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PubMed2001

Clinal variation for amino acid polymorphisms at the Pgm locus in Drosophila melanogaster.

Clinal variation is common for enzymes in the glycolytic pathway for Drosophila melanogaster and is generally accepted as an adaptive response to different climates. Although the enzyme phosphoglucomutase (PGM) possesses several allozyme polymorphisms, it is unique in that it had been reported to show no clinal variation. Our recent DNA sequence investigation of Pgm found extensive cryptic amino acid polymorphism segregating with the allozyme alleles. In this study, we characterize the geographic variation of Pgm amino acid polymorphisms at the nucleotide level along a latitudinal cline in the eastern United States. A survey of 15 SNPs across the Pgm gene finds significant clinal differentiation for the allozyme polymorphisms as well as for many of the cryptic amino acid polymorphisms. A test of independence shows that pervasive linkage disequilibrium across this gene region can explain many of the amino acid clines. A single Pgm haplotype defined by two amino acid polymorphisms shows the strongest correlation with latitude and the steepest change in allele frequency across the cline. We propose that clinal selection at Pgm may in part explain the extensive amino acid polymorphism at this locus and is consistent with a multilocus response to selection in the glycolytic pathway.

Amino Acids↗
PubMed2025

Genome-wide association meta-regression identifies stem cell lineage orchestration as a key driver of acne risk.

Over 85% of the population experience acne at some point in their lives, with its severity spanning a quantitative spectrum, from mild, transient outbreaks to more persistent, severe forms of the condition. Moderate to severe disease poses a substantial global burden arising from both the physical and psychological impacts of this highly visible condition. The analytical approach taken in this study aimed to address the impact of variation in the dichotomisation of acne case control status, driven by ascertainment and study design, on effect size estimates across independent genetic association studies of acne. Through a fixed intercept meta-regression framework, we combined evidence genome-wide for association with acne across studies in which case-control status had been ascertained in different settings, allowing for different severity threshold definitions. Across a combined sample of 73,997 cases and 1,103,940 controls of European, South Asian and African American ancestry we identify genetic variation at 165 genomic loci that influence acne risk. There is evidence for both shared and ancestry specific components to the genetic susceptibility to acne and for sex differences in the magnitude of effect of risk alleles at three loci. We observe that common genetic variation explains 13.4% of acne heritability on the liability scale. Consistent with the hypothesis that genetic risk primarily operates at the level of individual pilosebaceous units, a polygenic score derived from this case-control study of acne susceptibility is associated with both self-reported and clinically assessed acne severity in adolescence, further strengthening the link between genetic risk and disease severity. Prioritisation of causal genes at the identified acne risk loci, provides genetic validation of the targets of established and emerging acne therapies, including retinoid treatments. The identified acne risk loci are enriched for genes encoding downstream effectors of RXRA signalling, including SOX9 and components of the WNT and p53 pathways. Illustrating that the control of stem cell lineage plasticity and cellular fate are important mechanisms through which genetic variation influences acne susceptibility within the pilosebaceous unit.

Journal Article↗
PubMed1992

Quantitative measures of sympathetic skin response in diabetes: relation to sudomotor and neurological function.

The sympathetic skin response (SSR) at the foot to a deep inspiration was measured in 68 randomly selected diabetic patients and 46 age matched normal subjects and compared with other quantitative measures of neurological and sudomotor function. SSR was obtained in all but three diabetic patients. The upper limit of normal for the onset latency was 2202 ms and the lower limit for the amplitude of the first wave 92 microV. Ten diabetic patients had measurable but prolonged latencies, and 11 had measurable but low amplitudes. There were no significant associations between latency, height, and age, but in insulin dependent patients there was a significant diminution of response amplitude with increasing duration of diabetes. Latency was weakly associated with Marstock thermal thresholds, respiratory RR variation, and common peroneal nerve conduction velocity. SSR amplitude was associated with the density of pilocarpine activatable sweatspots in the same region of the foot. Patients with abnormal latencies were significantly older and had reduced thermal sensation than those with normal latencies. Median coefficients of variation for repeat testing in diabetic patients were 9% for latency and 13% for amplitude. The test is objective and reproducible, but latency measurements reflect conduction in a long multineuronal pathway and are not purely a measure of peripheral C fibre function; amplitude measurements reflect the density of spontaneously activable sweat glands and are therefore a valid measure of peripheral sympathetic activity, though they depend more on temperature than do latencies (mean change over the range 32-34 degrees C; 8.5% degrees C for amplitude, -2.5%/degrees C for latency).

