[Genetics facilitates the diagnosis of "complex" diseases: an example].
A case of Familial Mediterranean Fever is described. Advances in human genetics have simplified the diagnosis of some "complex" diseases.
Adult↗
SEARCH · Search PubMed
Results for “complex diseases”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Using inbred mouse strains to identify genes for complex diseases.
In recent years, genetic studies in humans have identified a handful of genes that are associated with common disorders, but our understanding of such diseases at the genetic level remains relatively rudimentary. The use of mice to dissect the complex genetic etiology of common disorders offers a viable alternative to human studies since experimental parameters, such as environmental influences, breeding scheme, and detailed phenotyping can be controlled. This review focuses on the utility of mouse genetics for identification of complex disease genes. Atherosclerosis is used as a representative example, followed by an overview for the prospects of successful gene discovery in the future.
Animals↗
Antimicrobial resistance among Pasteurella spp recovered from Missouri and Iowa cattle with bovine respiratory disease complex.
A retrospective study was conducted to determine the prevalence of antimicrobial resistance among Pasteurella spp recovered from cattle with bovine respiratory disease complex. The study extended from January 1976 through May 1980, and included a review of the necropsy records of 386 beef cattle. Susceptibility or resistance of the Pasteurella isolants was determined by using the standard disk diffusion susceptibility test. Each isolant was tested for susceptibility with 15 different antimicrobial agents. A high prevalence of resistance (greater than 80%) was found when Pasteurella was tested with triple sulfonamides. For P haemolytica isolants, 57% to 70% were resistant to ampicillin (56/97), penicillin (58/101), and streptomycin (70/100); for unidentified Pasteurella spp isolants, 64% to 91% were resistant to ampicillin (83/129), penicillin (89/129), and streptomycin (118/129). For P haemolytica (21/100) and P multocida (34/146) isolants, 21% to 23% were resistant to tetracycline. Most of the P multocida isolants did not show marked antimicrobial resistance to 9 of the 15 drugs tested. However, 58% of the P multocida isolants (84/145) were resistant to streptomycin and 88% of them were resistant to three combined sulfonamides (126/144).
Animals↗
Ancestral processes for non-neutral models of complex diseases.
We consider non-neutral models for unlinked loci, where the fitness of a chromosome or individual is not multiplicative across loci. Such models are suitable for many complex diseases, where there are gene-interactions. We derive a genealogical process for such models, called the complex selection graph (CSG). This coalescent-type process is related to the ancestral selection graph, and is derived from the ancestral influence graph by considering the limit as the recombination rate between loci gets large. We analyse the CSG both theoretically and via simulation. The main results are that the gene-interactions do not produce linkage disequilibrium, but do produce dependencies in allele frequencies between loci. For small selection rates, the distributions of the genealogy and the allele frequencies at a single locus are well-approximated by their distributions under a single locus model, where the fitness of each allele is the average of the true fitnesses of that allele with respect to the distribution of alleles at other loci.
Genetic Predisposition to Disease↗
Population choice in mapping genes for complex diseases.
The difficulty of identifying susceptibility genes for common diseases has polarized geneticists' views on what disease models are appropriate and how best to proceed once high-density genome maps become available. Different disease models have different implications for using linkage or linkage-disequilibrium-based approaches for mapping complex disease genes. We argue that the choice of study population is a critical factor when designing a study, and that genetically simplified isolates are more useful than diverse continental populations under most assumptions.
Alleles↗
A disease complex associated with pigeon circovirus infection, young pigeon disease syndrome.
In order to collect more convincing data on the aetiological agent of young pigeon disease syndrome (YPDS), a comprehensive study was performed on pigeons in German lofts with or without outbreaks of YPDS. The investigations included examination of histories, clinical signs and pathology, as well as parasitological and microbiological analysis. Pigeons in their 4th to 12th week of life exhibited clinical signs at higher frequency and with greater severity than pigeons of other ages. Greenish liquid in the crop, proventriculus and ventriculus, and yellow fluid in the small intestine were seen more often in YPDS-affected pigeons. Escherichia coli and Klebsiella pneumoniae were isolated more frequently from these birds. Depletion of splenic and bursal lymphocytes was only seen in pigeons with YPDS. Inclusion bodies were present in various organs, especially the bursa of Fabricius. The genome of pigeon circovirus was detected in lymphoid tissues from all pigeons with YPDS. The results of this study indicate that YPDS is a multifactorial disease in which pigeon circovirus might be a crucial factor, possibly by inducing immunosuppression in infected birds.
Animals↗
Genome scanning for complex disease genes using the transmission/disequilibrium test and haplotype-based haplotype relative risk.
Two tests for allelic association were applied to a simulated complex disease for the Genetic Analysis Workshop 9. The transmission/disequilibrium test [Spielman et al., 1993] and the haplotype-based haplotype relative risk approach [Terwilliger and Ott, 1992] were used to detect disease-associated alleles in a set of 360 computer-simulated markers located on six chromosomes and genotyped in 200 nuclear families. This analysis emulates a genome-based search for linked markers. Computer simulations were also performed to clarify statistical properties of the TDT.
