Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “common variation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 883 records · Page 49Linked to original sources
PubMedDate not supplied

A comprehensive review of genetic association studies.

Most common diseases are complex genetic traits, with multiple genetic and environmental components contributing to susceptibility. It has been proposed that common genetic variants, including single nucleotide polymorphisms (SNPs), influence susceptibility to common disease. This proposal has begun to be tested in numerous studies of association between genetic variation at these common DNA polymorphisms and variation in disease susceptibility. We have performed an extensive review of such association studies. We find that over 600 positive associations between common gene variants and disease have been reported; these associations, if correct, would have tremendous importance for the prevention, prediction, and treatment of most common diseases. However, most reported associations are not robust: of the 166 putative associations which have been studied three or more times, only 6 have been consistently replicated. Interestingly, of the remaining 160 associations, well over half were observed again one or more times. We discuss the possible reasons for this irreproducibility and suggest guidelines for performing and interpreting genetic association studies. In particular, we emphasize the need for caution in drawing conclusions from a single report of an association between a genetic variant and disease susceptibility.

Alleles↗
PubMed2006

Evolution of chloroplast mononucleotide microsatellites in Arabidopsis thaliana.

The level of variation and the mutation rate were investigated in an empirical study of 244 chloroplast microsatellites in 15 accessions of Arabidopsis thaliana. In contrast to SNP variation, microsatellite variation in the chloroplast was found to be common, although less common than microsatellite variation in the nucleus. No microsatellite variation was found in coding regions of the chloroplast. To evaluate different models of microsatellite evolution as possible explanations for the observed pattern of variation, the length distribution of microsatellites in the published DNA sequence of the A. thaliana chloroplast was subsequently used. By combining information from these two analyses we found that the mode of evolution of the chloroplast mononucleotide microsatellites was best described by a linear relation between repeat length and mutation rate, when the repeat lengths exceeded about 7 bp. This model can readily predict the variation observed in non-coding chloroplast DNA. It was found that the number of uninterrupted repeat units had a large impact on the level of chloroplast microsatellite variation. No other factors investigated--such as the position of a locus within the chromosome, or imperfect repeats--appeared to affect the variability of chloroplast microsatellites. By fitting the slippage models to the Genbank sequence of chromosome 1, we show that the difference between microsatellite variation in the nucleus and the chloroplast is largely due to differences in slippage rate.

Arabidopsis↗
PubMed2003

The future of regulatory toxicology: impact of the biotechnology revolution.

The molecular biology revolution and the advent of genomic and proteomic technologies are facilitating rapid advances in our understanding of the molecular details of cell and tissue function. These advances have the potential to transform toxicological and clinical practice, and are likely to lead to the supplementation or replacement of traditional biomarkers of cellular integrity, cell and tissue homeostasis, and morphological alterations that result from cell damage or death. New technologies that permit simultaneous monitoring of many hundreds, or thousands, of macro- and small molecules ("-omics" technologies) promise to allow functional monitoring of multiple (or perhaps all) key cellular pathways simultaneously. Elucidation of cellular responses to molecular damage, including evolutionarily conserved inducible molecular defense systems, suggests the possibility of new biomarkers based on molecular responses to functional perturbations and cellular damage. Our improved understanding of the molecular basis of various pathologies suggests that monitoring specific molecular responses may provide improved prediction of human outcomes. Responses that can be monitored directly in the human should provide "bridging biomarkers" that may eliminate much of the current uncertainty in extrapolating from laboratory models to human outcome. Another aspect of genomics is our enhanced ability to associate DNA sequence variations with biological outcomes and individual sensitivity. The human genome sequence has revealed that sequence variations are very common, and may be an important determinant of variation in biological outcomes. The impending availability of a complete human haplotype map linked to standard genetic markers greatly facilitates identification of genetic variations that convey sensitivity or resistance to chemical exposures. Genetic approaches have already linked a large number of genetic variants (polymorphisms) with human diseases and adverse reactions from exposure to drugs or toxicants, suggesting an important role in sensitivity to drugs and environmental agents, disease susceptibilities, and therapeutic responses. As these opportunities are transformed into reality, regulatory toxicological practice is likely to be shaped in the future by the combination of conventional pathology, toxicology, molecular genetics, biochemistry, cell biology, and computational bio-informatics-resulting in the broad application of molecular approaches to monitoring functional disturbances.

Animals↗
PubMed2002

The relationship between mimetic imperfection and phenotypic variation in insect colour patterns.