Adult↗
PubMed2001

Functional inferences vary with the method of analysis in fMRI.

Neuroanatomic substrates of specific cognitive functions have been inferred from anatomic distributions of activated pixels during fMRI studies. With declarative memory tasks, interest has focused on the extent to which various medial temporal lobe anatomic structures are activated while subjects encode new information. The aim of this project was to examine how commonly used variations in fMRI data processing methods affect the distribution of activation in anatomically defined medial temporal lobe regions of interest (ROIs) during a complex scene-encoding task. ROIs were drawn on an MRI anatomic template formed from 3D SPGR scans of eight subjects combined in Talairach space. Separate ROIs were drawn for the posterior and anterior hippocampal formation, parahippocampal gyrus, and entorhinal cortex. Twelve different activation maps were created for each subject by using four correlation coefficients and three cluster volumes. Friedman's two-way ANOVA by ranks was used to test the hypothesis that the distribution of activated pixels among defined anatomic ROIs varied as a function of the data processing method. By simply varying the combination of correlation coefficient and cluster volume, significantly different distributions of activation within named medial temporal lobe structures were obtained from the same fMRI datasets (P < 0.015; P < 0.001). The number of subjects studied (n = 8) is in a range commonly found in the literature yet this clearly resulted in spurious associations between processing parameter variations and activation distribution. Using data processing methods that are independent of the arbitrary selection of cutoff values for thresholding activation maps may reduce the likelihood of obtaining spurious results.

Adult↗
PubMed2002

Common psychiatric diseases and human genetic variation.

OBJECTIVE: A better understanding of human genetic variation is important in assessing disease epidemiology and phenotypic variation, and may be critical in evaluating genetic aspects of common genetic diseases, such as schizophrenia, bipolar disease and Parkinson's. These diseases are particularly difficult to investigate as there are few peripheral markers, and although a genetic aetiology has long been suspected, robust findings have been hard to establish. METHODS: Variations in alleles at 13 tri-nucleotide gene loci expressed in the brain and implicated in several neurodegenerative diseases, as well as certain other loci, were examined in the Indian population for comparison with other major ethnic groups. RESULTS AND CONCLUSION: In the Indian population, the distribution of alleles at the Machado-Joseph disease locus was similar to the Western European pattern of distribution. Analysis of haplotypes at the locus for Huntington's disease suggested multiple origins, and possible effects of population admixture because of the recent history of the country. At other alleles of neuropsychiatric interest (dopamine receptor, serotonin receptor, serotonin transporter, alcohol dehydrogenase), allele frequencies in the Indian population differed from other populations. Interspecies comparison suggests a gradual expansion in repeat size, with the exception of the CLOCK gene, which displays a contraction of CAG repeat numbers. World-wide differences in disease phenotypes need to be explored, and an appreciation of their genetic basis may provide a window of opportunity for improving our knowledge of the underlying genetic mechanisms.

Journal Article↗
PubMed2005

Differential gene expression in normal human mammary epithelial cells treated with malathion monitored by DNA microarrays.

Organophosphate pesticides are a major source of occupational exposure in the United States. Moreover, malathion has been sprayed over major urban populations in an effort to control mosquitoes carrying West Nile virus. Previous research, reviewed by the U.S. Environmental Protection Agency, on the genotoxicity and carcinogenicity of malathion has been inconclusive, although malathion is a known endocrine disruptor. Here, interindividual variations and commonality of gene expression signatures have been studied in normal human mammary epithelial cells from four women undergoing reduction mammoplasty. The cell strains were obtained from the discarded tissues through the Cooperative Human Tissue Network (sponsors: National Cancer Institute and National Disease Research Interchange). Interindividual variation of gene expression patterns in response to malathion was observed in various clustering patterns for the four cell strains. Further clustering identified three genes with increased expression after treatment in all four cell strains. These genes were two aldo-keto reductases (AKR1C1 and AKR1C2) and an estrogen-responsive gene (EBBP). Decreased expression of six RNA species was seen at various time points in all cell strains analyzed: plasminogen activator (PLAT), centromere protein F (CPF), replication factor C (RFC3), thymidylate synthetase (TYMS), a putative mitotic checkpoint kinase (BUB1), and a gene of unknown function (GenBank accession no. AI859865). Expression changes in all these genes, detected by DNA microarrays, have been verified by real-time polymerase chain reaction. Differential changes in expression of these genes may yield biomarkers that provide insight into interindividual variation in malathion toxicity.