Alleles↗
Whole-genome scan, in a complex disease, using 11,245 single-nucleotide polymorphisms: comparison with microsatellites.
Despite the theoretical evidence of the utility of single-nucleotide polymorphisms (SNPs) for linkage analysis, no whole-genome scans of a complex disease have yet been published to directly compare SNPs with microsatellites. Here, we describe a whole-genome screen of 157 families with multiple cases of rheumatoid arthritis (RA), performed using 11,245 genomewide SNPs. The results were compared with those from a 10-cM microsatellite scan in the same cohort. The SNP analysis detected HLA*DRB1, the major RA susceptibility locus (P=.00004), with a linkage interval of 31 cM, compared with a 50-cM linkage interval detected by the microsatellite scan. In addition, four loci were detected at a nominal significance level (P<.05) in the SNP linkage analysis; these were not observed in the microsatellite scan. We demonstrate that variation in information content was the main factor contributing to observed differences in the two scans, with the SNPs providing significantly higher information content than the microsatellites. Reducing the number of SNPs in the marker set to 3,300 (1-cM spacing) caused several loci to drop below nominal significance levels, suggesting that decreases in information content can have significant effects on linkage results. In contrast, differences in maps employed in the analysis, the low detectable rate of genotyping error, and the presence of moderate linkage disequilibrium between markers did not significantly affect the results. We have demonstrated the utility of a dense SNP map for performing linkage analysis in a late-age-at-onset disease, where DNA from parents is not always available. The high SNP density allows loci to be defined more precisely and provides a partial scaffold for association studies, substantially reducing the resource requirement for gene-mapping studies.
Arthritis, Rheumatoid↗
Parental genotypes in the risk of a complex disease.
Our understanding of the genetic etiology of complex disorders is still elusive. According to the common-variant/common-disease hypothesis, frequent functional polymorphisms are the best candidates for disease-susceptibility alleles. Implicitly, we also assume that disease-susceptibility alleles are preferentially transmitted from parents to the affected offspring and that this effect can be captured by the transmission/disequilibrium test (TDT). However, our study of genetic predisposition to childhood acute lymphoblastic leukemia suggests that a focus on the patient's genotype might, in certain instances, be misleading. Our results indicate that, at least at some loci, parental genetics might be of primary importance in predicting the risk of cancer in this pediatric model of a complex disease. Consequently, in addition to TDT, other complementary strategies will need to be simultaneously applied to dissect genetic predisposition to complex disorders.
Case-Control Studies↗
Assessing the effect of multiple linkage tests in complex diseases.
The significance of a lod score value of 3 is very difficult to assess in linkage studies between a genetic marker and a complex disease. One reason is that multiple tests may have been performed, voluntarily or otherwise. For the same disease, linkage may be tested by different laboratories with several markers under various genetic models and diagnostic schemes for the disease. In such a case, we show that the probability of getting a lod score value of 3 under independent transmission of the disease and the marker may be not negligible.
Female↗
Natural human interferon-alpha administered orally as a treatment of bovine respiratory disease complex.
Natural human interferon-alpha (nHuIFN-alpha) from three sources was given orally to 368 calves experiencing a natural outbreak of bovine respiratory disease complex (BRDC). In one study, 200 calves were given one treatment daily for 3 days of placebo or 20, 200, or 2,000 IU of nHuIFN-alpha before shipment. Calves treated with 20 or 200 IU had a significant (p < 0.05) weight gain benefit for the first 21 days in the feedlot, if they had rectal temperatures <40 degrees C when treated with nHuIFN-alpha. In a second trial, 168 mixed-breed calves (five groups randomized to 31-36 calves/group) were treated with one dose of placebo or 200 or 400 IU of nHuIFN-alpha after shipment to the feedlot. Using this regimen, a dose of 200 IU per calf significantly (p < 0.08) decreased the number of sick calves per group and delayed development of BRDC. Results of these studies demonstrate that oral administration of nHuIFN-alpha, which may partially mimic the nasally secreted IFN response reported during BRDC, may be beneficial in cattle.
Administration, Oral↗
Heterozygosity for a Mendelian disorder as a risk factor for complex disease.
While genetic diseases are generally classified as being either 'simple' monogenic or 'complex' polygenic, the distinction between Mendelian and complex disorders is becoming increasingly blurred. Mendelian disorders may demonstrate qualities more typical of multifactorial diseases through shared clinical presentations, the effect of genetic modifiers, moonlighting proteins, synergistic heterozygosity, disease manifestations in heterozygotes and situations where heterozygosity for a 'simple' disorder proves to be a risk factor for seemingly unrelated complex diseases. A recent example of the last instance is the observation that mutations in glucocerebrosidase, the enzyme deficient in Gaucher disease, may be a risk factor for the development of Parkinson disease and other synucleinopathies. Insights gleaned from the study of Mendelian disorders may ultimately lead to a better understanding of factors influencing complex diseases.
