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PubMed2005

Integrating QTL and high-density SNP analyses in mice to identify Insig2 as a susceptibility gene for plasma cholesterol levels.

The use of inbred strains of mice to dissect the genetic complexity of common diseases offers a viable alternative to human studies, given the control over experimental parameters that can be exercised. Central to efforts to map susceptibility loci for common diseases in mice is a comprehensive map of DNA variation among the common inbred strains of mice. Here we present one of the most comprehensive high-density, single nucleotide polymorphism (SNP) maps of mice constructed to date. This map consists of 10,350 SNPs genotyped in 62 strains of inbred mice. We demonstrate the utility of these data via a novel integrative genomics approach to mapping susceptibility loci for complex traits. By integrating in silico quantitative trait locus (QTL) mapping with progressive QTL mapping strategies in segregating mouse populations that leverage large-scale mapping of the genetic determinants of gene expression traits, we not only facilitate identification of candidate quantitative trait genes, but also protect against spurious associations that can arise in genetic association studies due to allelic association among unlinked markers. Application of this approach to our high-density SNP map and two previously described F2 crosses between strains C57BL/6J (B6) and DBA/2J and between B6 ApoE(-/-) and C3H/HeJ ApoE(-/-) results in the identification of Insig2 as a strong candidate susceptibility gene for total plasma cholesterol levels.

Animals↗
PubMed1993

Glutathione concentration and distribution in cervical cancers and adjacent normal tissues.

Intracellular glutathione (GSH) has been shown to play an important role in modulating the cellular response to many cytotoxic agents, including radiation and chemotherapeutic drugs. In this study, individual glutathione levels from contiguous blocks of cervical cancer tissue were determined in order to investigate the intratumor GSH distribution and variation, as well as the difference between tumor and its normal counterpart. The GSH content of a squamous cell carcinoma of the cervix was twofold higher than its normal counterpart, but there was no obvious difference in a case with adenoid cystic carcinoma. The tumor margin adjacent to normal tissue has a higher GSH content than the tumor center in a large tumor. Although the intertumor variation in GSH is different in these two tumors, a common coefficient of variation, 26, is observed, which may be used to estimate the range of tumor GSH if it can only be determined by a biopsy.

Carcinoma, Adenoid Cystic↗
PubMed2004

Analysis of among-site variation in substitution patterns.

Substitution patterns among nucleotides are often assumed to be constant in phylogenetic analyses. Although variation in the average rate of substitution among sites is commonly accounted for, variation in the relative rates of specific types of substitution is not. Here, we review details of methodologies used for detecting and analyzing differences in substitution processes among predefined groups of sites. We describe how such analyses can be performed using existing phylogenetic tools, and discuss how new phylogenetic analysis tools we have recently developed can be used to provide more detailed and sensitive analyses, including study of the evolution of mutation and substitution processes. As an example we consider the mitochondrial genome, for which two types of transition deaminations (C-->T and A-->G) are strongly affected by single-strandedness during replication, resulting in a strand asymmetric mutation process. Since time spent single-stranded varies along the mitochondrial genome, their differential mutational response results in very different substitution patterns in different regions of the genome.

Journal Article↗
PubMed1999

Plastic adherent stromal cells from the bone marrow of commonly used strains of inbred mice: variations in yield, growth, and differentiation.

