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PubMed1982

Observations on the seasonal variation of the most common acute pediatric diseases in the Helsinki area (Finland).

Seasonal variations in the incidence of the most common acute diseases in childhood during the inter-epidemic year 1978 were investigated using a sample of 7,068 walk-in patients attending. Aurora Hospital, Helsinki. At least seven out of the ten most common diseases were of infectious origin. Generally, boys and the younger groups were affected most often. The clearest seasonal difference in both sexes was observed in patients with gastroenteritis and otitis media. Among boys, there was also a marked fluctuation in the incidence of asthmatic bronchitis and asthma, pneumonia, and laryngitis, whereas, among girls, marked variations were observed only in urinary tract infections and acute upper respiratory infections. Children between 1 and 3 years of age appeared to be most prone to the common cold syndrome all the year round.

Acute Disease↗
PubMed1997

Integrated methods to solve the biological basis of common diseases.

Biological variations influence population variations of many common traits. Identification of the biological basis of many common diseases has been particularly difficult, but new reagents and analytical tools will greatly facilitate this process. The goal of this review is to discuss how to identify the biological basis of common traits by using mouse models. No single method will work for all traits. Understanding complex problems will require broadly based holistic approaches that use a wide array of tools and resources. A multiplicity of developed methods together provide the tools needed to identify the biological basis of any common trait. These tools, whole-genome linkage maps, maps of expressed genes, and statistical methods, deal with the complexities of multiple loci or correlated traits. This review provides some criteria for making choices about the likely productive approaches at each stage in the process of finding genes that influence common traits.

Animals↗
PubMed2007

Comprehensive evaluation of genetic variation in the IGF1 gene and risk of prostate cancer.

Insulin-like growth factor-I (IGF1) stimulates cell proliferation, decreases apoptosis, and has been implicated in cancer development. Epidemiological studies have shown elevated levels of circulating IGF1 to be associated with increased risk of prostate cancer. To what extent genetic variation in the IGF1 gene is related to prostate cancer risk is largely unknown. We performed a comprehensive haplotype tagging (HT) assessment of single nucleotide polymorphisms (SNPs) representing the common haplotype variation in the IGF1 gene. We genotyped 10 SNPs (9 haplotype tagging SNPs (htSNPs)) within Cancer Prostate in Sweden (CAPS), a case-control study of 2,863 cases and 1,737 controls, in order to investigate if genetic variation in the IGF1 gene is associated with prostate cancer risk. Three haplotype blocks were identified across the IGF1 gene and 9 SNPs were selected as haplotype tagging SNPs. Common haplotypes in the block covering the 3' region of the IGF1 gene showed significant global association with prostate cancer risk (p = 0.004), with one particular haplotype giving an odds ratio of 1.46 (95% CI = 1.15-1.84, p = 0.002). This haplotype had a prevalence of 5% in the study population. Our results indicate that common variation in the IGF1 gene, particularly in the 3' region, may affect prostate cancer risk. Further studies on genetic variations in the IGF1 gene in relation to prostate cancer risk as well as to circulating levels of IGF1 are needed to confirm this novel finding.

Case-Control Studies↗
PubMed2006

A simple physical model predicts small exon length variations.

One of the most common splice variations are small exon length variations caused by the use of alternative donor or acceptor splice sites that are in very close proximity on the pre-mRNA. Among these, three-nucleotide variations at so-called NAGNAG tandem acceptor sites have recently attracted considerable attention, and it has been suggested that these variations are regulated and serve to fine-tune protein forms by the addition or removal of a single amino acid. In this paper we first show that in-frame exon length variations are generally overrepresented and that this overrepresentation can be quantitatively explained by the effect of nonsense-mediated decay. Our analysis allows us to estimate that about 50% of frame-shifted coding transcripts are targeted by nonsense-mediated decay. Second, we show that a simple physical model that assumes that the splicing machinery stochastically binds to nearby splice sites in proportion to the affinities of the sites correctly predicts the relative abundances of different small length variations at both boundaries. Finally, using the same simple physical model, we show that for NAGNAG sites, the difference in affinities of the neighboring sites for the splicing machinery accurately predicts whether splicing will occur only at the first site, splicing will occur only at the second site, or three-nucleotide splice variants are likely to occur. Our analysis thus suggests that small exon length variations are the result of stochastic binding of the spliceosome at neighboring splice sites. Small exon length variations occur when there are nearby alternative splice sites that have similar affinity for the splicing machinery.

Animals↗
PubMed1999

Angiotensin converting enzyme gene insertion/deletion polymorphism, angiotensinogen gene polymorphisms, family history of hypertension, and childhood blood pressure.

