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PubMed2006

Concordance of functional in vitro data and epidemiological associations in complex disease genetics.

PURPOSE: We aimed to assess whether epidemiological evidence on genetic associations for complex diseases concord with in vitro functional data. METHODS: We examined 36 studies on bi-allelic markers and 23 studies on haplotypes where investigators had addressed both epidemiological associations and the functional effect of the same gene variants in luciferase reporter systems in vitro. RESULTS: There was no correlation between epidemiological odds ratios and luciferase activity ratios (-0.09, P = 0.60). Luciferase activity ratios could not tell whether a probed epidemiologic association would be significant or not (area under receiver operating characteristics curve, 0.52). Luciferase results usually were qualitatively similar across cell lines and experimental conditions, with some exceptions. A luciferase activity ratio of 1.44 adequately separated statistically significant from non-significant functional differences (area under receiver operating characteristics curve, 0.95). Binary and continuous disease outcomes usually gave concordant results; other in vitro methods, in particular EMSA, agreed with luciferase results. Selective reporting and use of different variants and contrasts between functional and epidemiological analyses were common in these studies. CONCLUSIONS: In vitro biological data and epidemiology provide independent lines of evidence on complex diseases. We provide suggestions for improving the design and reporting of studies addressing both in vitro and epidemiological effects.

Alleles↗
PubMed1978

Hereditary C2 deficiency associated with immune complex disease.

A patient presenting with a syndrome probably due to immune complex deposition was investigated and found to possess an inherited C2 complement deficiency. Family studies indicated that the deficiency was transmitted as an autosomal recessive trait. HLA typing for the HLA-A and HLA-B specificities and HLA-D specificities indicated a close linkage between the HLA and C2 genes, as has been described elsewhere. The HLA-A and B locus specificities HLA-AW25 and HLA-B18 were coded for by each of the two chromosomes carrying the C2(0) gene. However, the two chromosomes differed at the HLA-D locus, as one coded for HLA-DW2 whilst the other did not. This case, therefore, provides a unique haplotype and may be of importance in mapping the C2(0) locus, as it suggests that the gene order on chromosome 6 is HLA-D, C2(0), HLA-B, HLA-A. Extensive complement component assays indicated that utilization of complement in the patient was occurring via the alternate complement pathway. It is suggested that, as a result of the C2 deficiency, infections with viruses and other agents could lead to an immune complex disease due to an impaired capacity to effectively eliminate circulating complexes.

Adult↗
PubMed2002

Novel linkage mapping approach using DNA pooling in human and animal genetics. I. Detection of complex disease loci.

DNA pooling is a potential methodology for genetic loci with small effect contributing to complex diseases and quantitative traits. This is accomplished by the rapid preliminary screening of the genome for the allelic association with the most common class of polymorphic short tandem repeat markers. The methodology assumes as a common founder for the linked disease locus of interest and searches for a region of a chromosome shared between affected individuals. The general theory of DNA pooling basically relies on the observed differences in the allelic distribution between pools from affected and unaffected individuals, including a reduction in the number of alleles in the affected pool, which indicate the sharing of a chromosomal region. The power of statistic for associated linkage mapping can be determined using two recently developed strategies, firstly, by measuring the differences of allelic image patterns produced by two DNA pools of extreme character and secondly, by measuring total allele content differences by comparing between two pools containing large numbers of DNA samples. These strategies have effectively been utilized to identify the shared chromosomal regions for linkage studies and to investigate the candidate disease loci for fine structure gene mapping using allelic association. This paper outlines the utilization of DNA pooling as a potential tool to locate the complex disease loci, statistical methods for accurate estimates of allelic frequencies from DNA pools, its advantages, drawbacks and significance in associate linkage mapping using pooled DNA samples.

Animals↗
PubMedDate not supplied

Chronic immune complex disease: behavioral and immunological correlates.

Using a fear avoidance paradigm, behavioral effects were seen in Sprague-Dawley rats in which chronic immune complex disease was induced. These effects were related to changes in urine protein that developed during the course of the experiment. Experimental animals also had glomerular deposits of rat gamma globulin and BSA as determined by immunofluorescence; C3 deposits were observed in half of these animals. BSA and/or rat gamma-globulin, but not C3, was seen in the choroid plexus of half of the experimental animals. This is the first study to report behavioral changes associated with the induction of chronic immune complex disease in experimental animals.

Animals↗
PubMed2025

Genomics insight on passion fruit viral disease complexity.

