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At least 91 records · Page 5Linked to original sources
PubMed2006

Common sequence variations in the P2Y12 and CYP3A5 genes do not explain the variability in the inhibitory effects of clopidogrel therapy.

The efficacy of the platelet P2Y12 receptor antagonist clopidogrel, which undergoes cytochrome-mediated metabolism to its active form, shows marked inter-individual variability. We investigated whether polymorphic variations in the P2Y12 gene, which have been linked to platelet aggregation phenotypes, or the cytochrome P450 3A5 gene 6986G > A polymorphism, which largely determines CYP3A5 expression, influence the response to clopidogrel therapy. Fifty-four patients listed for elective percutaneous coronary intervention were studied using ADP-induced optical aggregometry, whole-blood single platelet counting (WBSPC) aggregometry, and flow-cytometric analysis of platelet P-selectin expression and platelet-monocyte conjugate formation. Platelet reactivity was measured at baseline, 4 h post clopidogrel 300 mg, and 10 and 28 days following clopidogrel 75 mg daily. A further 55 patients were studied using ADP-induced WBSPC at baseline and 4 h post clopidogrel 600 mg. Patients were genotyped for P2Y12 haplotype and the CYP3A5 6986G > A single nucleotide polymorphism. Neither genotype was found to significantly influence the inhibition of platelet responses by either clopidogrel regimen. In conclusion, common sequence variations within the P2Y12 and CYP3A5 genes do not contribute any major effect to the inter-patient variability in clopidogrel efficacy.

Clopidogrel↗
PubMed1976

Biological and analytical variation of commonly determined blood constituents in healthy blood donors.

The relative contributions of analytical error and non-systematic biological variation to the reference range for 19 commonly-determined blood chemistry values have been estimated during the course of studying 1000 healthy blood donors. Estimates of non-systematic biological variations are arrived at by determining the variation found in donors matched for factors known to affect blood chemistry such as age and sex, and deducting the within-batch analytical error which applied. Comparison of the within-batch and between-batch analytical precision with the biological variation showed that the percentage increases in the normal range attributable to between-batch analytical error varies between 1 and 29%. This contribution is particularly large in the case of the electrolytes and amounts to no less than 29% in the case of calcium. Apart from well-known relationships a remarkable lack of correlation between the concentration of the different constituents in health is demonstrated.

Adolescent↗
PubMed1995

No evidence that common allelic variation in the Amyloid Precursor Protein (APP) gene confers susceptibility to Alzheimer's disease.

In order to test the hypothesis that allelic variation within the Amyloid Precursor Protein (APP) gene influences susceptibility to common forms of Alzheimer's disease (AD) we screened the entire coding, promoter and 3' untranslated sequences of the APP gene for DNA variations in 30 unrelated patients and eight controls with probable AD by a combination of RT-PCR PCR and chemical cleavage mismatch analysis. Although we were unable to detect commonly occurring allelic variants, we were able to detect a novel mutation within the APP gene in one individual with late-onset AD. This mutation resulted in the substitution of a tryptophan residue for an arginine residue at codon 328 within exon 7 which encodes the so-called protease inhibitor domain of the 751 residue APP isoform. However, the pathological significance of this mutation is uncertain as neither this, nor any other mutation occurring within exon 7 of the APP gene was found in any of a further 102 AD patients and 86 age-matched controls. In conclusion, it is unlikely that susceptibility to AD results from commonly occurring allelic variants of the APP gene and it is even less probable that mutations within exon 7 of the APP gene are important risk factors for late-onset AD.

Adult↗
PubMed2006

The geographic incidence and treatment variation of common fractures of elderly patients.

Fractures of the hip, wrist, proximal humerus, and ankle frequently are observed among the elderly patient population in the United States. The Medicare patient population has shown dramatic geographic variation in the rates of these common fractures, with an increased incidence observed throughout the Southeast. Treatment (surgical versus nonsurgical) is also highly variable and dependent on the geographic location but not necessarily on the type of injury. Whereas regional variation in medical treatment may be attributed to variations in practice patterns, the etiology behind the dramatic variations in fractures is less well-defined and is likely multifactorial, related to environmental, occupational, genetic, or nutritional factors.

