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PubMed2005

Will investments in large-scale prospective cohorts and biobanks limit our ability to discover weaker, less common genetic and environmental contributors to complex diseases?

Increasing the size of prospective cohorts and biobanks is one approach to discovering previously unknown contributors to complex diseases, but it may come at the price of concealing contributors that are less common across all the participants in those larger studies and of limiting hypothesis generation. Prospective cohorts and biobanks constitute significant, long-term investments in research infrastructure that will have ongoing consequences for opportunities in biomedical research for the foreseeable future. Thus, it is important to think about how these major additions to research infrastructure can be designed to be more productive in generating hypotheses for novel environmental contributors to complex diseases and to help identify genetic and environmental contributors that may not be common across the larger samples but are more frequent within local or ancestral subsets. Incorporating open-ended inquiries and qualitative information about local communal and ecologic contexts and the political, economic, and other social structures that affect health status and outcome will enable qualitative hypothesis generation in those localized contexts, as well as the collection of more detailed genealogic and family health history information that may be useful in designing future studies. Using communities as building blocks for larger cohorts and biobanks presents some practical and ethical challenges but also enhances opportunities for interdisciplinary, multilevel investigations of the multifactorial contributors to complex diseases.

Disease↗
PubMed2002

Fine mapping of the IBD1 locus did not identify Crohn disease-associated NOD2 variants: implications for complex disease genetics.

Crohn disease (CD) is a chronic relapsing inflammatory condition of the gastrointestinal tract. Recently, polymorphisms in NOD2 (CARD15), a gene mapping to the chromosome 16 IBD1 susceptibility locus, have been associated with susceptibility to CD. One group identified the gene by using classic positional cloning methods. Here, we report linkage and fine mapping analyses using 27 microsatellite markers encompassing the IBD1 susceptibility locus in 131 CD affected sibling pairs, and a simplex family cohort. No evidence for linkage was observed, and microsatellite markers close to NOD2 did not show association. However, significant association was confirmed in 294 CD trios for the NOD2 variants Arg702Trp and Leu1007fsinsC. Our fine mapping study of the IBD1 locus did not enable us to identify NOD2 as a CD gene, despite the presence of association with disease-causing alleles. This study illustrates the difficulties facing microsatellite linkage and linkage disequilibrium mapping methods for identifying disease genes in complex traits.

Carrier Proteins↗
PubMedDate not supplied

Gaucher disease: complexity in a "simple" disorder.

Gaucher disease, the recessively inherited deficiency of the enzyme glucocerebrosidase and the most common sphingolipidosis, has both non-neurological and neuronopathic forms and a continuum of diverse clinical manifestations. Studies of genotype-phenotype correlations reveal significant genotypic heterogeneity among clinically similar patients, and vastly different phenotypes among patients with the same mutations. The region surrounding the glucocerebrosidase gene (GBA) on chromosome 1q is particularly gene-rich, with a highly homologous pseudogene sequence 16 kb downstream. Recombination events within the GBA locus contribute to the etiology of some mutations in Gaucher disease. Studies of patients with Gaucher disease and atypical manifestations, including parkinsonism, myoclonic epilepsy, cardiac involvement and collodion skin, seek to define other genetic or environmental factors contributing to the phenotypes. Recent reports demonstrating an association between Gaucher disease and parkinsonism provide an example of heterozygosity for a Mendelian disorder acting as a risk factor for a complex disease. There are rare patients with Gaucher disease and differing genotypes who develop early onset, treatment-refractory parkinsonism. Neuropathology in a group of these patients showed alpha-synuclein-reactive Lewy bodies in brain regions specifically associated with Gaucher disease. Family studies of these probands suggested that the incidence of parkinsonism might be more frequent in obligate heterozygotes. In a complementary finding, the examination of GBA in autopsy samples from individuals with sporadic Parkinson disease identified alterations in the GBA sequence in 14% of the cohort. These studies provide evidence that altered glucocerebrosidase may contribute to a vulnerability to parkinsonism. Moreover, this research demonstrates how insights from rare, single gene disorders like Gaucher disease can provide a window into the etiology of more common, multifactorial genetic diseases.