Passion fruit viral diseases pose a significant threat to Kenya's passion fruit industry. To unravel the complexity of these diseases, comprehensive virus surveys were conducted across major passion fruit-growing counties. Passion fruit woodiness disease symptoms, like fruit hardening, chlorotic mottling, and leaf distortion, were prevalent. The study unveiled the first 23 complete genomes of Ugandan passiflora virus (UPV) and two East Asian passiflora distortion virus (EAPDV) in Kenya. UPV showed 99% nucleotide (nt) match to a UPV genome from Uganda and 66% nt identity match to EAPDV. In addition, UPV variants and two partial passion fruit green spot virus sequences and partial (passiflora emaravirus) segment RNA1-5 (novel allexivirus and an emaravirus, respectively) were detected. Phylogenetic analysis revealed distinct lineages (I-III), indicating potential multiple introductions into Kenya. Recombination analysis detected no significant breakpoints. However, the study proposed the renaming of EAPDV to passiflora distortion virus (PDV) and UPV to passiflora virus (PV) for neutral nomenclature, without geographical association. Additionally, the study highlighted the role of coinfections in symptom expression, suggesting a potential synergistic relationship between PV, PDV, and other viruses. The results recommend stringent management strategies and enhanced surveillance to mitigate the economic impact of these viruses on the Kenyan passion fruit industry. The findings from this study underscore the need to strengthen nursery certification programs and pest diagnostic protocols in Kenya. Additionally, enhanced pest surveillance and import regulations are critical to preventing the introduction and spread of emerging plant viral diseases, thereby safeguarding the country's horticultural productivity and biosecurity. To our knowledge, this is the first comprehensive study of viral diseases of passion fruit in Kenya.IMPORTANCEThis study presents the first comprehensive survey of viral pathogens affecting passion fruit in Kenya, identifying Ugandan passiflora virus (UPV) and East Asian passiflora distortion virus (EAPDV) as major contributors. Through genomic sequencing, 23 complete genomes of UPV and two of EAPDV were characterized, revealing a 99% nucleotide (nt) similarity between UPV strains from Uganda and Kenya, and 66% nt match with EAPDV. Phylogenetic analysis identified distinct lineages, suggesting possible multiple viral introductions in Kenya. The study also highlights potential synergistic coinfections between UPV, EAPDV, and other viruses, leading to more severe disease symptoms. In light of these findings, the study proposes renaming EAPDV as passiflora distortion virus and UPV as passiflora virus for a more neutral name classification. The research underscores the urgent need for enhanced surveillance, stringent phytosanitary measures, and improved management strategies to mitigate the threat of viral diseases, to safeguard the Kenyan passion fruit industry, and elsewhere.

Plant Diseases↗
PubMed1998

Sonographic findings in familial juvenile nephronophthisis-medullary cystic disease complex.

PURPOSE: Familial juvenile nephronophthisis-medullary cystic disease complex (JN-MCD) is an autosomal inherited renal disease with insidious symptoms that ultimately progresses to renal failure. We describe the abnormal sonographic findings in JN-MCD at various stages of the disease in a Taiwanese family. METHODS: We collected 8 cases in a family via 2 symptomatic index siblings. The affected members were 4 males and 4 females whose ages at diagnosis ranged from 1 to 39 years (mean, 16.8 years). Serial sonographic examinations were performed. RESULTS: There were 4 abnormal findings: renal hyperechogenicity, poor corticomedullary differentiation, small kidney size, and corticomedullary cysts. Renal hyperechogenicity and poor corticomedullary differentiation were found in all cases. Renal cysts and reduced renal size sometimes appeared later, after the disease had progressed. Three cases had no visualized cysts. CONCLUSIONS: Because abnormal renal sonographic findings can be seen long before the appearance of any clinical symptoms or signs, sonography is the best technique for diagnosing JN-MCD and for screening a patient's family.

Adolescent↗
PubMed2003

Clinical analysis of pulmonary Mycobacterium avium complex disease in association with corticosteroid treatment.