Bone marrow stroma contains a unique cell population, referred to as marrow stromal cells (MSCs), capable of differentiating along multiple mesenchymal cell lineages. A standard liquid culture system has been developed to isolate MSCs from whole marrow by their adherence to plastic wherein the cells grow as clonal populations derived from a single precursor termed the colony-forming-unit fibroblast (CFU-F). Using this liquid culture system, we demonstrate that the relative abundance of MSCs in the bone marrow of five commonly used inbred strains of mice varies as much as 10-fold, and that the cells also exhibit markedly disparate levels of alkaline phosphatase expression, an early marker of osteoblast differentiation. For each strain examined, the method of isolating MSCs by plastic adherence yields a heterogeneous cell population. These plastic adherent cells also exhibit widely varying growth kinetics between the different strains. Importantly, of three inbred strains commonly used to prepare transgenic mice that we examined, only cells derived from FVB/N marrow readily expand in culture. Further analysis of cultures derived from FVB/N marrow showed that most plastic adherent cells express CD11b and CD45, epitopes of lymphohematopoietic cells. The later consists of both pre-B-cell progenitors, granulocytic and monocytic precursors, and macrophages. However, a subpopulation of the MSCs appear to represent bona fide mesenchymal progenitors, as cells can be induced to differentiate into osteoblasts and adipocytes after exposure to dexamethasone and into myoblasts after exposure to amphotericin B. Our results point to significant strain differences in the properties of MSCs and indicate that standard methods cannot be applied to murine bone marrow to isolate relatively pure populations of MSCs.

Alkaline Phosphatase↗
PubMed2006

An increased coronary risk is paradoxically associated with common cholesteryl ester transfer protein gene variations that relate to higher high-density lipoprotein cholesterol: a population-based study.

BACKGROUND: Several cholesteryl ester transfer protein (CETP) polymorphisms affect high-density lipoprotein (HDL) cholesterol, but the impact of CETP gene variants on incident coronary disease in the general population is uncertain after correction for their effect on HDL cholesterol. DESIGN: We determined relationships between the CETP -629C-->A promoter (n = 8141), the TaqIB (n = 8289), and the I405V (n = 8265) polymorphisms, serum lipids, C-reactive protein, and clinical factors with incident coronary heart disease (defined as death from or hospitalization for myocardial infarction, ischemic heart disease, or coronary intervention) during a median of 4.94 yr follow-up. SUBJECTS: A predominantly Caucasian general population was studied. RESULTS: HDL cholesterol was 0.08 mmol/liter higher in -629A carriers than in -629CC homozygotes (P < 0.001). The unadjusted coronary hazard was 1.26 [95% confidence interval (CI), 0.95-1.68; P = 0.11] in A carriers compared with CC homozygotes and increased to 1.46 (95% CI, 1.10-1.95; P = 0.01) after adjustment for HDL cholesterol. This effect remained after additional adjustment for apolipoprotein A-I, triglycerides, C-reactive protein, age, and gender. Likewise, the HDL-cholesterol-adjusted hazard ratio was also higher in AA than in CC homozygotes (hazard ratio, 1.72; 95% CI, 1.22-2.42; P < 0.01). Similar findings were obtained with the TaqIB polymorphism. The 405V allele was weakly associated with incident coronary heart disease after HDL cholesterol adjustment (P = 0.09). CONCLUSIONS: A common CETP promoter polymorphism, which beneficially contributes to higher HDL cholesterol, is paradoxically associated with increased incidence of coronary disease in the general population. Thus, CETP gene variation may affect coronary risk apart from the level of HDL cholesterol.

Apolipoprotein A-I↗
PubMed1996

Seasonal variation in sudden infant death syndrome and bronchiolitis--a common mechanism?

The purpose of this study was to compare epidemiologic features of sudden infant death syndrome (SIDS) and bronchiolitis and to apply statistical examination in order to examine the hypothesis that similar mechanisms could be at work in both conditions. The setting was Scotland from 1982 through 1990. We compared 1,211 deaths from SIDS with 10,058 hospital admissions for bronchiolitis in infancy. The comparisons included age, sex ratio, and seasonality. The sex ratios were similar (SIDS [M:F]:1.61:1; bronchiolitis: 1.63:1), but age distribution was different (chi 2 = 104.6, p < 0.001). When monthly rates throughout the year were compared using correlation of residuals from average season variation and by autocorrelation of residual series, no significant relationships were found between the two conditions (r2 = 0.0004). Once the seasonal pattern common to both conditions was accounted for, SIDS was not autocorrelated between months whereas bronchiolitis exhibited a high level of autocorrelation indicating an epidemic pattern for the latter but not for the former. While a common seasonal variation may indicate some shared etiologic factors associated with winter season, the two conditions do not appear to be closely related. The hypothesis that a common host susceptibility is at work is not supported. Further investigations of seasonal influences are warranted.