Epithelial Cells↗
PubMed1992

Hydroquinone: a developmental toxicity study in rats.

To determine the potential developmental toxicity of hydroquinone (HQ), pregnant rats (COBS-CD-BR) were given 0, 30, 100, or 300 mg/kg HQ by gavage on the 6th through the 15th days of gestation. Maternal effects included a slight, but significant (p less than or equal to 0.05), reduction in body weight gain and feed consumption for the 300 mg/kg HQ dams. Reproductive indices, i.e., pregnancy rate, numbers of corpora lutea, implantation sites, viable fetuses, and early and late resorptions, fetal sex ratio, pre- and postimplantation losses, and gravid uterine weights, were not affected by treatment with HQ. A slightly reduced (p less than or equal to 0.05) mean fetal body weight seen at the 300 mg/kg dose level was associated with the slightly reduced body weight gain seen for the dams at this dose level. Gross external, internal soft tissue, and skeletal examinations of the fetuses revealed no HQ-related malformations. The incidences of gross external variations (small hematomas) and internal soft tissue variations (dilated renal pelvis, hydronephrosis, and hydroureter) in the HQ-treated litters were not statistically different from the control incidences. Skeletal variations (delayed ossification of membranous skull bones, hyoid bone, thoracic centra 1-3, sacral arches 3 and 4, and bilobed thoracic centra 9-13) were seen with similar frequency in the control and HQ-treated groups. A statistically significant increase in the incidence of total common vertebral variations seen at the 300 mg/kg HQ dose level was not considered toxicologically significant. The incidences of total skeletal variations were not statistically different between the control and the HQ-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1992

Childhood brucellosis in southwestern Saudi Arabia: a 5-year experience.

One-hundred-and-fifty-seven children admitted with brucellosis at Abha, Saudi Arabia, were studied prospectively. Ninety-two per cent gave a history of animal contact, usually with sheep or goats, or ingesting raw milk, milk products, or raw liver. Three-quarters of the patients had an acute or subacute presentation with diverse symptomatology: fever (100 per cent), malaise (91 per cent), anorexia (68 per cent), cough (20 per cent), abdominal symptoms (20 per cent), arthralgia (25 per cent). Hepatomegaly (31 per cent), splenomegaly (55 per cent), and lymphadenopathy (18 per cent) were common findings. Organ complications were rare except for arthritis (36 per cent) which usually presented as a peripheral oligoarthritis involving the hips and knees. All patients had significant agglutination titres; B. melitensis was grown from the blood in 7 of 16 (44 per cent) patients. Haematological variations were common, but non-specific: anaemia (64 per cent), thrombocytopenia (28 per cent), leucopenia (38 per cent), leucocytosis (12 per cent), and elevated erythrocyte sedimentation rate (81 per cent). Varying combinations of rifampicin, co-trimoxazole, tetracycline, and streptomycin resulted in a prompt pyrexial response (mean: 3.8 days), and a slower response in the arthropathy and hepatosplenomegaly. Relapses were related to poor compliance, use of a single drug or a shorter duration of chemotherapy. Brucellosis is a common childhood problem in southwestern Saudi Arabia as in other parts of the country and the Middle East. It should be considered in every child from an endemic area presenting with a febrile illness and a history of animal contact.

Agglutination Tests↗
PubMed1999

The study of genetic polymorphisms related to serotonin in Alzheimer's disease: a new perspective in a heterogenic disorder.

