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PubMed2006

[PPARgamma variants and complex diseases].

Peroxisome proliferator-activated receptor gamma is a member of the nuclear hormone receptor superfamily. Mainly expressed in adipose tissue, PPARgamma promotes the differentiation of adipocytes and modulates the expression of many genes involved in the synthesis of adipocytokines in the adipose tissue. It is also the target molecule of the thiazolidinediones. Polymorphisms of the PPARgamma gene may influence pancreatic beta-cell function and result in changes in insulin secretion and insulin sensitivity of the peripheral tissues. They are also associated with risks of type 2 diabetes, obesity, cardiovascular diseases and cancer. Elucidation of its mechanism could be of major importance to the diagnosis, prevention and treatment of complex diseases.

Animals↗
PubMed2004

Mining OMIM for insight into complex diseases.

Understanding clinical phenotypes through their corresponding genotypes is one of the principal goals of genetic research. Though achieving this goal is relatively simple with single gene syndromes, more complex diseases often consist of varied clinical phenotypes that may be the result of interactions among multiple genetic loci. Microarray technology has brought the phenotype -genotype relationship to the molecular level, using differently behaving cancers, for example, as the basis for comparing patterns of gene expression. With this feasibility study, we attempted to use similar methods of analysis at the clinical level, in order to evaluate our hypothesis that the clustering of clinical phenotypes would provide information that would be useful in elucidating their underlying genotypes. Because of its breadth of content and detailed descriptions, we used OMIM as our source material for phenotypic and genetic information. After processing the source material, we then performed self-organizing map and hierarchical clustering analysis on representative diseases by phenotypic category. Through pre-determined queries over this analysis, we made two findings of potential clinical significance, one concerning diabetes and another concerning progressive neurologic diseases. Our methods provide a formal approach to analyzing phenotypes among diverse diseases, and may help indicate fruitful areas for further research into their underlying genetic causes.

Cluster Analysis↗
PubMed2003

Association mapping of complex diseases in linked regions: estimation of genetic effects and feasibility of testing rare variants.

Association mapping in linked regions is a current major approach for the identification of genes for complex diseases. Loci contributing to linkage, even with small values of sibling recurrence risk (lambda(s)), may be equivalent to substantial underlying genetic effects for association studies. For disease alleles with a frequency as low as 1%, highly reliable association studies (80% power for significance level alpha=10(-6)) require only 277, 781, and 1289 families or cases and controls for loci detected with lambda(s) of 1.5, 1.1, and 1.05, respectively, under a multiplicative genetic model. Under alternative models, provided epistatic effects are minor, larger achievable sample sizes will provide sufficient power to map almost any disease gene that may have initially contributed to linkage.

Bias↗
PubMed2006

Direct or indirect association in a complex disease: the role of SLC22A4 and SLC22A5 functional variants in Crohn disease.

A common haplotype spanning 250 kb on chromosome 5q31 is strongly associated with Crohn disease (CD). Recently, two functional variants within the SLC22A4 and SLC22A5 genes at this locus (IBD5), L503F (c.1507C > T) and G-207C (c.-207G > C), have been proposed to contribute directly to susceptibility to CD. However, extensive linkage disequilibrium at the IBD5 locus has complicated efforts to distinguish causal variants from association of the general risk haplotype. We genotyped the SLC22A4 and SLC22A5 variants and other polymorphisms across the risk haplotype in four populations of European origin, and applied regression-based haplotype analysis to over 1,200 fully genotyped case-control pairs, modeling case/control status on the presence of one or more SNPs to test for conditional association and to identify risk haplotypes. We found highly significant association of SNPs at the IBD5 locus with Crohn disease in all populations tested. However, the frequencies of L503F and G-207C in individuals who did not carry the general IBD5 risk haplotype were not significantly different in cases and controls, with associated disease odds ratios (ORs) of 0.90 (95% CI, 0.57-1.40) and 0.90 (95% CI, 0.65-1.23), respectively. Haplotype analysis showed that addition of the SLC22A4 and SLC22A5 variants to a null model that included the background risk haplotype did not significantly improve the model fit. In addition to the common risk haplotype, several rare haplotypes had an increased frequency in cases compared to controls. This study suggests that the molecular basis for Crohn disease susceptibility at the IBD5 locus remains to be defined, and highlights the challenge of the identification of causal variants in a complex disease in regions of extensive linkage disequilibrium.

Case-Control Studies↗
PubMed1999

Genetic linkage analysis of simulated complex disease data.

The purpose of this analysis was to apply current analytic methods to a simulated data set with a recognized genetic model in order to identify the loci that affect a complex disease, detect evidence for the interaction among two of the loci, and detect the gene-environment interaction. The following analytic tools were used: two multipoint linkage analysis programs, a stratification strategy based on the results of the multipoint analysis, and a case-control analysis using discordant sib pair data. The results were consistent with the underlying genetic model: a disease due to a major gene on chromosome 3 associated with an environmental risk factor, and two minor interacting loci on chromosomes 1 and 5.