Age Distribution↗
PubMed2006

A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses.

Fasting glucose is associated with future risk of type 2 diabetes and ischemic heart disease and is tightly regulated despite considerable variation in quantity, type, and timing of food intake. In pregnancy, maternal fasting glucose concentration is an important determinant of offspring birth weight. The key determinant of fasting glucose is the enzyme glucokinase (GCK). Rare mutations of GCK cause fasting hyperglycemia and alter birth weight. The extent to which common variation of GCK explains normal variation of fasting glucose and birth weight is not known. We aimed to comprehensively define the role of variation of GCK in determination of fasting glucose and birth weight, using a tagging SNP (tSNP) approach and studying 19,806 subjects from six population-based studies. Using 22 tSNPs, we showed that the variant rs1799884 is associated with fasting glucose at all ages in the normal population and exceeded genomewide levels of significance (P=10-9). rs3757840 was also highly significantly associated with fasting glucose (P=8x10-7), but haplotype analysis revealed that this is explained by linkage disequilibrium (r2=0.2) with rs1799884. A maternal A allele at rs1799884 was associated with a 32-g (95% confidence interval 11-53 g) increase in offspring birth weight (P=.002). Genetic variation influencing birth weight may have conferred a selective advantage in human populations. We performed extensive population-genetics analyses to look for evidence of recent positive natural selection on patterns of GCK variation. However, we found no strong signature of positive selection. In conclusion, a comprehensive analysis of common variation of the glucokinase gene shows that this is the first gene to be reproducibly associated with fasting glucose and fetal growth.

Adult↗
PubMed2006

Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis.

Cholesterol and its metabolites play a variety of essential roles in living systems. Virtually all animal cells require cholesterol, which they acquire through synthesis or uptake, but only the liver can degrade cholesterol. The ABCA1 gene product regulates the rate-controlling step in the removal of cellular cholesterol: the efflux of cellular cholesterol and phospholipids to an apolipoprotein acceptor. Mutations in ABCA1, as seen in Tangier disease, result in accumulation of cellular cholesterol, reduced plasma high-density lipoprotein cholesterol, and increased risk for coronary artery disease. To date, more than 100 coding variants have been identified in ABCA1, and these variants result in a broad spectrum of biochemical and clinical phenotypes. Here we review genetic variation in ABCA1 and its critical role in cholesterol metabolism and atherosclerosis in the general population.

ATP Binding Cassette Transporter 1↗
PubMed1994

Seasonal variations in gonadotropin responsiveness, self-priming, and desensitization to GnRH peptides in the common carp pituitary in vitro.

Seasonal variations of the GtH release response to salmon GnRH (sGnRH) and [D-Arg6,Pro9NEt]-sGnRH (sGnRH-A) were investigated in female common carp at different stages of the reproductive cycle using perifused pituitary fragments. The responsiveness to sGnRH and sGnRH-A varied seasonally in common carp pituitaries in vitro, with the greatest GtH release response in pituitaries from sexually mature (preovulatory) fish compared to pituitaries from sexually regressed fish. The magnitude of this seasonal change in the GtH release response was greater for sGnRH-A than for sGnRH, and sGnRH-A has a higher potency than sGnRH, particularly in pituitaries from sexually mature fish. Desensitization of perifused pituitary fragments to sGnRH and sGnRH-A, and a self-priming effect of sGnRH-A on the GtH release response, caused by repeated pulse administrations of the GnRH peptides, varied with the stage of reproductive cycle of the common carp. Using pituitaries from sexually regressed female common carp, desensitization occurred only when a high dose of sGnRH or sGnRH-A was given as repeated pulses at short time intervals, and no self-priming was observed by repeated administrations of sGnRH and sGnRH-A. Using pituitaries from sexually mature female common carp, desensitization occurred when a high dose of sGnRH and both high and low dosages of sGnRH-A were given as repeated pulses at short time intervals. Self-priming, largely due to the increase in basal GtH levels, occurred in response to repeated pulses of low dosages of sGnRH-A given at long intervals.