Genetic and environmental factors have been implicated in the development of Alzheimer's disease (AD), the most common form of dementia in the elderly. Mutations in 3 genes mapped on chromosomes 21, 14 and 1 are related to the rare early onset forms of AD while the epsilon 4 allele of the apolipoprotein E (APOE) gene (on chromosome 19) is the major susceptibility locus for the most common late onset AD (LOAD). Serotonin (5-hydroxytryptamine or 5-HT) is a key neurotransmitter implicated in the control of mood, sleep, appetite and a variety of traits and behaviors. Recently, a polymorphism in the transcriptional control region upstream of the 5-HT transporter (5-HTT) gene has been studied in several psychiatric diseases and personality traits. It has been demonstrated that the short variant(s) of this 5-HTT gene-linked polymorphic region (5-HTTLPR) is associated with a different transcriptional efficiency of the 5-HTT gene promoter resulting in decreased 5-HTT expression and 5-HT uptake in lymphocytes. An increased frequency of this 5-HTTLPR short variant polymorphism in LOAD was recently reported. In addition, another common polymorphic variation in the 5-HT2A and 5-HT2C serotonin receptor genes previously analyzed in schizophrenic patients was associated with auditory and visual hallucinations in AD. These observations suggest that the involvement of the serotonin pathway might provide an explanation for some aspects of the affective symptoms commonly observed in AD patients. In summary, research on genetic polymorphisms related to AD and involved in receptors, transporter proteins and the enzymatic machinery of serotonin might enhance our understanding of this devastating neurodegenerative disorder.

Alzheimer Disease↗
PubMed1989

Genetics of variability of CHD risk.

Many genetic and environmental factors act in combination to determine inter-individual variability in risk factor traits for coronary artery disease (CAD). Geneticists have focused on the study of continuously distributed biological traits such as total plasma cholesterol. In every population, plasma cholesterol has been implicated as a risk factor for CAD. Every biometrical study of the distribution of cholesterol in families has established a significant role of genetic variability in determining inter-individual differences in the population at large. While a few genes have been identified that have rare alleles with large effects on this trait, variability among individuals in most families is influenced by allelic variation in many genes as well as various environmental exposures. Therefore, in most families, one does not expect CAD to cosegregate with allelic variation at a single gene, and one does not expect each family to be segregating for the same subset of genes that influence variability in risk among individuals in the population at large. Strategies have been developed to address questions about the role of genes with common alleles in studies of intra- and interpopulation differences in risk for CAD. These strategies are illustrated here by a review of studies of the association between common allelic variations in the structure of the apolipoprotein (apo) E molecule and levels of total plasma cholesterol. This polymorphic gene may explain as much as 6% of the variation in risk for CAD in a North American population. In international comparisons, populations with a higher relative frequency of the E4 allele at this gene locus have higher cholesterol levels and higher rates of CAD deaths. Other candidate genes, in addition to apo E, need to be studied before individuals, families and populations at high risk for CAD can be identified more accurately.

Alleles↗
PubMed1989

Cysteine-rich variant surface proteins of Giardia lamblia.

Surface antigenic variation was previously demonstrated in vitro and in vivo using Giardia lamblia isolate WB. To determine whether other isolates undergo similar changes, isolates GS and N were cloned and exposed to cytotoxic anti-isolate sera or monoclonal antibodies (MAbs) specific to particular surface antigen. The surviving Giardia (progeny) and clones showed different surface antigens as judged by resistance to cytotoxicity, loss of antigens determined by surface radiolabeling, and failure of MAbs to recognize epitopes by immunoprecipitation. The major varying surface antigens incorporate large amounts of [35S]cysteine compared to [35S]methionine. Surface antigenic variation occurs commonly in Giardia isolates, and the major surface antigens appear to comprise a family of cysteine-rich proteins.

Animals↗
PubMed1993

Lead-catalyzed cleavage of ribonuclease P RNA as a probe for integrity of tertiary structure.