Animals↗
PubMed1979

Soluble immune complex disease associated with antigen heterogeneity an HLA related disorder.

It is suggested that soluble immune complex diseases arising after infections may result from the liberation of partially synthesized bacterial polypeptide or viral nucleic acid antigens. These disrupted antigens will have heterogeneous molecular weights due to antigenic material which is incomplete as a result of premature termination of synthesis. Antigens of this type have been shown to result in significant soluble complex formation in vitro when reacted with antisera from many individuals. Interestingly, this was demonstrated using an antigen which has been instrumental in defining, in the mouse, immune response genes. These genes are known to be linked to genes which code for lymphocyte antigens. If particular immune response genes are linked to HLA types in humans, as is thought to be the case, there may be a large number of soluble immune complex diseases caused by infectious agents which may be HLA type associated.

Antigen-Antibody Complex↗
PubMed2005

Impact of genetic testing on complex diseases.

OBJECTIVE: Wide applications for genetic testing in the clinical care of complex diseases have been discussed. However, it has never been quantified to what extent genetic testing could eventually be useful in the clinical care of common disorders. We aimed to quantify the theoretically possible utilization in common ischemic stroke, an example of a complex disease. METHODS: We computed the possible impact of genetic testing on risk assessment, secondary prevention and prognosis of ischemic stroke. This was done for hypothetical genotypes with different frequencies and effects. RESULTS: To apply pharmacogenetic secondary prevention based on a genotype with a frequency of 10% and 33% risk reduction, 204 subjects would have to be screened and 110 given genotype specific treatment for 1 year, in order to prevent one recurrent stroke, compared with standard therapy. The application of genetic testing seems to be less promising in risk assessment and the assessment of prognosis of common ischemic stroke. CONCLUSIONS: The highest impact of genetic testing on clinical practice of stroke will be in the areas of secondary prevention. Given the weak effects of reported susceptibility genotypes, it is theoretically unlikely that genetic screening will be used for the assessment of risk or prognosis of a complex disorder, except for Mendelian types of disease.

Aged↗
PubMed1996

The geneticist's approach to complex disease.

Many studies are in progress worldwide to elucidate the genetics of complex diseases. Nevertheless, few articles are available that provide the scientific rationale and give guidelines for such ambitious endeavours. We describe the methodology and background necessary to study the genetics of complex disease and discuss how to analyze the data. We also provide a table of some ongoing studies. In particular, we wish to emphasize the analysis of intermediate, heritable, quantitative traits as a means of dissecting the genetic basis of a complex trait.

Animals↗
PubMed1982

Experimental antigen-antibody complex disease in mice. The role of antibody levels, antibody affinity and circulating antigen-antibody complexes.

Chronic antigen-antibody complex disease (A-ACD) was induced in mice by daily injections of HSA. The disease was characterized by death, intense glomerular basement membrane deposition of complexes in the kidneys, proteinuria and an impairment of the glomerular filtration rate. In mice that had been selectively bred to produce antibody of low affinity to protein antigens injected in saline, the incidence of chronic A-ACD was 61% compared to 21% in mice selectively bred to produce antibody of high affinity. Low affinity female mice produced approximately ten times as much free antibody to HSA as did low affinity males and high affinity males and females, but this did not result in an increase incidence of chronic A-ACD in low affinity female mice. Low affinity female mice also had the highest levels of circulating antigen-antibody complexes detected by conglutinin and Clq binding assays, but there was no correlation between the presence of high levels of complexes in serum and tissue damage. In both lines of mice the mean affinity of free antibody to HSA started low and increased with time and the number of injections of antigen. However, development of chronic A-ACD in individual low affinity mice appeared to be associated with a failure to produce this time-associated increase in antibody affinity. These results are discussed with reference to the relevance of the measurement of the amount of affinity of free antibody in serum and the levels of circulating antigen-antibody complexes to the production of tissue damage in this model of chronic A-ACD.

Animals↗
PubMed1992

The Seventh K Prathap Memorial Lecture. The pathogenesis of autoimmune immune complex disease.