We studied the clinical characteristics of nine patients with pulmonary Mycobacterium avium complex disease occurring in association with corticosteroid drugs collected from our associated hospitals during the past 6 years. The average age of the nine patients was 62.2 years and the male/female ratio was 3 : 6. Regarding underlying disease, respiratory diseases existed in four of the patients and nonrespiratory diseases in the other five patients. The duration of corticosteroid treatment ranged from 5 months to 5 years, and the total dose of corticosteroid drugs ranged from 1.78 to 43.20 g. Pulmonary Mycobacterium avium complex disease was detected by clinical symptoms during corticosteroid treatment in six patients, and purified protein derivative was positive in three of eight patients tested. Radiological findings showed an infiltration shadow without cavity and bronchiectasis in the lower lung field. Microbiological examination was smear-positive in three patients, and the isolated mycobacterium was Mycobacterium intracellulare in five patients and Mycobacterium avium in four. Tolerance was shown to all antituberculous drugs, except for clarithromycin, in all patients. Although treatment including clarithromycin was performed for seven patients, the sputum conversion rate was 33% and an improved clinical effect was noted in only one patient. No change occurred in four and worsening occurred in four. Attention should be paid to the clinical symptoms and radiological findings of patients who have received corticosteroid drugs over a long period of time, because pulmonary Mycobacterium avium complex is characterized by atypical radiographic findings with no relationship to the total dose or duration of the administered corticosteroid drugs.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Genetic discoveries and nursing implications for complex disease prevention and management.

The purpose of this article is to examine the management of patients with complex diseases, in light of recent genetic discoveries, and to explore how these genetic discoveries will impact nursing practice and nursing research. The nursing science processes discussed are not comprehensive of all nursing practice but, instead, are concentrated in areas where genetics will have the greatest influence. Advances in genetic science will revolutionize our approach to patients and to health care in the prevention, diagnosis, and treatment of disease, raising many issues for nursing research and practice. As the scope of genetics expands to encompass multifactorial disease processes, a continuing reexamination of the knowledge base is required for nursing practice, with incorporation of genetic knowledge into the repertoire of every nurse, and with advanced knowledge for nurses who select specialty roles in the genetics area. This article explores the impact of this revolution on nursing science and practice as well as the opportunities for nursing science and practice to participate fully in this revolution. Because of the high proportion of the population at risk for complex diseases and because nurses are occupied every day in the prevention, assessment, treatment, and therapeutic intervention of patients with such diseases in practice and research, there is great opportunity for nurses to improve health care through the application (nursing practice) and discovery (nursing research) of genetic knowledge.

Ecology↗
PubMed1980

The induction of chronic antigen-antibody complex disease in selectively bred mice producing either high or low affinity antibody to protein antigens.

Mice selectively bred to produce either high or low affinity antibody to protein antigens were injected daily with bovine serum albumin (BSA) and studied for the development of chronic antigen-antibody complex disease. After 41-44 injections of BSA, evidence of circulating antigen-antibody complexes and renal localization of complexes was obtained in both lines. However, low affinity mice had significantly higher levels of circulating complexes than high affinity mice. Impairment of renal function was seen in low affinity mice but not in high affinity mice and there was significantly more complex deposition in the glomeruli of low compared to high affinity mice. Furthermore, the pattern of localization of complexes was predominantly mesangial in high affinity mice but in low affinity mice the deposition was both mesangial and in the glomerular basement membrane. The role of antibody affinity in the induction of chronic antigen-antibody complex disease is discussed in the light of these results.

Animals↗
PubMed2002

EYE on bioinformatics: dissecting complex disease traits in silico.

Bioinformatics has provided an unprecedented power and resource for us to decipher the enigma of complex diseases. It can reveal otherwise promiscuous information from the tremendous amount of data generated by the new, powerful and high-throughput technologies of genomics and proteomics. In this paper, we review the cutting edge developments in complex disease trait mapping, databases, computational gene recognition, gene function prediction, pathway reconstruction and disease classification by expression profiling, and computational modelling of living systems. Integration of all this knowledge and the different technologies, alongside cooperation between experts from different fields, will enhance our understanding of the molecular and mechanistic abnormalities in disease state, and greatly assist the rational development of effective therapies.

Chromosome Mapping↗
PubMed1983

Pulmonary immune effector cells in guinea pigs with immune complex disease. I. Changes in T- and B-lymphocyte populations after exposure to antigen.

Changes in immunologic effector cell populations in lung tissue, bronchoalveolar spaces, tracheobronchial lymph nodes, spleen, and peripheral blood were evaluated during the course of a pulmonary immune complex disease in guinea pigs. The number of macrophages, lymphocytes, and neutrophils present in each cell population were determined. T and B lymphocytes were identified by E and EAC rosette formation, respectively. An increase in the total number of lymphocytes in tracheobronchial lymph nodes and a greater proportion of B cells in these lymphocyte populations were observed at 12 and 24 hr postchallenge. The total number of macrophages, lymphocytes, and neutrophils recovered from the bronchoalveolar spaces also increased, as did the proportion of lymphocytes and neutrophils. A similar proportional increase of lymphocytes obtained from lung tissue also occurred. The proportion of B cells in the lymphocyte populations of the bronchoalveolar spaces and lung tissue increased to a maximum at 24-48 hr postchallenge. Cell populations from peripheral blood or spleen remained stable, by all parameters examined, during the disease process. Thus, there appears to be a localization of the immune inflammatory response in the lungs during the course of this pulmonary immune complex disease. In addition, this study provides evidence that immune effector cells obtained by bronchial lavage accurately reflect the cellular changes associated with the acute inflammatory response in lung tissue and pulmonary lymph nodes.