Pb(2+)-catalyzed cleavage of RNA has been shown previously to be a useful probe for tertiary structure. In the present study, Pb2+ cleavage patterns were identified for ribonuclease P RNAs from three phylogenetically disparate organisms, Escherichia coli, Chromatium vinosum, Bacillus subtilis, and for E. coli RNase P RNAs that had been altered by deletions. Each of the native RNAs undergoes cleavage at several sites in the core structure that is common to all bacterial RNase P RNAs. All the cleavages occur in non-paired regions of the secondary structure models of the RNAs, in regions likely to be involved in tertiary interactions. Two cleavage sites occur at homologous positions in all the native RNAs, regardless of sequence variation, suggesting common tertiary structural features. The Pb2+ cleavage sites in four deletion mutants of E. coli RNase P RNA differed from the native pattern, indicating alterations in the tertiary structures of the mutant RNAs. This conclusion is consistent with previously characterized properties of the mutant RNAs. The Pb2+ cleavage assay is thus a useful probe to reveal alteration of tertiary structure in RNase P RNA.

Base Sequence↗
PubMed2000

Absence of any significant effects of circadian blood pressure variations on carotid artery elastic properties in essential hypertensive subjects.

We sought in this study to examine the effects of diurnal blood pressure variations upon common carotid artery (CCA) elasticity in selected subjects with uncomplicated moderate essential hypertension. Towards this end, 174 non-smoker subjects with stage I-II essential hypertension and without diabetes mellitus, left ventricular hypertrophy and carotid atherosclerosis, were classified as dippers and non-dippers according to the diurnal variation of >10% between mean daytime and night-time systolic and diastolic blood pressure (BP) in 24-h non-invasive ambulatory BP monitoring. CCA distensibility was derived by a combination of surface ultrasonographic data and simultaneous BP measurements at the brachial artery. The dippers and non-dippers were similar with respect to demographic characteristics. Non-dippers had significantly greater office systolic BP, 24-h systolic BP and ambulatory pulse pressure (PP) and significantly less (daytime-night-time) systolic and diastolic BP fall (by 16 mm Hg and 11 mm Hg respectively, P< 0.0001) compared to dippers. CCA distensibility was significantly reduced in non-dippers compared to dippers (by 0.89 dyne(-1)/cm(2/)10(-6), P < 0.05). Multiple linear regression analysis identified patient age and ambulatory PP as significant predictors of the CCA elasticity index. When patient age, 24-h systolic and diastolic BP were used as covariates in an analysis of covariance, the difference of CCA elasticity between dippers and non-dippers ceased to reach statistical significance. In contrast, when patient age, ambulatory PP, systolic (daytime-night-time) BP fall and diastolic (daytime-night-time) BP fall were used as covariates, the difference of CCA distensibility between dippers and non-dippers continued to be statistically significant. In conclusion, the excessive impairment of CCA elastic properties in non-dippers compared to dippers hypertensive seems to be ascribed to the increased of total 24-h haemodynamic load and not to the circadian pattern of BP. Journal of Human Hypertension (2000) 14, 813-818

Adult↗
PubMed1992

Measurement of whole blood phagocyte chemiluminescence in a microtitreplate format.

Zymosan-induced luminol-enhanced chemiluminescence of phagocytes was measured in whole blood using a microtitreplate format. A consistent reaction response curve could be obtained using a normal blood sample, with low intra-assay variations in peak light index, cumulated response as well as time taken to reach the peak. Variations were common when tests were done on different days for the same individual, or when different persons were compared simultaneously. Reactions were hastened and enhanced if continuous shaking at 37 degrees C was applied. The interval between time zero and peak was the most consistent variable, with a coefficient of variation of 12% in inter-assay analysis. Because of its simplicity and ease of operation, the method is potentially useful in studying phagocyte functions in pathological states.

Hematologic Tests↗
PubMed1992

Genetic variation in two bone-related proteins: is there an association with bone mineral density or skeletal size in postmenopausal women?