Many hoverflies (Syrphidae) mimic wasps or bees through colour or behavioural adaptations. The relationship between phenotypic variation in colour pattern and mimetic perfection (as determined by pigeons) was investigated in three species of Müllerian mimics (Vespula spp.) and 10 Batesian hoverfly mimics, plus two non-mimetic species of flies. Four predictions were tested: (i) Batesian mimics might be imperfect because they are in the process of evolving towards perfection, hence there should be a positive relationship between variation and imperfection; (ii) some Batesian mimics are imperfect because they do not have the appropriate genetic variation to improve and have evolved to be as good as possible, hence there should be no differences between species, all displaying a low level of variation; (iii) very common hoverflies should show the highest levels of variation because they outnumber their models, resulting in high predation and a breakdown in the mimetic relationship; and (iv) social wasps (Vespula) have such a powerful defence that anything resembling a wasp, both Müllerian and perfect Batesian mimics, would be avoided, resulting in relaxed selection and high variance. Poor mimics may still evolve to resemble wasps as well as possible and display lower levels of variation. The data only provided support for the fourth prediction. The Müllerian mimics, one of the most perfect Batesian mimics, and the non-mimetic flies displayed much higher levels of variation than the other species of Batesian mimics.

Adaptation, Biological↗
PubMed1983

The laboratory diagnosis of prostatic adenocarcinoma.

At the close of each decade, we are reminded by medical statisticians that our longevity increases significantly. For the male, especially if he be of black race this statement has an ironic twist. Over age 70, prostatic "cancer" assumes the leadership list of "cancers" in general, supplanting lung and colo-rectal. One interesting point evolved by careful autopsy studies suggests that this incidence is found coincidentally and is not primarily responsible for the cause of death. This illustrates a different significance to other neoplasia, and offers useful opportunities to study the evolution of a neoplasm. In contrast to other "cancers" (for example pulmonary), the histological nature of the tumor is almost totally derived from the acinar lobules and designated adenocarcinoma. Neoplasia arising from the fibromuscular stroma (sarcoma) and metaplastic ductus (squamous cell carcinoma) constitute less than 1% of all prostate cancers. Histological appearances, however, are not as simple as hoped. As in many tumors the section may present a uniform well-differentiated adenocarcinoma in which the acinar structure is well maintained--yet at the opposing end of the spectrum show a fatally dedifferentiated picture whose organ origin is difficult to determine. Adding to the complication is the wide variation, far more commonly seen, of the mixed tumor with all variations presenting a composite panorama of histology. Indeed the pure type is rare. As with all neoplastic disease, early detection is critical, since opportunity for cure with the various forms of therapy from surgery through radiation to chemotherapy are increasing rapidly. The prostate gland is relatively accessible to the trained finger of the physician and later stages of the disease are palpable. However, the earliest Stage (I) is not discovered by rectal examination, hence provides an ideal opportunity for the serum tumor marker, to identify disease. Since 1938, disseminated prostatic adenocarcinoma has been associated with elevation of activity of an enzyme acid phosphatase. Although there are several isoenzymes the prostatic specific one has in the past been assayed by different spectrophotometric techniques using selective substrate and chemical inhibition. More recently various immunological methods have added a greater sensitivity and specificity to the early detection of prostatic adenocarcinoma. However is should be clearly stated that prostatic acid phosphatase is not cancer specific and can be associated with other nonmalignant lesions in the prostate gland.(ABSTRACT TRUNCATED AT 400 WORDS)

Acid Phosphatase↗
PubMed1997

Association between common alleles of the low-density lipoprotein receptor gene region and interindividual variation in plasma lipid and apolipoprotein levels in a population-based sample from Rochester, Minnesota.

This paper presents an analysis of the relationship between variation in the low-density lipoprotein receptor (LDLR) gene region and interindividual variation in plasma lipid and apolipoprotein levels in a sample representative of the adult population of Rochester, Minn. (217 females and 187 males aged 26 to 63). This relationship was analyzed by estimating the average excesses of alleles of the LDLR gene defined using RFLP markers both singly and simultaneously. We also used a cladistic approach to illustrate the consequences of incorporating evolutionary information into the analysis of genotype-phenotype relationships. Although results from both approaches supported the inference that common variation in the LDLR gene region associates with small effects on plasma lipid and apolipoprotein levels, only the cladistic approach provides direction for further work aimed at identifying the functional DNA sequence variations responsible for the observed associations.

Adult↗
PubMed2005

Microsatellite variation and structure of 28 populations of the common wetland plant, Lychnis flos-cuculi L., in a fragmented landscape.