Animals↗
PubMed2002

[Mapping genes of complex diseases in genetic isolates of Dagestan].

Original results of the analysis of genetic linkage between some genomic markers and two complex clinical phenotypes, schizophrenia and mental retardation, in pedigrees from Dagestan genetic isolates are described. Interpopulation differences in the epidemiology of the complex phenotypes were studied and in their genetic linkage was demonstrated. These differences are evidently related to the genetic structure of the isolates determined by their genetic history. The MR epidemiological index characterizing the lifetime morbid risk of schizophrenia varies in the Dagestan isolates studied from 0 to 4.95%, which is almost five times higher than the average worldwide population rate, 1%. Comparative genetic mapping permitted determination of the most probable genetic linkages and associations of loci from chromosomal regions 17p11.1-12, 3q13.3, and a locus from 22q with schizophrenia and locus 12q23 with mental retardation. There is evidence that this approach is effective for detailed study of the relationship between the genetic (allele and locus) and clinical heterogeneity of complex diseases, which favors successful identification of the genes determining them. The study of linkage disequilibrium (LD) in genetic isolates of Daghestan populations (which have a common genetic background) may be an effective methodological approach for revealing the numerous contradictory results of mapping of the same genes of complex disease performed by different researchers in different regions of the world.

Chromosome Mapping↗
PubMed1982

Development of chronic pulmonary inflammation in immunized guinea pigs by aerosol challenge with antigen: relationship of immune complex disease and cell-mediated hypersensitivity.

Immunized guinea pigs develop immune complex disease (ICD) in the lungs after a single aerosol challenge with specific antigen. In the current study, immunized guinea pigs developed chronic pulmonary inflammation and cellular immunity (CI) in the lungs when aerosol challenged daily with specific antigen for 2 wk. When immune serum was passively transferred to normal recipients that were then aerosol challenged with specific antigen for 2 wk, chronic pulmonary inflammation and CI did not develop. These results suggest that ICD produced by passive transfer of serum and subsequent aerosol exposure to antigen was inadequate to cause chronic pulmonary inflammation and CI. The development of chronic pulmonary inflammation by aerosol challenge with antigen was suppresed with cobra venom factor. However, because of other studies, we attribute this suppression to the diminution of complement (C) factors in the alternative C pathway that affect macrophage mobility rather than to the depletion of C5a, which is important in the development of ICD.

Aerosols↗
PubMed1981

The effect of protein deficiency on the development of chronic antigen-antibody complex disease in mice.

Mice genetically selected to produce antibodies of either high or low affinity to protein antigens injected in saline were fed either a normal protein diet or a protein-deficient diet and were given daily injections of HSA for up to 73 days to induce chronic antigen-antibody complex disease. In low-affinity mice fed the normal protein diet, this resulted in impairment of renal function, deposition of immunoglobulin, C3 and HSA in the glomeruli, high levels of circulating antigen-antibody complexes and death from apparent renal failure in 50% of the animals. High-affinity mice on either diet had no impairment of renal function, fewer deposits in the glomeruli, lower levels of circulating complexes and no deaths. Low-affinity mice fed the protein-deficient diet had less impairment of renal function and less glomerular deposition of complexes than did low-affinity mice fed the normal diet. In addition, none of these mice died from renal failure. These results demonstrate that the protein-deficient diet reduced the severity of the experimental chronic antigen-antibody complex disease in low affinity mice but did not increase the susceptibility of high-affinity mice to the disease.

Animals↗
PubMed2000

Cladistic analysis: its applications in association studies of complex diseases.

