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PubMed2004

Vertebrate floor-plate specification: variations on common themes.

Situated at the ventral-most part of the vertebrate neural tube, the floor plate (FP) is an important signalling centre that controls the regional differentiation of neurons in the nervous system. It secretes guidance molecules that direct ventrally navigating axons crucial for the correct wiring of neuronal circuits. Although the function of the FP is well-conserved from fish to humans, discrepancies exists with respect to both the signalling system involved in FP induction, and the origin of the FP in various vertebrate species. Recent findings from the embryos of zebrafish, chicken and mouse provide insights that reconcile previous results and suggest common themes in vertebrate FP specification.

Animals↗
PubMed1979

Intra-individual variation in commonly analyzed serum constituents.

Concentrations of 27 commonly estimated serum constituents were measured in blood sampled from 20 apparently healthy volunteers at 0830, 1230, and 1630 hours on each of four days, at weekly intervals. Time-dependent statistically significant (p less than or equal to 0.01) variation was observed in 12 of the constituents. The 15 constituents that showed no statistically significant diurnal variation included the immunoglobulins, other specific proteins, enzymes, cholesterol, calcium, copper, and magnesium. On the different days of the study consistent temporal patterns were observed in urea, creatinine, phosphate, zinc, bilirubin, triglyceride, total protein, and albumin. The magnitude of variation was particularly great in potassium, iron, zinc, and bilirubin. In general, day-to-day changes in concentration exceeded within-day changes, except for potassium, phosphate, and zinc, for which greater changes could be observed within-day than from one day to another at the same time.

Alanine Transaminase↗
PubMed2001

Role of common gene variations in the molecular pathogenesis of short-chain acyl-CoA dehydrogenase deficiency.

ABSTRACT Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is considered a rare inherited mitochondrial fatty acid oxidation disorder. Less than 10 patients have been reported, diagnosed on the basis of ethylmalonic aciduria and low SCAD activity in cultured fibroblast. However, mild ethylmalonic aciduria, a biochemical marker of functional SCAD deficiency in vivo, is a common finding in patients suspected of having metabolic disorders. Based on previous observations, we have proposed that ethylmalonic aciduria in a small proportion of cases is caused by pathogenic SCAD gene mutations, and SCAD deficiency can be demonstrated in fibroblasts. Another - much more frequent - group of patients with mild ethylmalonic aciduria has functional SCAD deficiency due to the presence of susceptibility SCAD gene variations, i.e. 625G>A and 511C>T, in whom a variable or moderately reduced SCAD activity in fibroblasts may still be clinically relevant. To substantiate this notion we performed sequence analysis of the SCAD gene in 10 patients with ethylmalonic aciduria and diagnosed with SCAD deficiency in fibroblasts. Surprisingly, only one of the 10 patients carried pathogenic mutations in both alleles, while five were double heterozygotes for a pathogenic mutation in one allele and the 625G>A susceptibility variation in the other. The remaining four patients carried only either the 511C>T or the 625G>A variations in each allele. Our findings document that patients carrying these SCAD gene variations may develop clinically relevant SCAD deficiency, and that patients with even mild ethylmalonic aciduria should be tested for these variations.

Acyl-CoA Dehydrogenase↗
PubMed2005

Genomic characterization of KIR2DL4 in families and unrelated individuals reveals extensive diversity in exon and intron sequences including a common frameshift variation occurring in several alleles.

The KIR2DL4 gene including a portion of exon 1 through exon 9 was sequenced from two families and eight cell lines from the International Histocompatibility Workshop (IHWS). Two known alleles and eight variants were detected. Overall, there were five synonymous and three non-synonymous changes when the variants were compared to the coding sequences of the most closely related known alleles plus a common frameshift change in five of the variant alleles. Alignment of the new variants with all known alleles showed that the regions encoding the extracellular region and the cytoplasmic tail were the most polymorphic. Two non-synonymous changes, P146H and L161V, occurred in an extracellular immunoglobulin-like domain. Five of the eight variants had a single adenine deletion in the exon encoding the transmembrane region, potentially resulting in a truncated protein lacking the cytoplasmic tail. The distribution of the deletion variant among many KIR2DL4 alleles may explain the high frequency of this variation in the population. Four of the eight consanguineous IHWS cell lines were found to be heterozygous for KIR2DL4 carrying two alleles that differed from one another by a few nucleotide substitutions. Analysis of intron sequences in the families revealed the nature and distribution of interspersed repeat elements which comprise 46% of the KIR2DL4 nucleotide sequence and consist of 12 elements including six SINEs (13.73% of the total length), one LINE (12.41%), and five LTR elements (19.51%). The results revealed the presence of extensive diversity in the KIR2DL4 gene. This is the first extensive report providing both exon and intron data in related individuals.