Animals↗
PubMed1975

Genetic differences between the Chinese and European races of the common carp. II. Multi-character variation-a response to the diverse methods of fish cultivation in Europe and China.

The European and Chinese races of the common carp and their F1 crossbreds were tested in five experimental environments. The two races differ widely and conspicuously in many characters. The Chinese carp has poorer growth rate but higher viability and fertility, earlier sexual maturity, higher resistance to crowding, better adaptation to unfavourable pond conditions, higher seine escapability, longer body and larger weight differences between females and males. The crossbreds between the two races are intermediate in some characters (differences in weight between females and males and seine escapability). In other characters (weight gain, specific adaptation to poor conditions and viability), the crossbreds showed dominance or even heterosis. An hypothesis was advanced to explain these genetic differences in terms of selection response to the different fish-farming practices that existed in the two regions. Specific suggestions were made for implementation of the present findings to genetic improvement of carp breeding stocks.

Animals↗
PubMed2003

No association between two polymorphisms at the 5HT2A gene and bipolar affective puerperal psychosis.

OBJECTIVE: To examine whether variation at two common polymorphisms, T102C and -1438AG, of the serotonin 2A gene (5HT2A) are involved in the puerperal triggering mechanism of bipolar affective puerperal psychosis. METHOD: A total of 242 parous women diagnosed with bipolar disorder were genotyped for the two polymorphisms. Of these, 165 women had experienced a manic or psychotic episode, according to DSM-IV criteria, within 6 weeks of childbirth (the puerperal psychosis group). The comparison group comprised of 77 parous women who had not experienced psychiatric disturbance following childbirth. RESULTS: No significant differences between genotype or allelic frequencies were found between the two groups for either polymorphism. CONCLUSION: The results indicate that variation at two common polymorphisms of the 5HT2A gene does not appear to play a major role in the development of bipolar affective puerperal psychosis.

Adult↗
PubMed1998

Use of generalized linear mixed models in analyzing mutant frequency data from the transgenic mouse assay.

The transgenic mouse assay is now widely used for the study of mutagenesis in diverse rodent tissues and to test chemicals for genotoxic potential. This kind of assay generally involves nested observations at several levels of sampling, e.g., animals, packaging reactions, and plates. Due to the common origin, the mutant frequency (MF) in tissues from the same animal are likely to be positively correlated, inducing extra variation relative to the common binomial variation. In this article, a generalized linear mixed model is used to analyze the overdispersed binomial data on mutant frequency from the transgenic mouse assay, with a random effect for each level of the sampling hierarchy. This is a comprehensive framework within which different sources of variation in the data can be evaluated in nested factorial experiments and treatment effects can be assessed simultaneously. It avoids the current practice of repeated testing for excess binomial variability at each level of the sampling hierarchy and aggregating data up the levels, but fits the data with one single model. Parameters associated with the fixed effects, particularly dose, and the variance components for the random effects (e.g., animals, packages, and plates) can be estimated and tested for significance. Data previously reported in the literature involving the lacl gene from the Big Blue mouse are used to illustrate the proposed method.

Animals↗
PubMed2002

Pharmacology and physiology of human adrenergic receptor polymorphisms.

Adrenergic receptors are expressed on virtually every cell type in the body and are the receptors for epinephrine and norepinephrine within the sympathetic nervous system. They serve critical roles in maintaining homeostasis in normal physiologic settings as well as pathologic states. These receptors are also targets for therapeutically administered agonists and antagonists. Recent studies have shown that at least seven adrenergic receptor subtypes display variation in amino acid sequence in the human population due to common genetic polymorphisms. Variations in potential regulatory domains in noncoding sequence are also present. Here, we review the consequences of these polymorphisms in terms of signaling, human physiology and disease, and response to therapy.

Base Sequence↗
PubMed1997

Variation in transformation frequencies among six common wheat cultivars through particle bombardment of scutellar tissues.