Aged↗
PubMed1989

Biologic variation of common hematologic laboratory quantities in the elderly.

Analytic, within-subject, and between-subject biologic variations were estimated for leukocytes, erythrocytes, hemoglobin, hematocrit, mean cell volume (MCV), mean cell hemoglobin (MCH), mean cell hemoglobin content (MCHC), platelets, and a three-component differential count (lymphocytes, monocytes, and granulocytes in terms of both concentration and percentage of leukocytes) in cohorts of 12 male and 12 female healthy elderly subjects. The assays were performed with an Ortho ELT-800 automated analyzer. The estimates of within-subject biologic variation were similar to published data on young subjects, indicating that this aspect of homeostasis is not compromised in the elderly. The data were used to derive objective analytic goals; goals were surpassed except for assays of erythrocytes, hematocrit, and the derived MCV, MCH, and MCHC. The changes required for serial results to be significantly different were determined and found to be generally valid because most quantities have no heterogeneity of within-subject variation. All quantities had significant individuality; in consequence, conventional population-based reference values are of limited utility, and screening using reference limits will not detect latent or early disease in many subjects.

Aged↗
PubMed2003

Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium.

Common genetic polymorphisms may explain a portion of the heritable risk for common diseases. Within candidate genes, the number of common polymorphisms is finite, but direct assay of all existing common polymorphism is inefficient, because genotypes at many of these sites are strongly correlated. Thus, it is not necessary to assay all common variants if the patterns of allelic association between common variants can be described. We have developed an algorithm to select the maximally informative set of common single-nucleotide polymorphisms (tagSNPs) to assay in candidate-gene association studies, such that all known common polymorphisms either are directly assayed or exceed a threshold level of association with a tagSNP. The algorithm is based on the r(2) linkage disequilibrium (LD) statistic, because r(2) is directly related to statistical power to detect disease associations with unassayed sites. We show that, at a relatively stringent r(2) threshold (r2>0.8), the LD-selected tagSNPs resolve >80% of all haplotypes across a set of 100 candidate genes, regardless of recombination, and tag specific haplotypes and clades of related haplotypes in nonrecombinant regions. Thus, if the patterns of common variation are described for a candidate gene, analysis of the tagSNP set can comprehensively interrogate for main effects from common functional variation. We demonstrate that, although common variation tends to be shared between populations, tagSNPs should be selected separately for populations with different ancestries.

Algorithms↗
PubMedDate not supplied

Influence of stochastic events on the phenotypic variation of common white leg markings in the Arabian horse: implications for various genetic disorders in humans.

One method of assessing the influence of stochastic events on phenotypic variation is to study morphological differences in paired limbs of the same individual. These limbs have identical genotypes and similar intra-uterine environments and are analogous to monozygotic twins. Common white leg markings have a multifactorial mode of inheritance in the Arabian horse. Asymmetry occurs frequently for these markings. Using computerized registration records obtained from the Arabian Horse Registry of America, Inc., the types of markings were quantified in the left foreleg and left hind leg of bay and chestnut horses when a specific marking occurred in (1) a paired right leg, (2) both right legs, and (3) both right legs and the other left leg. The variation in the markings in the left legs of these horses is evidence of the role of stochastic events during development. The relatively high frequency of a specific type of asymmetry, with one leg being completely pigmented, is of special biological interest and has implications for various human disorders that are characterized by reduced penetrance and variable expressivity.

Animals↗
PubMed1993

[Computerized tomography in the evaluation of anatomic variations of the ostiomeatal complex].

This work was aimed at showing the main anatomical variations in the ostiomeatal complex which are usually depicted by CT. A hundred and thirty CT exams including 59 normal cases (45.4%) and 71 cases of chronic sinus disease (54.6%) were reviewed. The following anatomical variations were considered: concha bullosa, middle turbinate, septum, uncinate process and bulla changes, Haller cells and agger nasi cells. Anatomical variations were demonstrated in 69 patients--31 normal subjects and 38 patients with chronic sinusitis. The incidence of every anatomical variation was investigated and the results were compared with literature data. Excluding agger nasi cells, which were seen in nearly all patients, the most common variations were concha bullosa and septal spur and deviations, while the least common variations were those in the middle turbinate and uncinate process.