Alleles↗
PubMed1999

Paraoxonase genes and disease.

The paraoxonase gene family contains at least three members, including PON1, PON2 and PON3, which are located on chromosome 7q21.3-22.1. Until recently, there has been little insight into the role of the respective gene products in human physiology and pathology. However, emerging evidence from biochemical and genetic experiments is providing clues about the role(s) of the products of these genes. For example, the PON1 gene product is serum paraoxonase, which is expressed mainly in the liver and which hydrolyzes organophosphates. 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 and phenotypes related to atherosclerosis and lipoprotein metabolism. In contrast, the PON2 mRNA is expressed ubiquitously, and to date there are no mechanistic experiments that yield insights into its physiological role. However, there have been reports of association between common variation in PON2 and some metabolic quantitative phenotypes, such as plasma lipoproteins, plasma glucose, birthweight and atherosclerosis. Such genetic associations could point to the possible physiological role(s) of PON2. At present, the role of the PON3 gene product is very poorly understood. Complementary lines of research should soon clarify whether there might be merit in clinical testing for genetic variation in the paraoxonase gene family or whether the gene products might be good candidates for therapeutic interventions.

Animals↗
PubMed2004

Common ataxia telangiectasia mutated haplotypes and risk of breast cancer: a nested case-control study.

INTRODUCTION: The ataxia telangiectasia mutated (ATM) gene is a tumor suppressor gene with functions in cell cycle arrest, apoptosis, and repair of DNA double-strand breaks. Based on family studies, women heterozygous for mutations in the ATM gene are reported to have a fourfold to fivefold increased risk of breast cancer compared with noncarriers of the mutations, although not all studies have confirmed this association. Haplotype analysis has been suggested as an efficient method for investigating the role of common variation in the ATM gene and breast cancer. Five biallelic haplotype tagging single nucleotide polymorphisms are estimated to capture 99% of the haplotype diversity in Caucasian populations. METHODS: We conducted a nested case-control study of breast cancer within the Nurses' Health Study cohort to address the role of common ATM haplotypes and breast cancer. Cases and controls were genotyped for five haplotype tagging single nucleotide polymorphisms. Haplotypes were predicted for 1309 cases and 1761 controls for which genotype information was available. RESULTS: Six unique haplotypes were predicted in this study, five of which occur at a frequency of 5% or greater. The overall distribution of haplotypes was not significantly different between cases and controls (chi2 = 3.43, five degrees of freedom, P = 0.63). CONCLUSION: There was no evidence that common haplotypes of ATM are associated with breast cancer risk. Extensive single nucleotide polymorphism detection using the entire genomic sequence of ATM will be necessary to rule out less common variation in ATM and sporadic breast cancer risk.

Adult↗
PubMed1982

Incidence, pattern, and African variations of common benign disorders of the esophagus. Experience from Nigeria.

As a result of the dearth and cost of specialized personnel and investigative facilities, noncommunicable diseases have aroused no real epidemiologic interest in many parts of Africa, and consequently reports on some diseases have been sporadic and often lacking in detail. Therefore a comprehensive study of benign lesions of the esophagus, such as achalasia, hiatal hernia, and the gastroesophageal reflux complex including peptic stricture, was undertaken among Nigerians resident in the African environment. Striking variations from known patterns became evident. Answers were sought for the peculiarities in the manifestation and natural history of these disorders.

Adolescent↗
PubMed2003

18S rRNA gene variation among common airborne fungi, and development of specific oligonucleotide probes for the detection of fungal isolates.