It has been proposed that autoimmune immune complex disease, of which SLE is the type example, is caused essentially by a failure to properly metabolise immune complexes and that this allows the establishment of feedback cycles which cause more immune complexes to be formed. The essential genetic predisposition to this disease is complement deficiency of the components of the early classical pathway and some degree of genetic complement deficiency, particularly of C4a, is found in more than half the patients. It seems likely that acquired complement deficiencies, possibly present at the time of initiation of the disease, may be important in many of the other cases.

Autoimmune Diseases↗
PubMed2005

The importance of modelling heterogeneity in complex disease: application to NIMH Schizophrenia Genetics Initiative data.

As for other complex diseases, linkage analyses of schizophrenia (SZ) have produced evidence for numerous chromosomal regions, with inconsistent results reported across studies. The presence of locus heterogeneity appears likely and may reduce the power of linkage analyses if homogeneity is assumed. In addition, when multiple heterogeneous datasets are pooled, inter-sample variation in the proportion of linked families (alpha) may diminish the power of the pooled sample to detect susceptibility loci, in spite of the larger sample size obtained. We compare the significance of linkage findings obtained using allele-sharing LOD scores (LOD(exp))-which assume homogeneity-and heterogeneity LOD scores (HLOD) in European American and African American NIMH SZ families. We also pool these two samples and evaluate the relative power of the LOD(exp) and two different heterogeneity statistics. One of these (HLOD-P) estimates the heterogeneity parameter alpha only in aggregate data, while the second (HLOD-S) determines alpha separately for each sample. In separate and combined data, we show consistently improved performance of HLOD scores over LOD(exp). Notably, genome-wide significant evidence for linkage is obtained at chromosome 10p in the European American sample using a recessive HLOD score. When the two samples are combined, linkage at the 10p locus also achieves genome-wide significance under HLOD-S, but not HLOD-P. Using HLOD-S, improved evidence for linkage was also obtained for a previously reported region on chromosome 15q. In linkage analyses of complex disease, power may be maximised by routinely modelling locus heterogeneity within individual datasets, even when multiple datasets are combined to form larger samples.

Chromosomes, Human, Pair 10↗
PubMed1984

Antigen feeding modifies the course of antigen-induced immune complex disease.

Low affinity mice, prone to chronic immune complex disease (ICD) induced by daily injection of antigen, were fed 0.05% HSA in their drinking water for 7 days before the start of daily injections of HSA. Antigen feeding resulted in a marked decrease in the incidence of ICD despite the presence of high levels of circulating immune complexes. These complexes, which persisted in the circulation for long periods, were of low molecular weight and did not localize in the glomeruli. Antigen fed mice had lower levels of free antibody in their sera compared with control mice which may have favoured the formation of small latticed complexes in antigen excess. Antibody affinity was not apparently affected by prior feeding with antigen.

Administration, Oral↗
PubMed2005

[Nephronophthisis and medullary cystic kidney disease complex].

BACKGROUND: Nephronophthisis and medullary cystic kidney disease complex refers to the genetic heterogeneous group of inherited tubulointerstital nephritis. Nephronophthisis comprises at last 3 clinical manifestations, has the autosomal recessive pattern of inheritance, appears early in life and is the most frequent inherited kidney disease that causes terminal renal failure in childhood, while medullary cystic kidney disease has the autosomal dominant pattern of inheritance, is less frequent, and terminal renal failure appears later in life. These two forms have similar clinical and morphological findings but extrarenal manifestations, the median ages of occurence of terminal renal failure, and siblings presence help us distinguish these diseases. CASE REPORT: In this article we illustrated the case of a 20-years old patient with the suspicion of having complex nephornophthisis and medullary cystic kidney disease based upon mild renal failure, seen in routinely taken laboratory findings and bilateral cysts in corticomedullary region of the kidneys verified on abdominal ultrasound examination. CONCLUSION: This disease should rise suspicion in children or adolescents with progressive renal failure, a typical clinical manifestation, blood and urine samples results, bilateral cysts in the corticomedullary region of the kidneys seen during ultrasound examination of the kidneys and family inheritance.

Adult↗
PubMed1980

Biochemical aspects of immune complex formation and immune complex diseases.