The transformation technique in common wheat has already been established by using microprojectile bombardment and scutellar tissues of immature embryos. In this study, in vitro culture response of immature embryos and the production of transgenic wheat plants were examined in six common wheat cultivars, i.e., Chinese Spring, Akadaruma, Haruhikari, Shiroganekomugi, Norin 12, and Norin 61. In all genotypes, more than seven hundred immature embryos were bombarded with a plasmid containing a bialaphos-resistant gene under control of the rice actin 1 gene. (Act1) promoter. Although the transient expression of the reporter gene encoding beta-glucuronidase following the rice Act1 promoter was similar in five of the six cultivars tested, the frequency of stable transformation varied with the genotype. The frequency of transformation was the highest in Akadaruma and Norin 12 of the six wheat cultivars; independently transformed plants were produced from 1.4% and 1.7% of bombarded embryos, respectively. On the other hand, the immature embryos of Norin 61 and Shiroganekomugi showing low efficiency of in vitro culture generated no transgenic plants. This variation of the transformation frequency was generally caused by the difference in the in vitro culture response with the genotype, rather than the efficiency of the introduction of the transgene into wheat cells by particle bombardment.

Fertility↗
PubMed1997

Ethnic variation in the prevalence of a common NAD(P)H quinone oxidoreductase polymorphism and its implications for anti-cancer chemotherapy.

The NAD(P)H quinone oxidoreductase (NQO1:EC 1.6.99.2) is an important biotransformation enzyme system that is also known to metabolize important novel chemotherapeutic compounds. The gene that codes for this enzyme has recently been found to be polymorphic in humans. Here, we describe the ethnic distribution of the polymorphism and note that this may have implications for anti-tumour drug development and use.

Antineoplastic Agents↗
PubMed1991

Changes in serum immunoglobulin patterns in adults with common variable immunodeficiency.

Striking variations of serum immunoglobulin class and IgG subclass levels were observed in five patients with common variable immunodeficiency. They occurred mainly in untreated patients or, in those patients who received substitutive therapy, could not be merely due to replacement. They result in major changes in the immunoglobulin deficiency patterns, such as a shift from profound hypoimmunoglobulinaemia to IgA/IgG2/IgG4 deficiency or to isolated IgG2 deficiency. These findings have practical implications for the diagnosis and management of patients with primary humoral immunodeficiency.

Adult↗
PubMed2003

[Genetic variation in two forms of the common spadefoot toad Pelobates fuscus (Pelobatidae, Anura, Amphibia) distinguished by genome size].

Genetic differences (presumed 23 loci) between two cryptic forms of Pelobates fuscus, differing in genome size, were examined by means of polyacrylamide-gel electrophoresis. This method allowed to discriminate between these forms. Average genetic distance (DN) between both the forms was equal to 0.311, ranging from 0.055 to 0.563. As a rule, differences within these groups were smaller (0.021-0.388). The data show obvious genetic differentiation between these two cryptic forms of P. fuscus. Differences between these forms and P. syriacus were significantly higher (in average 0.943). Genetic distances in relation to speciation and species concepts are discussed.

Animals↗
PubMed1989

Urethral pressure variations diagnosed by multiple urethral pressure transducers. A common phenomenon in women suffering from urinary incontinence.

The prevalence of urethral pressure variations (variation of urethral pressure greater than 15 cm H2O) was investigated, with the use of a data-based multitransducer catheter, in female patients suffering from urinary incontinence. Urethral pressure variations were diagnosed in 45 (63%) of 71 patients. This prevalence was greater than in previous studies, possibly for methodological reasons; the urethral pressure was simultaneously measured by five urethral microtransducers, thereby registering all variations in maximal urethral pressure. The present method also showed that urethral pressure variations were simultaneously present in different urethral sites, but that the amplitude of variation differed between the different points of registration. In most cases, urethral pressure variations were already apparent at the start of urethrocystometry. Voluntary holding, in an effort to inhibit the desire to void, can cause these variations in urethral pressure. Hence urethral pressure variations may be a normal physiological phenomenon.

Female↗