Case-Control Studies↗
PubMed2004

'Racial' differences in genetic effects for complex diseases.

'Racial' differences are frequently debated in clinical, epidemiological and molecular research and beyond. In particular, there is considerable controversy regarding the existence and importance of 'racial' differences in genetic effects for complex diseases influenced by a large number of genes. An important question is whether ancestry influences the impact of each gene variant on the disease risk. Here, we addressed this question by examining the genetic effects for 43 validated gene-disease associations across 697 study populations of various descents. The frequencies of the genetic marker of interest in the control populations often (58%) showed large heterogeneity (statistical variability) between 'races'. Conversely, we saw large heterogeneity in the genetic effects (odds ratios) between 'races' in only 14% of cases. Genetic markers for proposed gene-disease associations vary in frequency across populations, but their biological impact on the risk for common diseases may usually be consistent across traditional 'racial' boundaries.

Gene Frequency↗
PubMed2005

Animal models of complex diseases: an initial strategy.

We speculated that the rise in atmospheric oxygen from 2 billion years ago was so integral for the evolution of biocomplexity that it must also associate strongly with complex diseases. As a remote test of this idea, we hypothesized that lines contrasting for disease and health would emerge from artificial selection for low and high aerobic treadmill running capacity. Eleven generations of selection in rats produced lines that differed by 347% in running capacity. The low line demonstrated health risk factors including higher visceral adiposity, blood pressure, insulin, and triglycerides. The high line was superior for VO2max, economy of running, heart function, and nitric oxide-induced vascular dilation.

Adipose Tissue↗
PubMed1996

The satellite RNAs associated with the groundnut rosette disease complex and pea enation mosaic virus: sequence similarities and ability of each other's helper virus to support their replication.

Pea enation mosaic virus (PEMV) and the causal agents of groundnut rosette disease are diverse examples of disease complexes involving two RNA species, one of which is related to the genomes of luteoviruses and the other to those of umbraviruses. In both complexes, these viral RNA components may be supplemented with satellite RNAs that are dependent on the umbravirus component for replication and systemic movement, and on the luteovirus component for encapsidation and vector transmission. Sequence analysis identified regions of similarity between the satellites of groundnut rosette virus (GRV) and PEMV, particularly at the 5' and 3' termini and around duplicate sequence repeats present in each satellite RNA. The umbravirus GRV and the umbravirus-like PEMV RNA-2 were each able to support the replication and systemic spread of homologous and heterologous satellites. The presence of the PEMV satellite in infections with GRV had no effect on symptom expression in Nicotiana spp. or in Arachis hypogaea. Likewise, in Pisum sativum, the GRV satellite had no effect on the symptoms induced by PEMV. However, the intense yellow blotch symptoms induced in Nicotiana benthamiana by the YB3 GRV satellite in conjunction with GRV were also manifested when PEMV was the helper. Although PEMV RNA-1 was capable of supporting the encapsidation and aphid transmission of the GRV satellite, no evidence was obtained that the essential role of the GRV satellite in the aphid transmission of GRV could be supplied by the PEMV satellite. These data further strengthen the hypothesis of an evolutionary relationship between PEMV and the luteovirus-umbravirus complexes.

Animals↗
PubMed2003

Genetic variation and hematology: single-nucleotide polymorphisms, haplotypes, and complex disease.

In the course of generating a draft sequence of the human genome, we now recognize the enormous scope of genetic variation among humans, which can be used to probe the genetics of complex diseases such as leukemia or thrombosis. There is already mounting evidence of new susceptibility genes and genes that interact with environmental factors. Genetic variants, especially single-nucleotide polymorphisms (SNPs), also can be utilized to investigate potential modifiers of disease. Genetic variation can be applied to study pharmacogenomics, which could eventually drive the choice of therapeutic and interventional strategies. The genomic revolution ultimately should give insights into key mechanisms in hematological disorders that can be translated into targeted therapies.

Genetic Predisposition to Disease↗
PubMedDate not supplied

The relationship between frontal sinus drainage and osteomeatal complex disease: a CT study in 217 patients.

Over a period of 2 years we reviewed the CT scans of 217 patients with recurrent sinusitis. Our findings revealed a number of cases of osteomeatal complex disease with no frontal sinus involvement. This result is difficult to reconcile with the concept of a common drainage in the middle meatus shared by the frontal and anterior ethmoid sinuses. We conclude that the frontal sinus drains separately from the other paranasal sinuses in a large percentage of cases, and that the frontal sinus is frequently spared when there is ethmoid or maxillary sinusitis.

