified loss of heterozygosity at 8p23 as independent prognostic marker for disease-free interval. CONCLUSION: Our data suggest that 8p23 allelic loss is associated with poor prognosis in head and neck squamous cell carcinoma and could be useful refining diagnosis of these tumors.

Alleles↗

PubMed2001

VEGFR3 gene structure, regulatory region, and sequence polymorphisms.

Vascular endothelial growth factor receptor 3 (VEGFR-3) is required for cardiovascular development during embryogenesis. In adults, this receptor is expressed in lymphatic endothelial cells, and mutant VEGFR3 alleles have been implicated in human hereditary lymphedema. To better understand the basis of its specific endothelial lineage-restricted expression, we have characterized the VEGFR3 gene and its regulatory 5' flanking region. The human gene contains 31 exons, of which exons 30a and 30b are alternatively spliced. The VEGFR3 proximal promoter is TATA-less and contains stretches of sequences homologous with the mouse Vegfr3 promoter region. In transfection experiments of cultured cells, the Vegfr3 promoter was shown to control endothelial cell-specific transcription of downstream reporter genes. This result was further confirmed in vivo; in a subset of transgenic mouse embryos, a 1.6 kb Vegfr3 promoter fragment directed weak lymphatic endothelial expression of the LacZ marker gene. This suggests that endothelial cell-specific elements occur in the proximal promoter, although further enhancer elements are probably located elsewhere. The sequence, organization, and variation in the VEGFR3 gene and its regulatory region provide important tools for the molecular genetic analysis of the lymphatic system and its disorders.

3T3 Cells↗

PubMed2001

Specific genetic markers of endurance performance and VO2max.

Specific genetic markers of endurance performance and VO2max. Exerc. Sport Sci. Rev., Vol. 29, No. 1, pp 15-19, 2001. Recent advances have revolutionized genetic studies of quantitative traits. Mitochondrial DNA and creatine kinase variations may influence VO2max. Other data strongly suggest that angiotensin-converting enzyme genotype affects VO2max and endurance performance capacity, but the mechanisms are unclear. A recent genome-wide scan study also has provided candidate loci requiring further study.

Creatine Kinase↗

PubMed2001

A combinatorial partitioning method to identify multilocus genotypic partitions that predict quantitative trait variation.

Recent advances in genome research have accelerated the process of locating candidate genes and the variable sites within them and have simplified the task of genotype measurement. The development of statistical and computational strategies to utilize information on hundreds -- soon thousands -- of variable loci to investigate the relationships between genome variation and phenotypic variation has not kept pace, particularly for quantitative traits that do not follow simple Mendelian patterns of inheritance. We present here the combinatorial partitioning method (CPM) that examines multiple genes, each containing multiple variable loci, to identify partitions of multilocus genotypes that predict interindividual variation in quantitative trait levels. We illustrate this method with an application to plasma triglyceride levels collected on 188 males, ages 20--60 yr, ascertained without regard to health status, from Rochester, Minnesota. Genotype information included measurements at 18 diallelic loci in six coronary heart disease--candidate susceptibility gene regions: APOA1--C3--A4, APOB, APOE, LDLR, LPL, and PON1. To illustrate the CPM, we evaluated all possible partitions of two-locus genotypes into two to nine partitions (approximately 10(6) evaluations). We found that many combinations of loci are involved in sets of genotypic partitions that predict triglyceride variability and that the most predictive sets show nonadditivity. These results suggest that traditional methods of building multilocus models that rely on statistically significant marginal, single-locus effects, may fail to identify combinations of loci that best predict trait variability. The CPM offers a strategy for exploring the high-dimensional genotype state space so as to predict the quantitative trait variation in the population at large that does not require the conditioning of the analysis on a prespecified genetic model.

Adult↗