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Many diseases that have a substantial effect on health have a complex pathogenesis. Examples are atherosclerosis, diabetes mellitus, and rheumatoid arthritis. Here, we discuss a hierarchy of goals of research in complex diseases, and introduce a stepwise approach for the development of disease models, paying specific attention to the position of genetic factors and stochastic variables in these models.
After nearly 10 years of intense academic and commercial research effort, large genome-wide association studies for common complex diseases are now imminent. Although these conditions involve a complex relationship between genotype and phenotype, including interactions between unlinked loci, the prevailing strategies for analysis of such studies focus on the locus-by-locus paradigm. Here we consider analytical methods that explicitly look for statistical interactions between loci. We show first that they are computationally feasible, even for studies of hundreds of thousands of loci, and second that even with a conservative correction for multiple testing, they can be more powerful than traditional analyses under a range of models for interlocus interactions. We also show that plausible variations across populations in allele frequencies among interacting loci can markedly affect the power to detect their marginal effects, which may account in part for the well-known difficulties in replicating association results. These results suggest that searching for interactions among genetic loci can be fruitfully incorporated into analysis strategies for genome-wide association studies.
Two lines of mice selectively bred for producing high and low affinity antibody to protein antigens were repeatedly injected with human serum albumin and the severity and pattern of immune complex disease induced in this way was studied in the two lines. In low affinity mice, there was a greater intensity of deposits in the glomeruli shown by immunofluorescence, and more antibody was eluted from kidney homogenates compared to high affinity line mice. In the low affinity mice, complexes were mainly on the basement membrane whereas in high affinity mice, the localization of immune complexes was predominantly mesangial. However, no significant difference in glomerular filtration rates between the two lines was obtained. The immunopathological significance of antibody affinity is discussed in the light of these results.
We compared the performance of six complement tests: electrophoresis, immunofixation, immunoelectrophoresis, and nephelometric quantifications of C3, C4, and C3d. We used 123 blood samples from 60 control subjects and 63 patients with immune complex diseases: systemic lupus erythematosus, idiopathic thrombocytopenic purpura, rheumatoid arthritis, acquired immunodeficiency syndrome, renal diseases, vasculitis, cryoglobulinemia, Gram-negative bacteremia, Hashimoto's thyroiditis, rheumatic heart disease, malaria, and chronic active hepatitis. Immunofixation and quantification of C3d were better for detecting complement activation, their sensitivity rates (90.5% and 89.3%, respectively) being higher than those of the other tests studied. Immunofixation is a relatively simple and inexpensive test, provides good resolution of protein bands, and yields results that are easily quantified with a densitometer. Nephelometry of C3d provides more rapid and accurate quantitative results than immunofixation, but commercial reagents are not yet available. The causes of false-positive results in complement tests and the mechanisms of complement activation in AIDS are also discussed.
The sequence of events in the relationship between membranous nephropathy and renal vein thrombosis is controversial. We postulate that occasionally, the thrombosis may precede the nephropathy and that release of autologous antigens from renal tissue damaged by occlusion of the vein may incite an autologous immune-complex disease. In a case of membranous nephropathy associated with renal vein thrombosis, renal tubular epithelial antigen (RTE) was localized in the glomerulus, along with the host immunoglobulins and complement components. Cryoproteins isolated from the serum contained RTE and anti-RTE. In addition, immunoglobulin eluted from the diseased glomeruli showed antibody activity to RTE. The membranous nephropathy was demonstrated to be secondary to an autologous immune-complex nephritis. Although the sequence of events is inconclusive, it is possible that the renal vein thrombosis preceded and was involved in the etiopathogenesis of the autologous immune-deposit nephropathy.
The complexity of RA challenges our search for a better understanding of the interconnected networks. Early treatment will certainly avoid some of the problems presented by the complexity of the disease, and combined treatments seem advantageous for advanced disease. The complexity of overt RA will probably not allow a single agent to exert superior efficacy. Unless a treatable infectious cause is identified, a magic bullet, though theoretically possible, might not exist in reality, in particular if the disease is advanced.