Frontal Sinus↗
PubMed1998

Allele frequency distributions in pooled DNA samples: applications to mapping complex disease genes.

Genetic studies of complex hereditary disorders require for their mapping the determination of genotypes at several hundred polymorphic loci in several hundred families. Because only a minority of markers are expected to show linkage and association in family data, a simple screen of genetic markers to identify those showing linkage in pooled DNA samples can greatly facilitate gene identification. All studies involving pooled DNA samples require the comparison of allele frequencies in appropriate family samples and subsamples. We have tested the accuracy of allele frequency estimates, in various DNA samples, by pooling DNA from multiple individuals prior to PCR amplification. We have used the ABI 377 automated DNA sequencer and GENESCAN software for quantifying total amplification using a 5' fluorescently labeled forward PCR primer and relative peak heights to estimate allele frequencies in pooled DNA samples. In these studies, we have genotyped 11 microsatellite markers in two separate DNA pools, and an additional four markers in a third DNA pool, and compared the estimated allele frequencies with those determined by direct genotyping. In addition, we have evaluated whether pooled DNA samples can be used to accurately assess allele frequencies on transmitted and untransmitted chromosomes, in a collection of families for fine-structure gene mapping using allelic association. Our studies show that accurate, quantitative data on allele frequencies, suitable for identifying markers for complex disorders, can be identified from pooled DNA samples. This approach, being independent of the number of samples comprising a pool, promises to drastically reduce the labor and cost of genotyping in the initial identification of disease loci. Additional applications of DNA pooling are discussed. These developments suggest that new statistical methods for analyzing pooled DNA data are required.

Alleles↗
PubMed1983

Mass medication in reducing shipping fever-bovine respiratory disease complex in highly stressed calves.

One thousand and eighty-five newly received, stressed calves were used in studies to determine the effectiveness of certain mass medication procedures for reducing morbidity from shipping fever-bovine respiratory disease complex. In two experiments, im injections of oxytetracycline at 11 mg/kg body wt for 3 successive days reduced treatment days/calf purchased 21 (P less then .05) and 31% (P less than .05). Oral administration of 150 mg of sulfadimethoxine/kg body wt reduced treatment days/calf purchased 20 (P less than .05) and 54% (P less than .05) in the same two experiments. When sulfadimethoxine followed oxytetracycline on the third injection day an 81% reduction in treatment days/calf purchased was obtained, indicating an additive effect of the two drugs. The use of long acting oxytetracycline and sustained release sulfadimethoxine at the time of processing resulted in a 90% reduction in treatment days/calf purchased (P less than .01) and required only one handling of the calves for mass medication purposes.

Animals↗
PubMed2005

Multi-locus penetrance variance analysis method for association study in complex diseases.

Common heritable diseases often result from the action of several different genes, each of which contributes to the total observed variability in the disease trait. Traditional single-locus association approaches rely heavily on the marginal effects of single-locus and tend to ignore the multigenic nature of complex diseases. The increasing request for localizing genes underlying traits in multi-gene diseases has led to the development of some statistical methods. In this study, we develop a multi-locus analysis method - multi-locus penetrance variance analysis (MPVA), and conduct systematical simulation studies to evaluate its performance. Our results show that compared with other multi-locus methods, MPVA has some advantage in detecting complicated interactions under different epistatic models, and its performance is stable and robust.

Analysis of Variance↗
PubMed1986

Immune thrombocytopenic purpura: autoimmune or immune complex disease?

To assess the pathogenic role of circulating immune complexes (CIC) in idiopathic thrombocytopenic purpura (ITP), 39 patients with ITP were compared to 17 patients with other forms of thrombocytopenia (hypersplenism (N = 12), impaired thrombopoiesis (3), thrombocytopenia of unknown origin (2)) and six nonthrombocytopenic subjects. In all patients, platelet mean life span (MLS), platelet associated IgG (PAIgG), as well as circulating anti-platelet antibodies and C1q binding activities were determined. In most cases, immune complex solubilization capacity (ICSC) and immune complex precipitation inhibition capacity (ICPIC) of sera were also assessed. All patients with ITP had a reduced platelet MLS, but PAIgG was elevated in only 16 out of 24 patients with chronic ITP, in six out of 10 patients with acute ITP and in four out of five patients with secondary ITP. In the group of patients with thrombocytopenia due to splenomegaly, seven out of 12 patients had elevated PAIgG while the platelet MLS was only slightly reduced. Of the 39 patients with ITP only one with secondary ITP had C1q binding material in his serum, as opposed to six out of 12 thrombocytopenic patients with splenomegaly. Whereas only three patients with ITP had abnormal immune-complex modulating capacities, such deviations were found in seven out of 12 patients with thrombocytopenia due to splenomegaly. We conclude that our data render the role of CIC in the pathogenesis of ITP very questionable.

Adolescent↗