Earlier epidemiologic studies have yielded inconsistent results on the extent and timing of the blood pressure (BP) increase in offspring of hypertensive parents. We hypothesized that a familial influence on the BP of the offspring exists from birth on, but becomes significant only later in childhood. We studied the influence of familial occurrence of hypertension on the BP of 3596 children aged 6 to 18 years during a 6-year follow-up. In addition, we examined the possible associations of BP variations with polymorphisms of two candidate genes for hypertension, ie, those coding for the angiotensin converting enzyme (ACE) and those coding for angiotensinogen. A positive family history of hypertension was reflected as the occurrence of higher systolic BP values from the age of 9 years and upward among the females and from the age of 12 years and upward among the males. The mean differences in BP varied from 3.2 to 5.8 mm Hg (systolic) and 2.1 to 5.9 mm Hg (diastolic) between the female offspring of normotensive and hypertensive parents and grandparents. The systolic BP values were significantly higher among females with a hypertensive history in two generations in comparison with females from normotensive families. Among the male offspring of hypertensive and normotensive families, the BP differences were inconsistent. The deletion/deletion males had higher systolic BP values than those with other ACE genotypes. In contrast, variation at the angiotensinogen gene locus was not significantly associated with BP. We conclude that parental history of hypertension is a risk factor for high blood pressure among the offspring from the ages of 9 to 12 years and upward, and hypertension within two generations may enhance this effect. Although the common genetic variation of ACE may influence blood pressure in male children and adolescents, our data do not suggest a role for the common variation of the angiotensinogen gene as a BP regulator during childhood.

Adolescent↗
PubMed2002

Conservation and variation in human and common chimpanzee CD94 and NKG2 genes.

To assess polymorphism and variation in human and chimpanzee NK complex genes, we determined the coding-region sequences for CD94 and NKG2A, C, D, E, and F from several human (Homo sapiens) donors and common chimpanzees (Pan troglodytes). CD94 is highly conserved, while the NKG2 genes exhibit some polymorphism. For all the genes, alternative mRNA splicing variants were frequent among the clones obtained by RT-PCR. Alternative splicing acts similarly in human and chimpanzee to produce the CD94B variant from the CD94 gene and the NKG2B variant from the NKG2A gene. Whereas single chimpanzee orthologs for CD94, NKG2A, NKG2E, and NKG2F were identified, two chimpanzee paralogs of the human NKG2C gene were defined. The chimpanzee Pt-NKG2CI gene encodes a protein similar to human NKG2C, whereas in the chimpanzee Pt-NKG2CII gene the translation frame changes near the beginning of the carbohydrate recognition domain, causing premature termination. Analysis of a panel of chimpanzee NK cell clones showed that Pt-NKG2CI and Pt-NKG2CII are independently and clonally expressed. Pt-NKG2CI and Pt-NKG2CII are equally diverged from human NKG2C, indicating that they arose by gene duplication subsequent to the divergence of chimpanzee and human ancestors. Genomic DNA from 80 individuals representing six primate species were typed for the presence of CD94 and NKG2. Each species gave distinctive typing patterns, with NKG2A and CD94 being most conserved. Seven different NK complex genotypes within the panel of 48 common chimpanzees were due to differences in Pt-NKG2C and Pt-NKG2D genes.

Alleles↗
PubMed2005

Geographical variation in rates of common mental disorders in Britain: prospective cohort study.

BACKGROUND: There is little geographical variation in the prevalence of the common mental disorders. However, there is little longitudinal research. AIMS: To estimate variance in rates of common mental disorders at individual, household and electoral ward levels prospectively. METHOD: A 12-month cohort study of 7659 adults aged 16-74 years in 4338 private households, in 626 electoral wards. Data were collected as part of the British Household Panel Survey. Common mental disorders were assessed using the 12-item General Health Questionnaire (GHQ). Ward-level socio-economic deprivation was measured using the Carstairs index. RESULTS: Less than 1% of total variance, in onset and maintenance of common mental disorders and change in GHQ score between waves, occurred at ward level. However, 12% of variance, which is a statistically significant difference, was found at household level (a much smaller geographical unit) and this difference remained after further analyses. CONCLUSIONS: Ward level socio-economic deprivation does not influence the onset and maintenance of common mental disorders in Britain but local factors at the household level do. Reasons for this remain unclear.

Adolescent↗
PubMed2003

Misfolding, degradation, and aggregation of variant proteins. The molecular pathogenesis of short chain acyl-CoA dehydrogenase (SCAD) deficiency.