An investigation was carried out into an outbreak of respiratory disease complex (RDC) in 3641 Menz and Awassi x Menz cross sheep in Central Ethiopia between 1998 and 1999 by clinical, serological, microbiological, post-mortem and histopathological examinations. The monthly incidence of RDC varied from 2.8% to 4.0% and the prevalence was as high as 17%. The case fatality rate was 18%, despite culling of sick sheep. Over 76% of the morbidity occurred in adults, followed by 19% among weaners. Similarly, 62% of the mortality was in adults. However, 27% of the mortality occurred in lambs despite the low morbidity in the group. Significant breed and age differences were seen in the morbidity and mortality rates (p < 0.05). Clinical signs, gross and microscopic lesions and serological and bacteriological examinations showed an interplay of several causes of the RDC, including pestes des petits ruminants (PPR) (72.3%, serologically confirmed), lung worms, maedi-visna, bacterial bronchopneumonia (staphylococcal and streptococcal), enzootic pneumonia and some fungal infections. Cold temperatures, which may be as low as -8.5 degrees C at night, are major predisposing factors along with managemental stresses. Vaccination of animals with a homologous PPR vaccine appeared to decrease dramatically the occurrence of the disease, showing that PPR played an important role in the outbreak. Several of the pathogens do not appear to be individually capable of causing the respiratory disease. Appropriate strategies for the prevention of RDC are suggested.
Anti-neutrophil cytoplasm antibodies (ANCA) with specificity for myeloperoxidase (MPO) occur in the sera of patients with microscopic angiitis, an autoimmune disease characterized by necrotizing vasculitis and crescentic glomerulonephritis. These autoantibodies have been shown to stimulate neutrophil degranulation and are believed to participate in pathogenesis. A neutrophilic vasculitis has been reported in MRL-lpr mice which has histological appearances similar to microscopic angiitis. In the present study we show that 22% of female MRL-lpr mice develop MPO autoantibodies. These animals develop a clinical syndrome of vasculitis and glomerulonephritis that is distinct from immune complex disease. Anti-MPO monoclonal antibodies derived from these mice are polyreactive and react with double-stranded DNA. They bind a conformational epitope on human MPO which is also expressed by activated human neutrophils. The results suggest that a subset of MRL-lpr mice develop ANCA-related vasculitis rather than systemic lupus erythematosus and may be used as a model for human microscopic angiitis.
The application of genetic mapping to human disease gene identification has led to the definition of many linkages and a few disease genes in complex traits over the past two years. Its application has also increased to include aspects of pharmacogenetics relating to pharmacokinetics and pharmacodynamics.
The understanding of complex diseases and insights to improve their medical management may be achieved through the deduction of how specific haplotypes may play a joint effect to change relative risk information. In this paper we describe an ascertainment adjusted likelihood-based method to estimate haplotype relative risks using pooled family data coming from association and/or linkage studies that were used to identify specific haplotypes. Haplotype-based analysis tends to require a large amount of parameters to capture all the information that leads to efficiency problems. An adaptation of the Stochastic Expectation Maximization algorithm is used for haplotypes inference from genotypic data and to reduce the number of nuisance parameters for risk estimation. Using different simulations, we show that this method provides unbiased relative risk estimates even in case of departure from Hardy-Weinberg equilibrium.
Thrombotic thrombocytopenic purpura is an acute, rare disorder with a poor prognosis, though the survival rate has improved dramatically in the past 20 years. It is a complex disease characterized by thrombocytopenia, hemolytic anemia, fluctuating neurologic symptoms, fever, and renal dysfunction. The incidence of thrombotic thrombocytopenic purpura appears to be increasing in frequency, with women affected twice as often as men. The median age of onset is in the fourth decade of life. The clinical manifestations of thrombotic thrombocytopenic purpura are caused by widespread deposition of platelet microthrombi that occlude the capillaries and arterioles, especially evident in the brain, kidney, and bone marrow. The resulting intravascular platelet consumption is responsible for bleeding and petechiae. The etiology is unknown, but may be caused by immune system mediated damage to the endothelium. The complexity of this disease challenges the health care team and demands highly skilled medical and nursing management. This article presents a summary of the history and pathophysiology of the disease, clinical course with case study, medical treatment, nursing diagnoses and interventions, and conclusions.