Chronic Disease↗
PubMed2006

Role of SOX2 mutations in human hippocampal malformations and epilepsy.

PURPOSE: Seizures are noted in a significant proportion of cases of de novo, heterozygous, loss-of-function mutations in SOX2, ascertained because of severe bilateral eye malformations. We wished to determine the underlying cerebral phenotype in SOX2 mutation and to test the candidacy of SOX2 as a gene contributing to human epilepsies. METHODS: We examined high-resolution MRI scans in four patients with SOX2 mutations, two of whom had seizures. We determined the Sox2 expression pattern in developing murine brain. We searched for SOX2 mutation in 24 patients with typical hippocampal sclerosis and for common variations in SOX2 in 655 patients without eye disease but with epilepsy, including 91 patients with febrile seizures, 93 with hippocampal sclerosis, and 258 with temporal lobe epilepsy. RESULTS: Striking hippocampal and parahippocampal malformations were seen in all cases, with a history of febrile seizures or epilepsy in two of four cases. The Sox2 expression pattern in developing mouse brain supports the pattern of malformations observed. Mutation screening in patients with epilepsy did not reveal any abnormalities in SOX2. No associations were found between any clinical epilepsy phenotype and common variation in SOX2. CONCLUSIONS: SOX2 haploinsufficiency causes mesial temporal malformation in humans, making SOX2 dysfunction a candidate mechanism for mesial temporal abnormalities associated with chronic epilepsy. However, although mutation of SOX2 in humans causes hippocampal malformation, SOX2 mutation or variation is unlikely to contribute commonly to mesial temporal lobe epilepsy or its structural (hippocampal sclerosis) or historic (febrile seizures) associations in humans.

Adolescent↗
PubMed1983

Genomic and biological variation among commonly used lymphocytic choriomeningitis virus strains.

Six commonly used strains of lymphocytic choriomeningitis virus (LCMV) [Armstrong (Arm) CA 1371, Arm E-350, WE, UBC, Traub and Pasteur C1PV 76001] were examined for distinctive genetic and biological properties. Agarose gel electrophoresis yielded no detectable differences among the L or S RNAs of these six strains. The RNase T1 fingerprint patterns of LCMV Arm CA 1371 and E-350 RNAs were similar, but in contrast, those of the WE, UBC, Traub and Pasteur strains differed from each other and from the pattern of LCMV Arm CA 1371 and E-350. There were also differences among LCMV strains in their biological properties. LCMV Arm CA 1371, E-350 and Pasteur caused severe vasculitis and focal necrotizing hepatitis in the livers of neonatally infected BALB/WEHI mice in contrast to LCMV WE which caused minimal lesions. LCMV Arm CA 1371 and E-350 were lethal for neonatal C3H/St mice. In contrast, LCMV WE, Traub and Pasteur induced persistent infections in C3H/St mice. Adult guinea-pigs resisted infection by Arm CA 1371, E-350, Traub and Pasteur but succumbed to WE and UBC LCMV strains. Our results show a wide variation in the RNA genomes of LCMV strains commonly used in research laboratories, and these genomic differences are accompanied by variations in the biological properties of LCMV strains.

Animals↗
PubMed2005

Genetics of drug resistance.

Drug resistance in epilepsy affects about a third of patients and is an important clinical problem, associated with increased morbidity and mortality. It is important to consider carefully the definition of drug resistance. Recent interest in the field has focused on the potential molecular mechanisms underlying drug resistance. Environmental and seizure-related acquired causes are likely to contribute to the multifaceted basis of resistance in most cases. Genetic causes have attracted particular attention, partly because they may allow prediction of drug resistance and, potentially, rational treatment strategies. Gene mutations, however, are unlikely to cause many cases of drug resistance. However, common variation in genes probably will turn out to generate an important contribution to drug resistance phenomena. Associations between common variations in a number of genes and clinical drug resistance have now been published. However, to date, none of these associations has been unequivocally replicated by others to the extent that the original association has been accepted. Some of these associations are considered. Despite this apparently uninspiring record, the genetics of drug resistance are likely to prove productive in the near future, but their pursuit will require painstaking studies and multicenter collaboration.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2003

Supernumerary humeral heads of the biceps brachii muscle revisited.