Short chain acyl-CoA dehydrogenase (SCAD) deficiency is an inborn error of the mitochondrial fatty acid metabolism caused by rare variations as well as common susceptibility variations in the SCAD gene. Earlier studies have shown that a common variant SCAD protein (R147W) was impaired in folding, and preliminary experiments suggested that the variant protein displayed prolonged association with chaperonins and delayed formation of active enzyme. Accordingly, the molecular pathogenesis of SCAD deficiency may rely on intramitochondrial protein quality control mechanisms, including degradation and aggregation of variant SCAD proteins. In this study we investigated the processing of a set of disease-causing variant SCAD proteins (R22W, G68C, W153R, R359C, and Q341H) and two common variant proteins (R147W and G185S) that lead to reduced SCAD activity. All SCAD proteins, including the wild type, associate with mitochondrial hsp60 chaperonins; however, the variant SCAD proteins remained associated with hsp60 for prolonged periods of time. Biogenesis experiments at two temperatures revealed that some of the variant proteins (R22W, G68C, W153R, and R359C) caused severe misfolding, whereas others (R147W, G185S, and Q341H) exhibited a less severe temperature-sensitive folding defect. Based on the magnitude of in vitro defects, these SCAD proteins are characterized as folding-defective variants and mild folding variants, respectively. Pulse-chase experiments demonstrated that the variant SCAD proteins either triggered proteolytic degradation by mitochondrial proteases or, especially at elevated temperature, aggregation of non-native conformers. The latter finding may indicate that accumulation of aggregated SCAD proteins may play a role in the pathogenesis of SCAD deficiency.

Animals↗
PubMed2001

Unusual aortic arch variation: distal origin of common carotid arteries.

As part of a larger study, the aortic arch and its branches were removed en bloc at autopsy from men of Japanese ancestry born in Hawaii. Of the 193 arterial trees examined, 182 (94.3%) had a typical branching pattern (e.g., brachiocephalic trunk, left common carotid, and left subclavian arteries, in that order). Two specimens had only two branches arising from the aortic arch, a common trunk uniting the brachiocephalic and left common carotid arteries and a left subclavian artery. Nine individuals (4.6%) had four branches off the aortic arch; in eight of these cases (4.1%), the left vertebral artery originated directly off the aortic arch just proximal to, or as a common trunk with, the left subclavian artery. A unique aortic arch branching pattern was found in one of these men. The four arteries arising from the arch of the aorta were, in sequence: right subclavian, left subclavian, right common carotid, and left common carotid. The literature on aortic arch variations is reviewed and the possible embryonic development of these branching patterns and their clinical significance is discussed briefly.

Aged↗
PubMed1999

Variation in immunoregulatory genes determines the clinical phenotype of common variable immunodeficiency.

Variation in clinical phenotype is a hallmark of many complex diseases. The cause of this clinical heterogeneity is unknown, but it may be determined by genetic factors distinct from those conferring disease susceptibility. Common variable immunodeficiency (CVID) is a complex disease of unknown aetiology and diverse clinical manifestations. We have developed a unified polymerase chain reaction and sequence-specific primer (PCR-SSP) method to simultaneously genotype multiple polymorphisms under identical conditions, and have used this method to test the hypothesis that the clinical phenotype of CVID is determined by immunoregulatory gene polymorphism. Twenty-three polymorphisms in 13 genes were studied in 163 CVID patients. Vitamin D receptor and IL-6 alleles were associated with immunophenotypic abnormalities characteristic of more severe disease; and tumour necrosis factor and IL-10 alleles conferred susceptibility to the granulomatous form of CVID in an interacting fashion. These findings demonstrate that different clinical features of a disease may have unique pathogenetic abnormalities, determined by multiple interacting genetic factors. The ease of application of this efficient, robust genotyping technique to polymorphisms throughout the genome will make it a powerful tool in the investigation of the genetic basis of phenotypic variability in a wide variety of diseases.

Abatacept↗
PubMed2006

Variation in the human genome and the inherited basis of common disease.

The availability of a reference human genome sequence-an increasingly dense catalog-knowledge of common genetic variation, and new developments in technology present an unprecedented opportunity to systematically explore the genetic basis of complex human diseases such as cancer. An understanding of the common mutations that can cause distinct human cancers will be critical for identifying new targets for drug discovery, patient stratification for clinical trials, and analysis of drug response data to delineate classes of patients that respond to therapy. The genome structure of cancer can be investigated in several ways. Germline mutations can be investigated in large-scale, case-control, or family studies. Somatic alternations can be identified using state-of-the-art genomic technologies such as high-density oligonucleotide arrays and targeted resequencing. Combined, these approaches will lead to a better understanding of the cancer genome.