In this study, we sequenced 18S rRNA genes (rDNA) from 49 fungal strains representing 31 species from 15 genera. Most of these species are common airborne fungi and pathogens that may cause various public health concerns. Sequence analysis revealed distinct divergence between Zygomycota and Ascomycota. Within Ascomycota, several strongly supported clades were identified that facilitate the taxonomic placement of several little-studied fungi. Wallemia appeared as the group most diverged from all the other Ascomycota species. Based on the 18S rDNA sequence variation, 108 oligonucleotide probes were designed for each genus and species included in this study. After homology searches and DNA hybridization evaluations, 33 probes were verified as genus or species specific. The optimal hybridization temperatures to achieve the best specificity for these 33 probes were determined. These new probes can contribute to the molecular diagnostic research for environmental monitoring.

Air Microbiology↗
PubMed2003

Common genetic variation in a basal promoter element alters DDAH2 expression in endothelial cells.

Synthesis of the vasodilator nitric oxide (NO) can be inhibited by the endogenous methylarginines L-NMMA and ADMA. ADMA is elevated in a number of cardiovascular disorders in which NO availability is reduced. Elimination of ADMA from the body occurs primarily by enzymatic breakdown through the action of DDAH, of which two isoforms exist, DDAH1 and DDAH2. In this study we have identified a core promoter region of the DDAH2 gene, and transcription factor sites that play an important role in the regulation of DDAH2 expression. Using PCR-SSCP analysis we also identified six common polymorphisms. One of these polymorphisms (an insertion/deletion at position -871) within the core promoter element influenced basal transcription. The discovery of a functional polymorphism within the DDAH2 promoter suggests that there may be common, individual differences in the ability to metabolise ADMA in vivo, that in turn, might underlie susceptibility to cardiovascular disease.

Amidohydrolases↗
PubMed1997

Rare arterial variation: a common trunk from the external iliac artery for the obturator, inferior epigastric and profunda femoris arteries.

In this anomaly, observed in the right pelvic region of a female newborn cadaver among 100 studied (1%), a common arterial trunk arose from the medial side of the external iliac a. 1 cm proximal to the inguinal ligament. The trunk first divided into an ascending branch, which finally divided into the obturator and inferior epigastric arteries, and a descending branch, the profunda femoris a. from which arose the medial circumflex femoral a. The origin of the profunda femoris, obturator and inferior epigastric aa. is explained on the basis of the embryologic development and their course and variations are compared with reports in the literature.

Epigastric Arteries↗
PubMed1995

Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia.

Overexpression of plasma apolipoprotein CIII (apo CIII) causes hypertriglyceridemia in transgenic mice. A genetically variant form of the human apo CIII promoter, containing five single base pair changes, has been shown to be associated with severe hypertriglyceridemia in a patient population. In animals and in cultured cells the apo CIII gene is transcriptionally downregulated by insulin. In this study we demonstrate that, unlike the wild-type promoter, the variant promoter was defective in its response to insulin treatment, remaining constitutively active at all concentrations of insulin. The loss of insulin regulation was mapped to polymorphic sites at -482 and -455, which fall within a previously identified insulin response element. Loss of insulin regulation could result in overexpression of the apo CIII gene and contribute to the development of hypertriglyceridemia. The variant apo CIII promoter is common in the human population and may represent a major contributing factor to the development of hypertriglyceridemia.

Alleles↗
PubMed2002

JSNP: a database of common gene variations in the Japanese population.

JSNP is a repository of Japanese Single Nucleotide Polymorphism (SNP) data, begun in 2000 and developed through the Prime Minister's Millennium Project. The aim of this undertaking is to identify and collate up to 150 000 SNPs from the Japanese population, located in genes or in adjacent regions that might influence the coding sequence of the genes. The project has been carried out by a collaboration between the Human Genome Center (HGC) in the Institute of Medical Science (IMS) at the University of Tokyo and the Japan Science and Technology Corporation (JST). JSNP serves as both a storage site for the Japanese SNPs obtained from the ongoing project and as a facility for public dissemination to allow researchers access to high quality SNP data. A primary motivation of the project is the construction of a basic data set to identify relationships between polymorphisms and common diseases or the reaction to drugs. As such, emphasis has been placed on the identification of SNPs that lie in candidate regions which may affect phenotype but which would not necessarily directly cause disease. Unrestricted access to JSNP and any associated files is available at http://snp.ims.u-tokyo.ac.jp/.