Habitat fragmentation is known to cause genetic differentiation between small populations of rare species and decrease genetic variation within such populations. However, common species with recently fragmented populations have rarely been studied in this context. We investigated genetic variation and its relationship to population size and geographical isolation of populations of the common plant species, Lychnis flos-cuculi L., in fragmented fen grasslands. We analysed 467 plants from 28 L. flos-cuculi populations of different sizes (60 000-54 000 flowering individuals) in northeastern Switzerland using seven polymorphic microsatellite loci. Genetic differentiation between populations is small (F(ST) = 0.022; amova; P < 0.001), suggesting that gene flow among populations is still high or that habitat fragmentation is too recent to result in pronounced differentiation. Observed heterozygosity (H(O) = 0.44) significantly deviates from Hardy-Weinberg equilibrium, and within-population inbreeding coefficient F(IS) is high (0.30-0.59), indicating a mixed mating breeding system with substantial inbreeding in L. flos-cuculi. Gene diversity is the only measure of genetic variation which decreased with decreasing population size (R = 0.42; P < 0.05). While our results do not indicate pronounced effects of habitat fragmentation on genetic variation in the still common L. flos-cuculi, the lower gene diversity of smaller populations suggests that the species is not entirely unaffected.

Altitude↗
PubMed2006

KRAS variation and risk of endometriosis.

Endometriosis is a common gynaecological disease with symptoms of pelvic pain and infertility which affects 7-10% of women in their reproductive years. Activation of an oncogenic allele of Kirsten rat sarcoma viral oncogene homologue (KRAS) in the reproductive tract of mice resulted in the development of endometriosis. We hypothesized that variation in KRAS may influence risk of endometriosis in humans. Thirty tagSNPs spanning a region of 60.7 kb across the KRAS locus were genotyped using iPLEX chemistry on a MALDI-TOF MassARRAY platform in 959 endometriosis cases and 959 unrelated controls, and data were analysed for association with endometriosis. Genotypes were obtained for most individuals with a mean completion rate of 99.1%. We identified six haplotype blocks across the KRAS locus in our sample. There were no significant differences between cases and controls in the frequencies of individual single-nucleotide polymorphisms (SNPs) or haplotypes. We also developed a rapid method to screen for 11 common KRAS and BRAF mutations on the Sequenom MassARRAY system. The assay detected all mutations previously identified by direct sequencing in a panel of positive controls. No germline variants for KRAS or BRAF were detected. Our results demonstrate that any risk of endometriosis in women because of common variation in KRAS must be very small.

Adolescent↗
PubMed2006

Challenges of SNP genotyping and genetic variation: its future role in diagnosis and treatment of cancer.

Thorough annotation of common germline genetic variation in the human genome has generated a foundation for the investigation of the contribution of genetics to the etiology and pathogenesis of cancer. For many malignancies, it has become increasingly apparent that numerous alleles, with small-to-moderate effects, additively contribute to cancer susceptibility. The most common genetic variant in the genome, the single nucleotide polymorphism, is of special interest for the study of susceptibility to and protection from cancer. Similarly, intense effort has focused on genetic variants that can predict either response or toxicity to therapeutic interventions. This review discusses the challenges and prospects of genetic association studies in cancer research. On the basis of recent changes in genomics and high-throughput genotyping platforms, future genetic findings of association studies could impact clinical care and public health screening.

Gene Expression Regulation, Neoplastic↗
PubMed2006

Analysing the performance of in vitro fertilization clinics in the United Kingdom.

During the past century, the manufacturing industry has achieved major successes in improving the quality of its products. An essential factor in these successes has been the use of Walter A. Shewhart's pioneering work in the economic control of variation, which culminated in the development of a simple yet powerful theory of variation, which classifies variation as having a common or special cause and thus guides the user to the most appropriate action to effect improvement. Using publicly available performance data, which includes percentage of live births and multiple births, for in vitro fertilization (IVF) clinics in the United Kingdom, we show a central role for Shewhart's approach in moving away from the limitations and controversies associated with performance league tables towards data analyses to support continual improvement. We outline strategies for dealing with common and special causes of variation in IVF clinic performance data.

Female↗
PubMed2004

Population genomics of drug response.

Genetic diversity contributes to both disease susceptibility and variability in response to drugs. However, it has proven difficult to isolate genes that underlie common complex disease, and genetic variations that influence clinical responses to drugs remain largely uncovered. The candidate gene approach to uncover genetic variations that contribute to disease susceptibility or variations in response to common drugs has not met expectations. Although the sib-pair linkage approach has certain theoretical advantages in dealing with common/complex disease, success has been slow in coming. Meanwhile family studies including siblings, cousins and second cousins, and studies in well-defined founder populations, have increasingly gained popularity and enabled scientists to map and isolate genes for common complex disease, such as schizophrenia and asthma. The latter method has generated new hope that this approach may also be effective in mapping genes that regulate drug response. Indeed, there is compelling evidence that corticosteroid sensitivity is a mapable trait in patients with asthma. Collectively, these studies support the value of leveraging information available within population-based data systems to map and isolate genes for common complex disease and drug response.