Supernumerary humeral heads of the biceps brachii muscle were found in 27 (15.4%) of 175 cadavers. They were bilateral in five cadavers and unilateral in 22 (8 left, 14 right), giving a total of 32 examples in 350 arms (9.1%). Depending on their origin and location, the supernumerary heads were classified as superior, infero-medial, and infero-lateral humeral heads. Previous studies were reviewed using this classification. The infero-medial humeral head was observed in 31 of 350 (9%) arms and was therefore the most common variation. The superior humeral head was observed in five (1.5%). The infero-lateral humeral head was the least common variation, observed only in one (0.3%) of 350 arms. A biceps brachii with three heads was observed in 27 of 350 (7.7%) arms and with four heads in five (1.4%) arms.

Aged↗
PubMed2000

The axillary arch of Langer--the most common muscular variation in the axilla.

A case of an 'Axillary Arch of Langer' is reported during a routine axillary lymphadenectomy for breast carcinoma. The features of this muscle are described together with other less common axillary muscular anomalies. Knowledge of these anomalies is important for surgeons performing safe axillary surgery [1].

Axilla↗
PubMed1997

Variation of common carotid artery elasticity with intimal-medial thickness: the ARIC Study. Atherosclerosis Risk in Communities.

The Atherosclerosis Risk in Communities (ARIC) study is a prospective investigation of the etiology and natural history of atherosclerosis and cardiovascular disease in four U.S. communities. The purpose of this work is to investigate the relationship between common carotid artery elasticity and intimal-medial thickness (IMT) in the four race-gender groups represented in the ARIC cohort. Noninvasive ultrasonic methods were used to measure IMT and the [systolic minus diastolic] diameter change (DC) of the left common carotid artery in 10,920 black and white, men and women between the ages of 45 and 64 y. The relationship between DC and IMT and IMT2 was examined after adjustment of DC for age, height, diastolic diameter, diastolic blood pressure and linear and quadratic terms for pulse pressure. This adjusted value of DC was used as an index of elasticity of the common carotid artery in the ARIC cohort with larger values of adjusted DC implying a more elastic vessel. The general behavior of adjusted DC with increasing IMT was observed to be qualitatively similar in all four race-gender groups. Adjusted DC remained nearly constant or increased slightly for values of IMT between approximately 0.4 and 0.8 mm, up to approximately the 90th percentile of IMT, and then decreased above the 90th percentile of IMT. Common carotid artery elasticity, defined as adjusted DC, varies with increasing IMT in the ARIC cohort in a manner consistent with results from previous studies in animals and human subjects addressing the variation of several elasticity indices with atherosclerotic involvement and risk factor exposure in the aorta, and brachial and radial arteries. Our results suggest that thicker common carotid artery walls in middle-aged U.S. populations are no stiffer than thinner walls, except for the thickest 10% of arteries. Since the distal common carotid artery frequently contains atheromatous plaques in this population, the lack of change in stiffness, indeed, the reduction in stiffness per unit thickness, may reflect the various stages of early common carotid atherosclerosis most often found in this population. These are characterized more by destruction of arterial wall structural elements than by changes such as widespread or circumferential sclerosis, which would strengthen and stiffen the artery.

Arteriosclerosis↗
PubMed2006

The contributions of age and sex to variation in common tern population growth rate.