Formation of immune complexes is a normal part of the immune defence against soluble antigens. Immune complexes may nevertheless play a pathogenic role of their own. The present review discusses antigen antibody interactions with special regard to immune complex formation. A new classification of antigen antibody interactions is proposed, based on the antigenic valence. Oligovalent antigens and bivalent antibodies form genuine immune complexes. Experimental observations and theoretical considerations indicate that although a vast variety of complexes is possible genuine immune complex formation is a self-limiting process, so it is typical that the smallest possible complexes are formed in the largest amounts. Formation of immune complexes differs in mechanism from most other biological ligand binding reactions, and the extent to which immune complex formation follows its own laws is discussed. To explain the mechanism of precipitin reactions, a two-stage model is proposed. The outcome of antigen antibody interactions is further complicated because antibody preparations are typically heterogeneous, and the impact of antibody heterogeneity is also discussed.

Animals↗
PubMed2005

How many genes underlie the occurrence of common complex diseases in the population?

BACKGROUND: Most common human diseases are due to complex interactions among multiple genetic variants and environmental risk factors. There is debate over whether variants of a relatively small number of genes, each with weak or modest individual effects, account for a large proportion of common diseases in the population, or whether a large number of rare variants with large effects underlie genetic susceptibility to these diseases. It is not clear how many genes are necessary to account for an appreciable population-attributable fraction of these diseases. METHODS: In this analysis, we estimated the number of disease susceptibility genes needed to account for varying population attributable fractions of a common complex disease, taking into account the genotype prevalence, risk ratios for individual genes, and the model of gene-gene interactions (additive or multiplicative). RESULTS: Very large numbers of rare genotypes (e.g. those with frequencies of 1 per 5000 or less) are needed to explain 50% of a common disease in the population, even if the individual risk ratios are large (RR = 10-20). On the other hand, only approximately 20 genes are usually needed to explain 50% of the burden of a disease in the population if the predisposing genotypes are common (> or = 25%), even if the individual risk ratios are relatively small (RR = 1.2-1.5). CONCLUSIONS: Our results suggest that a limited number of disease susceptibility genes with common variants can explain a major proportion of common complex diseases in the population. Our findings should help focus the search for common genetic variants that provide the most important predispositions to complex human diseases.

Algorithms↗
PubMed2003

IBD International Genetics Consortium: international cooperation making sense of complex disease.

The Inflammatory Bowel Disease International Genetic Consortium was formed in Oxford in 1997. Since then it has grown to include twelve groups from around the world that are each actively involved in identifying the genes that are involved in susceptibility to IBD. The approach of the IBDIGC is to attempt to overcome one of the major issues in complex disease analysis-that of obtaining sufficient power to analyze successfully the inheritance of IBD-by collaboratively studying large numbers of well documented families with multiple affected individuals. This strategy has been marked by considerable success with the publication of a paper authored by the IBDIGC substantiating the localization of IBD1 to chromosome 16. This publication served to encourage researchers and eventually resulted in the identification by several groups simultaneously of risk alleles in the NOD2 gene that cosegregate with disease. The IBDIGC provides a model for studies in complex disease genetics, showing that research groups both large and small can participate equally in complex disease gene identification through the formation of large international consortia.

Congresses as Topic↗
PubMed2000

Discontinuation of prophylaxis against Mycobacterium avium complex disease in HIV-infected patients who have a response to antiretroviral therapy. Terry Beirn Community Programs for Clinical Research on AIDS.