Animals↗
PubMed1997

Intravenous cholangiography is superfluous prior to laparoscopic cholecystectomy.

OBJECTIVE: Intravenous cholangiography (IVC) re-introduced into the preoperative diagnostic work-up of cholecystectomy after the change to the laparoscopic technique, was suggested to detect anatomical anomalies and bile duct stones. The value of IVC in this context was to be evaluated by this study. DESIGN: Prospectively controlled study. IVC findings were controlled by intraoperative imaging techniques such as laparoscopic sonography and intraoperative cholangiography. SETTING: Surgical unit of a university hospital. SUBJECTS: One hundred patients underwent laparoscopic cholecystectomy between January 1992 and January 1993. Eighty-five of these patients had both IVC and intraoperative cholangiography (IOC). There were nine technical failures for IVC and five for IOC. MAIN OUTCOME MEASURES: Anatomical variations and previously unsuspected common duct stones. RESULTS: Anatomical variations of the biliary tree and the hepatic vessels were detected by IVC in only three cases while IOC demonstrated 31 biliary and vascular anomalies in 28 patients. IVC demonstrated bile duct stones in one and IOC in two cases. CONCLUSIONS: We conclude that IVC is of little help in the diagnosis of anatomical variations of the biliary tree and should be omitted from the preoperative diagnostic work-up of laparoscopic cholecystectomy.

Adult↗
PubMed1982

Genetic variation and joint segregation of biochemical loci in the common meadow mushroom, Agaricus campestris.

In this paper we report the results of an electrophoretic examination of genetic variation in the common meadow mushroom, Agaricus campestris. An examination of variability at 10 biochemical loci in a single natural population revealed an average heterozygosity of 0.281. Mendelian segregation was verified for 13 loci in single-spore-derived lines from individual sporophores. One linkage was found (Gpt-2 with Pep-GL-1, r = 0.065) among 47 pairwise examinations for joint segregation.

Basidiomycota↗
PubMed2006

Identification and functional significance of SNPs underlying conserved haplotype frameworks across ethnic populations.

BACKGROUND: The study of genetic variation will promote our understanding of the differential predisposition to common diseases and variation in drug responses of individuals and ethnic populations. Such genetic variation is intrinsically structured into blocks of haplotypes in populations. Therefore, a comprehensive haplotype map based on the most abundant form of genetic variation, single nucleotide polymorphisms, will be useful. At the present time, however, our knowledge of the similarities and differences of haplotype structure among different ancestral populations is still inadequate. METHODS: To determine whether common underlying haplotype patterns existed across ethnic populations, we analyzed data derived from African and European Americans for twenty-two genes spanning a total of 516 kb and the HapMap ENCODE data across 500 kb on chromosome 2p16.3 from three major world populations. RESULTS AND CONCLUSIONS: We observed that strong pairwise linkage disequilibrium (LD) between SNPs selected from populations having African ancestry was highly conserved across other non-African populations. Common haplotypes described by these LD-selected SNPs demonstrated a simple evolutionary structure with up to three major frameworks, which were likely ancestral backgrounds upon which more recent mutations have been superimposed. Also, haplotype block boundaries defined in populations having African ancestry revealed completely concordant recombinant haplotypes across all populations, providing a consistent definition of block structure. Finally, a large fraction of regulatory polymorphisms described in the literature appeared to tag these conserved haplotype frameworks, strongly suggesting their significance for disease association and pharmacogenetic studies.

Black or African American↗
PubMed2004

No association between variation of the FOXP3 gene and common type 1 diabetes in the Sardinian population.

Mutations of the forkhead/winged helix transcription factor FOXP3 gene on chromosome Xp11.23 cause a rare recessive monogenic disorder called IPEX (immune dysregulation, polyendocrinopathy, including type 1 diabetes, enteropathy, and X-linked syndrome). FOXP3 is necessary for the differentiation of a key immune suppressive subset of T-cells, the CD4+CD25+ regulatory T-cells. Previously, we reported a significant male-female bias in the common, multifactorial form of type 1 diabetes in Sardinia and evidence of linkage of chromosome Xp11 to the disease. These findings indicate that FOXP3 is a prime functional and positional candidate locus for the common form of type 1 diabetes. In the present study, we initially scanned 82 kb of the FOXP3 region for common polymorphisms, including sequencing all of the coding and functionally relevant portions of the gene in 64 Sardinian individuals. Then the most informative polymorphisms in 418 type 1 diabetic families and in 268 male case and 326 male control subjects were sequentially genotyped and tested for disease association. There is no evidence that variants in the FOXP3 regions analyzed are associated with type 1 diabetes and account for the male-female bias observed in Sardinia. Our data indicate that allelic variation in or near the coding regions of the FOXP3 gene does not have a major role in the inherited susceptibility to the common form of type 1 diabetes.