Gene Expression Profiling↗
PubMed1997

Genetic variation in factor VII associated with variation in plasma lipoprotein(a) concentration.

Cross-sectional and prospective studies have shown that individuals with high plasma lipoprotein(a) [Lp(a)] concentrations are at increased risk for coronary heart disease. Size polymorphism of the apolipoprotein(a) [apo(a)] glycoprotein accounts for approximately 35% of the variation in plasma Lp(a) concentrations. However, there is no convincing evidence for associations between plasma Lp(a) and common genetic variation outside APO(a), the gene that encodes apo(a). We tested for association of common genetic variation of candidate genes in lipid metabolism and also of F7 with variation of plasma Lp(a) concentrations in Alberta Hutterites. Variation at codon 353 of F7 has been associated with variation in the plasma factor VII activity (FVIIc), with the 353Q allele associated with lower FVIIc and the 353R allele associated with higher FVIIc. We found significant associations between variation in plasma concentrations of Lp(a) and both apo(a) isoform size and F7 codon 353 genotype (both P < .0001). The effects on plasma Lp(a) concentration of the alleles at codon 353 were additive. The average effects of the F7 353Q and 353R alleles were, respectively, to decrease by 1.71 micrograms/mL and to increase by 0.301 microgram/mL plasma Lp(a) concentration from the sample mean. This suggests that common genomic variation in F7 is associated with variation in plasma Lp(a) concentration.

Alleles↗
PubMed2002

Evolution of heteroplasmy at a mitochondrial tandem repeat locus in cultured rabbit cells.

Surveys of animal mitochondrial DNA (mtDNA) polymorphism reveal that mtDNA length variation is common. Much of this variation involves non-coding tandem repeat arrays in the main control region of the molecule. Despite a high mutation rate, generating systematic individual mtDNA length heteroplasmy, the number of repeats in a tandem array is maintained within a narrow range in lagomorphs. To investigate the basis for this apparent paradox, we studied the evolution of mtDNA length polymorphism in several rabbit cell clones containing different proportions of mtDNA, with four or five 153-bp repeats. Our data show that equivalent amounts of two mtDNA molecular types are not stable (evolution towards a predominant type being the rule) and that other types remain represented, maintaining the length polymorphism. The data suggest that mtDNA molecules with a longer array of repeats have a replicative advantage that could depend on the nuclear background.

Animals↗
PubMed2003

Phylogeography and population structure of the common warthog (Phacochoerus africanus) inferred from variation in mitochondrial DNA sequences and microsatellite loci.

Global climate fluctuated considerably throughout the Pliocene and Pleistocene, influencing the evolutionary history of a wide range of species. Using both mitochondrial sequences and microsatellites, we have investigated the evolutionary consequences of such environmental fluctuation for the patterns of genetic variation in the common warthog, sampled from 24 localities in Africa. In the sample of 181 individuals, 70 mitochondrial DNA haplotypes were identified and an overall nucleotide diversity of 4.0% was observed. The haplotypes cluster in three well-differentiated clades (estimated net sequence divergence of 3.1-6.6%) corresponding to the geographical origins of individuals (i.e. eastern, western and southern African clades). At the microsatellite loci, high polymorphism was observed both in the number of alleles per locus (6-21), and in the gene diversity (in each population 0.59-0.80). Analysis of population differentiation indicates greater subdivision at the mitochondrial loci (FST=0.85) than at nuclear loci (FST=0.20), but both mitochondrial and nuclear loci support the existence of the three warthog lineages. We interpret our results in terms of the large-scale climatic fluctuations of the Pleistocene.

Animals↗
PubMed2004

Single nucleotide polymorphisms associated with rat expressed sequences.

Single nucleotide polymorphisms (SNPs) are the most common source of genetic variation in populations and are thus most likely to account for the majority of phenotypic and behavioral differences between individuals or strains. Although the rat is extensively studied for the latter, data on naturally occurring polymorphisms are mostly lacking. We have used publicly available sequences consisting of whole-genome shotgun (WGS), expressed sequence tag (EST), and mRNA data as a source for the in silico identification of SNPs in gene-coding regions and have identified a large collection of 33,305 high-quality candidate SNPs. Experimental verification of 471 candidate SNPs using a limited set of rat isolates revealed a confirmation rate of approximately 50%. Although the majority of SNPs were identified between Sprague-Dawley (EST data) and Brown Norway (WGS data) strains, we found that 66% of the verified variations are common among different rat strains. All SNPs were extensively annotated, including chromosomal and genetic map information, and nonsynonymous SNPs were analyzed by SIFT and PolyPhen prediction programs for their potential deleterious effect on protein function. Interestingly, we retrieved three SNPs from the database that result in the introduction of a premature stop codon and that could be confirmed experimentally. Two of these "in silico-identified knockouts" reside in interesting QTL regions. Data are publicly available via a Web interface (http://cascad.niob.knaw.nl), allowing simple and advanced search queries.