In an effort to determine if structural variation in proteins important in bone metabolism might influence bone mineral density (BMD) and thus be a determinant of susceptibility to osteoporosis in older women, the authors typed a group of 258 non-Black women (age 65-90) participating in the Study of Osteoporotic Fractures (SOF) for two polymorphic bone-related proteins, group specific component (Gc), also known as vitamin D-binding protein, and alpha 2HS glycoprotein (AHSG). These two proteins exhibit common structural variation in populations that can be detected by isoelectric focusing/immunoblotting of serum. An important function of Gc is the binding, solubilization, and transport of vitamin D sterols in the bloodstream while AHSG is a glycoprotein constituent of calcified cortical bone matrix. There are six common phenotypes of Gc and four of AHSG. Using Gc or AHSG phenotypes as categorical variables, statistical analyses were done to determine if bone mineral density of the proximal or distal radius or calcaneus differed by phenotype. Neither Gc nor AHSG phenotype demonstrated a statistically significant relationship with BMD at any site. Adjustments for age and degree of obesity did not substantively affect these results. Subsequent analyses to determine if phenotype of either of these proteins was associated with variables related to skeletal size showed an association of AHSG with height (P less than .02). This may indicate that AHSG phenotype is related to postmenopausal loss of height, or it may be a chance statistical finding.

Aged↗
PubMed1987

Canine AV nodal artery: anatomical variations and a detailed description of cannulation technique.

Cannulation of the atrioventricular (AV) nodal artery for selective perfusion of the AV node is a useful physiological method for evaluating the direct effects of pharmacological agents on the AV node. However, previous reports have not included a detailed description of the technique for AV nodal artery cannulation. Furthermore, successful cannulation is dependent on familiarity with the anatomical variations of the AV nodal artery [i.e., the most superior posterior septal artery (PSA)], which supplies blood to the AV nodal region and the posterior descending artery (PDA). The purpose of this report is to describe in detail the technique for cannulation of the AV nodal artery as well as the common anatomical variations of this artery. The anatomy of the PDA and PSA was studied at postmortem examination with ink injection in 30 dogs. Verification of the anatomical location of the AV nodal artery was aided by the induction of transient AV nodal conduction block following intracoronary administration of acetylcholine in the beating heart, as was done in previous studies. Two main variations and two subtypes of PDA anatomy and three main variations of AV nodal artery were found. Based on the present findings, an improved technique for cannulation of the AV nodal artery was established. Using this technique, we achieved a high rate of successful cannulation.

Animals↗
PubMed1998

Evolution of a D2 dopamine receptor intron within the great apes and humans.

Although direct DNA sequencing may allow rapid and high quality comparative phylogenetic analyses among species, such an approach may not be the most efficient method by which to make a large number of cross-species comparisons. We illustrate the use of Denaturing Gradient Gel Electrophoresis (DGGE) to screen a D2 Dopamine Receptor intron for DNA sequence variation, both within and between closely related species, in order to infer their evolutionary relationships. Our results suggest that: a) humans have less genetic variation than the great apes; b) pygmy chimpanzees have less genetic variation than common chimpanzees; and c) DNA sequence comparative analyses of primates require adequate sampling, both in number and in geographical range.

Animals↗
PubMed2004

Study of reference values and biological variation: a necessity and a model for Preventive Medicine Centers.

Laboratory tests were at the origin of the modern approach to the evaluation of the health status in many Preventive Medicine Centers. Guided by the theory of reference values and its applications, years of efforts have been devoted to defining the health status of people, and understanding the biological variation of the population. At the Nancy Center for Preventive Medicine, 40,000 people are invited every year for health examination; many coming with their families. French legislation authorized every citizen to have full health examination every five years. Annually, 600,000 people are seen at 70 centers. The visit includes answering questionnaires, physiological and biological testing modified for age, risks, and social criteria. The process concludes with consultation with a general practitioner. Data accumulated over 30 years have led to the identification of primary factors influencing biological variation of common laboratory tests. For example, body mass index (BMI) has to be considered, in addition to age and gender, for measurement of gamma-glutamyltransferase, alanine aminotransferase, and other analytes. More recently, the familial Stanislas cohort has shown that apolipoprotein E (apoE) genetic polymorphism has to be considered as a factor for variation in some individuals. For example, there was greater than 100% difference in the mean concentration of apoE between epsilon2/epsilon2 and epsilon4/epsilon4 individuals. This example nicely illustrates the relationship between genotype and phenotype. Demonstrating the effects of multiple gene polymorphisms on phenotypes will be a valid approach to predictive laboratory medicine.

Adult↗