Adolescent↗
PubMed2005

Common themes and cell type specific variations of higher order chromatin arrangements in the mouse.

BACKGROUND: Similarities as well as differences in higher order chromatin arrangements of human cell types were previously reported. For an evolutionary comparison, we now studied the arrangements of chromosome territories and centromere regions in six mouse cell types (lymphocytes, embryonic stem cells, macrophages, fibroblasts, myoblasts and myotubes) with fluorescence in situ hybridization and confocal laser scanning microscopy. Both species evolved pronounced differences in karyotypes after their last common ancestors lived about 87 million years ago and thus seem particularly suited to elucidate common and cell type specific themes of higher order chromatin arrangements in mammals. RESULTS: All mouse cell types showed non-random correlations of radial chromosome territory positions with gene density as well as with chromosome size. The distribution of chromosome territories and pericentromeric heterochromatin changed during differentiation, leading to distinct cell type specific distribution patterns. We exclude a strict dependence of these differences on nuclear shape. Positional differences in mouse cell nuclei were less pronounced compared to human cell nuclei in agreement with smaller differences in chromosome size and gene density. Notably, the position of chromosome territories relative to each other was very variable. CONCLUSION: Chromosome territory arrangements according to chromosome size and gene density provide common, evolutionary conserved themes in both, human and mouse cell types. Our findings are incompatible with a previously reported model of parental genome separation.

Animals↗
PubMed1996

Molecular genetics of human blood pressure variation.

Hypertension is a common multifactorial vascular disorder of largely unknown cause. Recognition that hypertension is in part genetically determined has motivated studies to identify mutations that confer susceptibility. Thus far, mutations in at least 10 genes have been shown to alter blood pressure; most of these are rare mutations imparting large quantitative effects that either raise or lower blood pressure. These mutations alter blood pressure through a common pathway, changing salt and water reabsorption in the kidney. These findings demonstrate the utility of molecular genetic approaches to the understanding of blood pressure variation and may provide insight into the physiologic mechanisms underlying common forms of hypertension.

Absorption↗
PubMed1994

Evaluation of reproducibility of a vessel wall movement detector system for assessment of large artery properties.

OBJECTIVE: Arterial distensibility (DC) and compliance (CC) are vessel wall properties of large arteries that can be measured non-invasively with a custom made vessel wall movement detector system (VWMDS). This study investigated the reproducibility of this device in 10 volunteers. METHODS: To investigate intraobserver intrasession and intraobserver intersession variability, arterial diameter (D) and relative change in diameter during the heart cycle (delta D/D) were measured in the elastic common carotid artery, and in the muscular femoral and brachial arteries. Interobserver intrasession variability was examined in common carotid artery by two observers, while interobserver variability on the same image was assessed for common carotid and femoral arteries. Variability was expressed as the coefficient of variation. RESULTS: For common carotid artery, intraobserver intrasession variability was 7.9(SEM 1.6)% (delta D/D), 4.5(1.1)% (D), 8.3(1.3)% (DC), and 9.1(2.6)% (CC), respectively. In femoral artery it was 12.4(2.2)% (delta D/D), 2.7(0.6)% (DC), 13.4(2.2)% (DC), and 12.5(2.1)% (CC). For brachial artery it was 13.4(2.8)% (delta D/D), 2.5(0.5)% (D), 16.1(2.5)% (DC), and 15.6(2.6)% (CC). Intraobserver intersession variability was comparable to intraobserver intrasession variability for all vessels. Interobserver intrasession variability for common carotid artery was 11.3(2.6)% (delta D/D) and 8.6(1.9)% (D), but was larger for DC and CC. Interobserver variability on the same image was < 5% for common carotid and femoral arteries. CONCLUSIONS: In conclusion, the vessel wall movement detector system has a good technical reproducibility. Intraobserver intrasession and intersession variability are comparable, and are larger in muscular arteries. This might be due to a larger variation in tone of these arteries, which are under permanent neurohumoral control. Interobserver intrasession variability was larger than intraobserver variability and might be influenced by differences in observers' skill and spontaneous variation in vessel wall properties.

Adolescent↗