Animals↗
PubMed2005

Investigation of the bifurcation level of the common carotid artery and variations of the branches of the external carotid artery in human fetuses.

Variations in the position of the bifurcation of the common carotid artery (CCA) and the origin or branching pattern of the external carotid artery (ECA) are well known and documented. In this study, the bifurcation levels of the CCA and origin variations of the branches of the ECA have been extensively investigated in human fetuses. Bilaterally, 40 carotid bifurcations and 40 ECA and their branches have been examined. A latex solution, which had been diluted with water at a ratio of 25% and colored with red India ink, was injected into the aortic arch. Fetuses were kept at room temperature for 24 h before the ECA and its branches were dissected under the microsurgery microscope. Cases of variation were determined and photographed. The bifurcation level of the CCA was determined to be 55% at the C3 level, 35% at the C4 level, 10% at the C5 level on the right side and 60% at the C3 level, 40% at the C4 level on left side. The distribution of the ECA trunks was determined as follows: A linguofacial trunk was present in 20% of the cases, a thyrolingual trunk in 2.5%, a thyrolinguofacial trunk in 2.5% and an occipitoauricular trunk in 12.5%. Beyond this the ascending pharyngeal artery (APA) was observed in one fetus to originate from the internal carotid artery (ICA). Knowledge of variations in the origin and course of the ECA and its branches is of great importance in surgery and radiological examinations.

Carotid Artery, Common↗
PubMedDate not supplied

Plantar fibromatosis: most common sonographic appearance and variations.

PURPOSE: The aim of this study was to describe the most common sonographic appearances of plantar fibromatosis, thus enabling sonographic diagnosis of this benign, focally invasive fibrous neoplasm. METHODS: The medical records, pathologic reports, and sonographic reports and images of 22 patients with palpable plantar masses were reviewed retrospectively. The sonographic findings were used to characterize those masses with respect to location, shape, size, and echogenicity. Sixteen patients were included in this study because of the proximity of their lesions to the plantar fascia; 6 patients were excluded because their lesions were metatarsophalangeal bursae or ganglia. RESULTS: The 20 feet examined in the 16 patients studied contained 43 distinct lesions, all located on the surface of the plantar fascia. Thirty-seven (86%) of the 43 were 20 mm long or less. Thirty-seven (86%) of the 43 lesions were elongated; the remaining 6 (14%) were round or oval. Twenty-five (68%) of the 37 elongated lesions had tapered ends, and the other 12 (32%) had rounded ends. Thirty-one (72%) of the 43 lesions were hypoechoic; 25 (81%) of these 31 measured as long as 10 mm. Ten (83%) of the 12 lesions that had mixed echogenicity were longer than 10 mm. CONCLUSIONS: The lesions of plantar fibromatosis were characteristically located on the surface of the plantar fascia, sagittally elongated, most often less than 20 mm long, fusiform, and hypoechoic. Lesions longer than 10 mm often exhibited mixed echogenicity. The superficial location and appearance should strongly suggest plantar fibromatosis, although careful examination is required to exclude other possibilities, such as sarcoma.

Adolescent↗
PubMed2003

Age variation in a fluctuating population of the common vole.

We analysed variation in age in a fluctuating population of the common vole ( Microtus arvalis) in southern Moravia, Czech Republic, to test the assumption of the senescence hypothesis that the age of voles increases with increasing population density. Between 1996 and 1998, we monitored the demographic changes by snap-trapping and live-trapping in a field population passing through the increase, peak and decline phase of the population cycle. We used the eye lens mass method to determine the age of snap-trapped animals and those that died in live-traps. The average age of winter males was clearly higher after the peak phase breeding season than before it. No such phase-dependent shift in age, however, was observed in the female component. Male age continued to increase from autumn to spring over the pre-peak winter, and the highest age was in spring of the peak phase year. However, after the peak phase breeding season the highest age was achieved in winter, with the decline phase males during the next spring tending to be younger. The average age of females in spring populations was always lower than in winter populations. The average age of voles from live-traps was always higher than voles from snap-traps, particularly in winter and spring populations, suggesting the presence of senescent animals. Although the density-dependent changes in age are consistent with those observed for other voles, they provide only weak evidence that population cycles in the common vole are accompanied by pronounced shifts in individual age, particularly in female voles.

Age Factors↗