1. The decomposition of population growth rate into contributions from different demographic rates has many applications, ranging from evolutionary biology to conservation and management. Demographic rates with low variance may be pivotal for population persistence, but variable rates can have a dramatic influence on population growth rate. 2. In this study, the mean and variance in population growth rate (lambda) is decomposed into contributions from different ages and demographic rates using prospective and retrospective matrix analyses for male and female components of an increasing common tern (Sterna hirundo) population. 3. Three main results emerged: (1) subadult return was highly influential in prospective and retrospective analyses; (2) different age-classes made different contributions to variation in lambda: older age classes consistently produced offspring whereas young adults performed well only in high quality years; and (3) demographic rate covariation explained a significant proportion of variation in both sexes. A large contribution to lambda did not imply a large contribution to its variation. 4. This decomposition strengthens the argument that the relationship between variation in demographic rates and variation in lambda is complex. Understanding this relationship and its consequences for population persistence and evolutionary change demands closer examination of the lives, and deaths, of the individuals within populations within species.

Aging↗
PubMed2006

Common genetic variation in IGF1 and prostate cancer risk in the Multiethnic Cohort.

BACKGROUND: Insulin-like growth factor I (IGF-I) appears to play a role in prostate development and carcinogenesis. We investigated whether genetic variation at the IGF1 locus is associated with prostate cancer risk. METHODS: We sequenced IGF1 exons in germline DNA from 95 men with advanced prostate cancer to identify missense variants. IGF1 linkage disequilibrium patterns and common haplotypes were characterized by genotyping 64 single-nucleotide polymorphisms (SNPs) spanning 156 kilobases in 349 control subjects. Associations between IGF1 haplotypes and genotypes were investigated among 2320 patients with prostate cancer and 2290 control subjects from the Multiethnic Cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression to determine the association between prostate cancer and IGF1 haplotypes and genotypes. We used permutation testing to correct for multiple hypothesis testing. All statistical tests were two-sided. RESULTS: No IGF1 missense variants were observed. We identified four blocks of strong linkage disequilibrium and selected a subset of 29 tagging SNPs that could accurately predict both the common IGF1 haplotypes and the remaining SNPs. Haplotype analysis revealed nominally statistically significant associations with prostate cancer risk in each of the four haplotype blocks: haplotype 1B (OR = 1.21, 95% CI = 1.04 to 1.40), haplotype 2C (OR = 1.24, 95% CI = 1.06 to 1.44), haplotype 3C (OR = 1.25, 95% CI = 1.03 to 1.50), and haplotype 4D (OR = 1.19, 95% CI = 1.02 to 1.39). Two SNPs--rs7978742 (Ptrend = .002) and rs7965399 (Ptrend = .002)--were perfectly correlated (correlation coefficient = 1.0) with one another and also associated with prostate cancer risk. These two SNPs were strong proxies for haplotypes 1B, 2C, 3C, and 4D and could account for the haplotype findings. Permutation testing revealed that a similarly strong result would be observed by chance only 5.6% of the time. CONCLUSION: Inherited variation in IGF1 may play a role in the risk of prostate cancer.

Black or African American↗
PubMed2000

Association between PON1 L/M55 polymorphism and plasma lipoproteins in two Canadian aboriginal populations.

Serum paraoxonase circulates on a subfraction of high density lipoproteins and appears to use phospholipids on both low and high density lipoprotein particles as a physiological substrate. This functional relationship could explain the reported associations between common variation in the PON1 gene--at codons 55 and 192--and phenotypes related to atherosclerosis and lipoprotein metabolism. We evaluated associations between plasma lipoproteins and PON1 L/M55, PON1 Q/R192 and PON2 A/G148 polymorphisms in samples from two Canadian aboriginal populations, namely the Oji-Cree and the Inuit. In diabetic Oji-Cree, we found that carriers of PON1 M55 had a higher mean plasma triglyceride concentration than non-carriers. In non-diabetic Oji-Cree, we found that carriers of PON1 M55 had higher mean plasma concentrations of total and low density lipoporetein cholesterol and apo B than non-carriers. In Inuit, we found that carriers of PON1 M55 had higher mean plasma concentrations of total and low density lipoprotein cholesterol than non-carriers. The other polymorphic markers were not associated with variation in any plasma lipoprotein trait. Thus, the PON1 M55 allele appeared to be associated with deleterious changes in the plasma lipoprotein profile from two independent Canadian aboriginal samples. These results suggest that common variation in PON1 codon 55 is associated with variation of intermediate traits in plasma lipoprotein metabolism in aboriginal Canadians.

Adolescent↗