Mycobacterium avium complex (MAC) organisms cause disseminated disease in patients with AIDS. The organisms penetrate the gastrointestinal mucosa by unknown mechanisms and are phagocytosed by macrophages in the lamina propria. These cells cannot kill the organisms, and MAC spreads through the submucosal tissue. Lymphatic drainage transports mycobacteria to abdominal lymph nodes, from which the organisms enter the bloodstream. Hematogenous spread can occur to many sites, but spleen, bone marrow, and liver are the most common. Tissue destruction is rare, and most signs and symptoms of MAC disease are due to elaboration of cytokines. MAC is rarely the direct cause of death but increases the risk for superinfection; death may result from malnutrition or other infections.
Risk of Mycobacterium avium complex disease was examined in human immunodeficiency virus (HIV)-infected patients with and without a history of tuberculosis. Information was obtained by retrospective review of charts of patients in HIV clinics in 10 US cities. Among 1363 patients with <200 CD4 cells/mm3 seen at Grady Memorial Hospital (GMH), 11 (17%) of 66 with a history of a positive purified protein derivative (PPD) skin test acquired M. avium infection, while 29 (16%) of 185 who were PPD-negative (but not anergic) did not (P = .85). Only 4 (8%) of 49 GMH patients with a history of tuberculosis acquired M. avium infection compared with 252 (19%) of 1314 GMH patients without a history of tuberculosis (P = .05). Proportional hazards analysis of risk factors for M. avium infection among 441 persons with and 8702 persons without a history of tuberculosis in 9 other cities confirmed protection from M. avium infection in persons with a history of tuberculosis (relative risk, 0.52; 95% confidence interval, 0.36-0.76; P < .001). Prior tuberculosis provides protection against M. avium infection in HIV-infected persons, possibly by stimulation of antimycobacterial immunity.
Recent linkage findings for psychiatric disorders, in particular schizophrenia, manic-depression, and Alzheimer disease, have raised a number of important conceptual issues regarding the genetic etiology of these diseases, as well as the appropriate interpretation of linkage results in studying complex diseases. Perspectives on mode of inheritance, genetic heterogeneity, and phenotypic variation are given.
Affinity (KR) of antibody to human serum transferrin in New Zealand mice was measured by a globulin precipitation technique. KR was low in mice immunized early in life, increased with age of immunization up to 16-26 weeks, and then fell to low levels. KR in young and old NZB mice was increased by immunization with antigen in Freund's complete adjuvant. The correlation between low affinity antibody production and susceptibility to immune complex disease is discussed.
Although current methods in genetic epidemiology have been extremely successful in identifying genetic loci responsible for Mendelian traits, most common diseases do not follow simple Mendelian modes of inheritance. It is important to consider how our current methodologies function in the realm of complex diseases. The aim of this study was to determine the ability of conventional association methods to fine map a locus of interest. Six study populations were selected from 10 replicates (New York) from the Genetic Analysis Workshop 14 simulated dataset and analyzed for association between the disease trait and locus D2. Genotypes from 45 single-nucleotide polymorphisms in the telomeric region of chromosome 3 were analyzed by Pearson's chi-square tests for independence to test for association with the disease trait of interest. A significant association was detected within the region; however, it was found 3 cM from the documented location of the D2 disease locus. This result was most likely due to the method used for data simulation. In general, this study showed that conventional case-control association methods could detect disease loci responsible for the development of complex traits.
In the present study we have estimated the serum levels of early, middle, and distal complement components, e.g., Clq, C3, C4, C5, C8, and C9 along with C1-inactivator and CH50 in patients with tuberculoid and lepromatous leprosy and have compared these results with the levels in healthy subjects as well as with levels in patients with other immune complex diseases. We have also analyzed the cryoglobulins present in the sera of these patients; they consisted of either a single or mixed IgG, IgA, IgM or fibrinogen in most instances. The component C3 was found in only one sample. It appears that unlike lupus nephritis, in which complement is activated by direct path in which complement is activated by direct path in about 30% to 50% of leprosy patients, significant C3 complement consumption takes place primarily via the alternate pathway and is probably initiated by the aggregated immunoglobulins represented in cryoprecipitates. This is further supported by the study of serum factor B and its breakdown product (Ba) in these patients. The question of the role of the middle and distal complement components, such as C5, C8 and C9, during total hemolytic complement and C3 consumption in leprosy remains unanswered.
A two-stage linkage strategy was employed to identify major genes for a simulated complex disease via a genome scan. The importance of several approaches for improving the ability to locate major genes has been illustrated. These approaches are: adjusting for covariates, ascertaining through multiple affected family members, increasing the sample size, and using multipoint linkage analysis.