Chromosomes, Human↗
PubMedDate not supplied

Common rotational variations in children.

Most rotational variations in young children, such as in-toeing, out-toeing, and torticollis, are benign and resolve spontaneously. Understanding the normal variations in otherwise healthy children is vital to identifying true structural abnormalities that require intervention. A deliberate assessment of the rotational profile is necessary when evaluating children who in-toe or out-toe. In-toeing is usually attributable to metatarsus adductus in the infant, internal tibial torsion in the toddler, and femoral anteversion in children younger than 10 years. Out-toeing patterns largely result from external rotation hip contracture, external tibial torsion, and external femoral torsion. Although congenital muscular torticollis is the most common explanation for the atypical head posture in children, more serious disorders, including osseous malformations, inflammation, and neurogenic disorders, should be excluded.

Child↗
PubMed1996

A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.

We have examined the prothrombin gene as a candidate gene for venous thrombosis in selected patients with a documented familial history of venous thrombophilia. All the exons and the 5'- and 3'-UT region of the prothrombin gene were analyzed by polymerase chain reaction and direct sequencing in 28 probands. Except for known polymorphic sites, no deviations were found in the coding regions and the 5'-UT region. Only one nucleotide change (a G to A transition) at position 20210 was identified in the sequence of the 3'-UT region. Eighteen percent of the patients had the 20210 AG genotype, as compared with 1% of a group of healthy controls (100 subjects). In a population-based case-control study, the 20210 A allele was identified as a common allele (allele frequency, 1.2%; 95% confidence interval, 0.5% to 1.8%), which increased the risk of venous thrombosis almost threefold {odds ratio, 2.8; 95% confidence interval, 1.4 to 5.6}. The risk of thrombosis increased for all ages and both sexes. An association was found between the presence of the 20210 A allele and elevated prothrombin levels. Most individuals (87%) with the 20210 A allele are in the highest quartile of plasma prothrombin levels (> 1.15 U/mL). Elevated prothrombin itself also was found to be a risk factor for venous thrombosis.

Alleles↗
PubMed2003

Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease.

OBJECTIVES: We sought to evaluate the association between cholesteryl ester transfer protein (CETP) genotypes and the risk of future cardiovascular mortality in patients with coronary artery disease (CAD). BACKGROUND: Polymorphisms of the CETP gene influence CETP activity and high-density lipoprotein (HDL) cholesterol concentration and might affect the long-term prognosis and response to statin therapy in patients with CAD. METHODS: We used serum samples and deoxyribonucleic acid collected at baseline from a prospective cohort of 1,211 patients with CAD prospectively followed up (median follow-up of 4.1 years), 82 of whom experienced a fatal cardiovascular event. The CETP/C-629A and I405V polymorphisms, CETP activity, and HDL cholesterol were determined. RESULTS: Patients carrying the -629A allele had significantly lower CETP activity and higher HDL cholesterol levels. There was a significant association between this polymorphism and the risk of future cardiovascular death. Mortality decreased from 10.8% in CC homozygotes to 4.6% in CA heterozygotes and 4.0% in AA homozygotes (p < 0.0001). This association was independent of potential confounders, particularly HDL cholesterol and CETP activity levels. The clinical benefit of statin therapy was restricted to CC homozygotes, in whom cardiovascular mortality was divided by half (p = 0.01 for treatment x genotype interaction). Similar trends were observed with the CETP/I405V polymorphism, but these effects seemed to be mainly the consequence of linkage disequilibrium with the CETP/C-629A polymorphism. CONCLUSIONS: In patients with CAD, the CETP/-629A allele had a strong protective effect on future mortality from cardiovascular causes, independent of its role on HDL cholesterol and CETP activity levels. Additionally, this common polymorphism appeared to predict which patients with CAD will experience a survival benefit from statin therapy.

Aged↗
PubMed2004

Colour perception in twins: individual variation beyond common genetic inheritance.