INTRODUCTION: With the increase in genotype data generated by high throughput typing technologies, there is currently a lack of complexity-oriented analytical methods that can maximise the information obtained from these raw data for the study of complex diseases. We introduce the cladistic analysis that is traditionally applied in evolution studies and taxonomy, to specify relevant comparisons of traits associated with each haplotype/genotype in a population sample. METHODS: Haplotypes are determined from the genotype data and linked to each other by their evolutionary relationships to form a cladogram. This is then used to specify relevant statistical comparisons. The central assumption is that any functionally important genetic variation causing a phenotypic effect at any point in the course of evolution will be embedded in the framework of haplotypes represented by the cladogram. APPLICATIONS: There are various applications of cladistic analysis in the study of complex diseases. Basically, it helps in the identification of haplotypes that are associated with a disease state or a significantly altered level of quantitative trait. However, its limitations are that only polymorphic sites on the same DNA strand can be analysed and that recombination events must be relatively rarer than mutational events. CONCLUSIONS: In the absence of methods that can recognise the complexity of the genotype organization, and given its ability to exploit evolutionary information for optimising the analytical strategy, cladistic analysis would be a method of choice for studying multi-loci effects on a quantitative trait or disease outcome.

Genetic Variation↗
PubMed2004

Regulatory polymorphisms underlying complex disease traits.

There is growing evidence that genetic variation plays an important role in the determination of individual susceptibility to complex disease traits. In contrast to coding sequence polymorphisms, where the consequences of non-synonymous variation may be resolved at the level of the protein phenotype, defining specific functional regulatory polymorphisms has proved problematic. This has arisen for a number of reasons, including difficulties with fine mapping due to linkage disequilibrium, together with a paucity of experimental tools to resolve the effects of non-coding sequence variation on gene expression. Recent studies have shown that variation in gene expression is heritable and can be mapped as a quantitative trait. Allele-specific effects on gene expression appear relatively common, typically of modest magnitude and context specific. The role of regulatory polymorphisms in determining susceptibility to a number of complex disease traits is discussed, including variation at the VNTR of INS, encoding insulin, in type 1 diabetes and polymorphism of CTLA4, encoding cytotoxic T lymphocyte antigen, in autoimmune disease. Examples where regulatory polymorphisms have been found to play a role in mongenic traits such as factor VII deficiency are discussed, and contrasted with those polymorphisms associated with ischaemic heart disease at the same gene locus. Molecular mechanisms operating in an allele-specific manner at the level of transcription are illustrated, with examples including the role of Duffy binding protein in malaria. The difficulty of resolving specific functional regulatory variants arising from linkage disequilibrium is demonstrated using a number of examples including polymorphism of CCR5, encoding CC chemokine receptor 5, and HIV-1 infection. The importance of understanding haplotypic structure to the design and interpretation of functional assays of putative regulatory variation is highlighted, together with discussion of the strategic use of experimental tools to resolve regulatory polymorphisms at a transcriptional level. A number of examples are discussed including work on the TNF locus which demonstrate biological and experimental context specificity. Regulatory variation may also operate at other levels of control of gene expression and the modulation of splicing at PTPRC, encoding protein tyrosine phosphatase receptor-type C, and of translational efficiency at F12, encoding factor XII, are discussed.

Autoimmune Diseases↗
PubMed1999

Evidence of Pasteurella haemolytica linked immune complex disease in natural and experimental models.

The pathogenesis of bovine pneumonic pasteurellosis is not completely understood, and studies have not established that Pasteurella haemolytica A1 (Ph1) virulence is exclusively responsible for the development of acute pulmonary lesions. The purpose of this investigation was to determine if immune complex disease is involved in the pathogenesis of bovine pneumonic pasteurellosis. A retrospective immunohistologic study of lung tissue from natural cases of bovine pneumonic pasteurellosis (44) as performed, and immune complexes were observed in alveloar spaces and walls in 88% of these cases. To study this pathologic mechanism experimentally, groups of mice were immunized with purified Ph1 outer membranes (OMs) or sham immunized on days 0 and 14. Mice were challenged intratracheally on day 24 with either live Ph1 or Ph1 OMs, and pulmonary lesions were assessed 24 h after challenge. Placebo immunized mice developed focal infiltrates of neutrophils and macrophages centered around large caliber bronchi. Mice immunized with Ph1 OMs and challenged with live Ph1 or OMs developed severe bronchointerstitial pneumonia with diffuse neutrophilic infiltration, focal necrosis, hemorrhage and edema, that is histologically similar to bovine pneumonic pasteurellosis. Immunohistology revealed flocculent aggregates of IgG and complement positive material within alveolar spaces and walls from mice challenged with live Ph1, and fine granular deposits of IgG and complement positive material were observed lining the alveolar walls from mice challenged with Ph1 OMs. Immunized mice exhibited high serum IgG antibody titers to Ph1 outer membrane proteins (OMPs). Results of this study suggest that immune complex disease plays a role in the pathogenesis of bovine pneumonic pasteurellosis.

Animals↗