BACKGROUND: Several agents are effective in preventing Mycobacterium avium complex disease in patients with advanced human immunodeficiency virus (HIV) infection. However, there is uncertainty about whether prophylaxis should be continued in patients whose CD4+ cell counts have increased substantially with antiviral therapy. METHODS: We conducted a multicenter, double-blind, randomized trial of treatment with azithromycin (1200 mg weekly) as compared with placebo in HIV-infected patients whose CD4+ cell counts had increased from less than 50 to more than 100 per cubic millimeter in response to antiretroviral therapy. The primary end point was M. avium complex disease or bacterial pneumonia. RESULTS: A total of 520 patients entered the study; the median CD4+ cell count at entry was 230 per cubic millimeter. In 48 percent of the patients, the HIV RNA value was below the level of quantification. The median prior nadir CD4+ cell count was 23 per cubic millimeter, and 65 percent of the patients had had an acquired immunodeficiency syndrome-defining illness. During follow-up over a median period of 12 months, there were no episodes of confirmed M. avium complex disease in either group (95 percent confidence interval for the rate of disease in each group, 0 to 1.5 episodes per 100 person-years). Three patients in the azithromycin group (1.2 percent) and five in the placebo group (1.9 percent) had bacterial pneumonia (relative risk in the azithromycin group, 0.60; 95 percent confidence interval, 0.14 to 2.50; P=0.48). Neither the rate of progression of HIV disease nor the mortality rate differed significantly between the two groups. Adverse effects led to discontinuation of the study drug in 19 patients assigned to receive azithromycin (7.4 percent) and in 3 assigned to receive placebo (1.1 percent; relative risk, 6.6; P=0.002). CONCLUSIONS: Azithromycin prophylaxis can safely be withheld in HIV-infected patients whose CD4+ cell counts have increased to more than 100 cells per cubic millimeter in response to antiretroviral therapy.

AIDS-Related Opportunistic Infections↗
PubMed2001

The power of genome-wide association studies of complex disease genes: statistical limitations of indirect approaches using SNP markers.

Genome-wide association studies using a dense map of single nucleotide polymorphism (SNP) markers seem to enable us to detect a number of complex disease genes. In such indirect association studies, whether susceptibility genes can be detected is dependent not only on the degree of linkage disequilibrium between the disease variant and the SNP marker but also on the difference in their allele frequencies. These factors, as well as penetrance of the disease variant, influence the statistical power of such approaches. However, the power of indirect association studies is not well understood. We calculated the number of individuals necessary for the detection of the disease variant in both direct and indirect association studies with a case-control design. The result shows that a remarkable reduction in the statistical power of indirect studies, compared with that of direct ones, is unavoidable in the genome-wide screening of complex disease genes. If there is a large difference in allele frequency between the disease variant and the marker, the disease variant cannot be detected. Because the frequency of the disease variant is unknown, SNP markers with various allele frequencies, or a large number of SNP markers, must be used in indirect association studies. However, if the number of SNP markers is increased, the obtained P value may not reach the significance level due to the Bonferroni adjustment. Thus, to test a possible association between functional variants and a complex disease directly, we should identify such SNPs in as many genes as possible for use in genome-wide association studies.

Gene Frequency↗
PubMed1981

Plasmapheresis in patients with leukaemia, multiple myeloma and immune complex diseases.

Therapeutical partial plasma exchange was performed on 9 patients with acute leukaemia, 14 patients with monoclonal and polyclonal gammopathies and 3 with primarily immune complex disease. The procedure was effective in 21 out of the 27 courses performed on patients with gammopathies and in all cases of the primarily immune complex diseases. In acute leukaemic patients the course of the disease was favourably influenced by plasmapheresis. The results show that partial plasma exchange is an effective adjunct therapy in the treatment of patients with haematological diseases.

Acute Disease↗
PubMed2006

Population isolates in South Tyrol and their value for genetic dissection of complex diseases.

The study of genetic isolates is a promising approach for the study of complex genetic traits. The small and constant population size, lack of migration, and multiple relationships between individuals in the isolate population could reduce the genetic diversity, and lead to increased levels of linkage disequilibrium (LD). We studied the extent of LD on Xq13 in six population isolates from South Tyrol in the Eastern Italian Alps. We found different levels of LD in our study samples, probably reflecting their degrees of isolation and their demographic histories. The highest values were obtained in Val Gardena (ranking among the highest levels of LD in Europe) and in Stelvio, which qualified as a microisolate according to historical information, and biodemographic and genealogical criteria. Phylogenetic analysis revealed that the two Ladin-speaking populations are genetically distant from each other, and from their German-speaking neighbours, and are characterized by a smaller effective population size than the neighbouring valleys. These peculiar characteristics suggest that South Tyrol could be a unique resource for the study of complex diseases, showing all the characteristics of isolated populations with the advantage of including, in a fairly homogeneous environment, two genetically differentiated sub-populations. This could allow investigators to gain an insight into the contribution of genetic heterogeneity in complex diseases.

Adult↗