BACKGROUND: The twin method was used to examine the genotype/phenotype relationship in colour vision, by determining concordance in colour perception within pairs of monozygotic (MZ) twins and dizygotic (DZ) twins. For MZ twins, whose photopigments are genetically identical, higher concordance in colour perception was expected; conversely, differences within each MZ pair would indicate a non-genetic contribution. METHOD: Ratings of dissimilarity between successively presented colours were elicited from four MZ and three DZ twin pairs. A non-twin sibling pair and three unrelated normal trichromats were enrolled, for comparison. Concordance for each twin (sibling) pair was estimated by Spearman correlations (rs) between data matrices and by Procrustes distances (gl) between colour spaces, reconstructed from individual data using multidimensional scaling (MDS). RESULTS: For MZ twins, rs) values (0.94-0.97) were comparable to intra-individual variability and significantly higher than those for DZ twins and siblings (0.72-0.82). Further, colour spaces for MZ co-twins were less discordant, with gl values (0.008-0.029) lower than for DZ co-twins (0.073-0.079) and siblings (0.052). Finally, concordances among all pairs of subjects were summarised by a geometrical 'subject space': the mean distance between MZ co-twins was 29 per cent of that between DZ and sibling pairs. DISCUSSION: Lower concordance rates in DZ twins and siblings can be attributed to differences in the inherited arrays of photopigment genes. The high concordance for MZ twins is in line with their shared photopigment genotype, placing an upper limit on contributions to discordance from possible individual variations in non-genetic factors. Potential photoreceptor, ocular and cognitive sources of inter-twin variation are discussed.

Adolescent↗
PubMed1998

Association and linkage of LDLR gene variation with variation in plasma low density lipoprotein cholesterol.

The role of common variation in the low density lipoprotein (LDL) receptor gene (LDLR) as a determinant of variation in plasma LDL cholesterol in normolipidemic populations is not well established. To address this question, we used both association and linkage analysis to evaluate the relationship between plasma LDL cholesterol and genetic variation in LDLR and in three other candidate genes for lipoprotein metabolism, namely, APOE, PONI, and LPL. We studied a sample of 719 normolipidemic Alberta Hutterites, who comprised 1217 sib pairs. Variation in each of the four candidate genes was significantly associated with variation in plasma LDL cholesterol, but the average effects of the alleles were small. In contrast, sib pair analysis showed that only the LDLR gene variation was linked with variation in plasma LDL cholesterol (P = 0.026). Thus, the common LDLR gene variation was both associated with and linked to variation in plasma LDL cholesterol, suggesting that there is a functional impact of structural variation in LDLR on plasma LDL cholesterol in this study sample. However, the absence of linkage of variation in LDL cholesterol with the other three candidate genes, in particular APOE, is consistent with a lower sensitivity of linkage analysis compared with association analysis for detecting modest effects on quantitative traits. Attributes such as the genetic structure of the study sample, the amount of variance attributable to the locus, and the information content of the marker appear to affect the ability to detect genotype-phenotype relationships using linkage analysis.

Adult↗
PubMed1997

Establishment and characterization of 12 uterine cervical-carcinoma cell lines: common sequence variation in the E7 gene of HPV-16-positive cell lines.

A total of 12 carcinoma cell lines of the human uterine cervix were established from 5 keratinizing and 5 nonkeratinizing squamous-cell carcinomas, and 2 small-cell carcinomas. Of these, 10 lines grew as adherent cells and 2 as floating aggregates. All lines showed (i) similarity in morphology to the primary tumor from which they were derived; (ii) high viability with relatively long doubling times (48-96 hr); (iii) absence of Mycoplasma and other bacteria, apart from one Mycoplasma-contaminated line; (iv) genetic heterogeneity by DNA-fingerprinting analysis; (v) absence of p53 mutation from exon 4 through 9; and (vi) the presence of HPV DNA sequence. Among the lines, 7 were infected by HPV-16, 3 by HPV-18, 1 by HPV-31, and 1 by HPV-33; the 2 cell lines derived from small-cell carcinomas contained HPV-18. Interestingly, 6 of the 7 cell lines containing HPV-16-type DNA harbored the same alteration of E7 at nucleotide position 647 (amino acid 29, AAT --> AGT, Asn --> Ser), whereas the 3 HPV-18-positive lines did not; 3 cell lines proved to have intact E1/E2 of HPV, suggesting the presence of episomally replicating HPV DNA as well as the integrated form, whereas the other 9 lines were shown to have integrated HPV. Taken together, these cell lines would be very useful for studying the biology of uterine cervical carcinoma.

Carcinoma↗