Gaucher Disease↗
Linkage analysis of a complex disease through use of admixed populations.
Linkage disequilibrium arising from the recent admixture of genetically distinct populations can be potentially useful in mapping genes for complex diseases. McKeigue has proposed a method that conditions on parental admixture to detect linkage. We show that this method tests for linkage only under specific assumptions, such as equal admixture in the parental generation and admixture that occurs in a single generation. In practice, these assumptions are unlikely to hold for natural populations, resulting in an inflation of the type I error rate when testing for linkage by this method. In this article, we generalize McKeigue's approach of testing for linkage to allow two different admixture models: (1) intermixture admixture and (2) continuous gene flow. We calculate the sample size required for a genomewide search by this method under different disease models: multiplicative, additive, recessive, and dominant. Our results show that the sample size required to obtain 90% power to detect a putative mutant allele at a genomewide significance level of 5% can usually be achieved in practice if informative markers are available at a density of 2 cM.
Alleles↗
Microarray genotyping resource to determine population stratification in genetic association studies of complex disease.
We have developed a robust microarray genotyping chip that will help advance studies in genetic epidemiology. In population-based genetic association studies of complex disease, there could be hidden genetic substructure in the study populations, resulting in false-positive associations. Such population stratification may confound efforts to identify true associations between genotype/haplotype and phenotype. Methods relying on genotyping additional null single nucleotide polymorphism (SNP) markers have been proposed, such as genomic control (GC) and structured association (SA), to correct association tests for population stratification. If there is an association of a disease with null SNPs, this suggests that there is a population subset with different genetic background plus different disease susceptibility. Genotyping over 100 null SNPs in the large numbers of patient and control DNA samples that are required in genetic association studies can be prohibitively expensive. We have therefore developed and tested a resequencing chip based on arrayed primer extension (APEX) from over 2000 DNA probe features that facilitate multiple interrogations of each SNP, providing a powerful, accurate, and economical means to simultaneously determine the genotypes at 110 null SNP loci in any individual. Based on 1141 known genotypes from other research groups, our GC SNP chip has an accuracy of 98.5%, including non-calls.
Animals↗
Spirometric performance in Belgian Blue calves: I. Effects on economic losses due to the bovine respiratory disease complex.
The aim of this study was to determine whether high spirometric performances in calves are associated with low economic losses due to the bovine respiratory disease complex (BRDC). Five spirometric variables (SV) were measured in 909 double-muscled Belgian Blue calves from 15 to 60 d of age. Afterward, calves were monitored for 6 mo to determine whether they developed BRDC and to determine the costs due to BRDC (i.e., medicine costs and veterinarians' fees, plus estimated financial losses due to mortality in case of death). To analyze the effects of spirometric performances on BRDC cost, a fixed linear model was used for each SV. In addition to SV, each model included the effects of sex, dam's parity, vaccination status, muscular development score, herd-period, and BW. Only herd-period and the maximal ventilation and the vital capacity had significant effects on costs due to BRDC, indicating that these two SV are major physiological determinants of economic losses associated with BRDC. Accordingly, it is assumed that an amelioration of maximal ventilation and vital capacity could result in increased resistance to BRDC in calves.
Airway Resistance↗
Novel genetic approaches to the resolution of complex diseases.
Up to very recent times, genetics as been the science of monogenic disorders based on Mendelian laws. Completion of human genome sequencing as well as that of other species, including mainly the mouse and rat are now providing the opportunity to resolve complex diseases, i.e., those based on several genes and significantly modified by the environment. This complex paradigm, however, requires novel strategies. We propose an integrated use of experimental genetic animal models, with that of relatively isolated human populations with large families and accessible genealogical data. Foreseeably, genetics will be part of this novel medicine in which the prediction of diseases will be based on individual genomic makeup.
Animals↗
[Simultaneous vascular and endovascular surgery of complex vascular diseases].
Complex vascular disease requires combined, intraoperative endovascular and reconstructive therapy. Hereby, transprosthetic, transluminal angioplasty is particularly well suited for this purpose. The 5-year patency rate after combined inguinal patch plasty and femoral balloon dilation (n = 58) was 70%. The 5-year patency rates following transgraft angioplasty, with subsequent stent implantation and cross-over bypass (n = 46) and after transprosthetic, popliteal-crural dilation was 83% and 63%, respectively. Three patients with a type IIb (after Allenberg) aneurysm were treated with an aortoiliac stent prosthesis, combined with a cross-over bypass. The follow-up examinations at 2, 16 and 36 months were uneventful.
Aneurysm↗
The design, execution, and interpretation of genetic association studies to decipher complex diseases.
Genetic association studies are becoming increasingly frequent in the obstetric and gynecologic literature and they are considered central to the deciphering of the genetic basis of complex disease. The purpose, design, execution, analysis, and interpretation of genetic association studies in reproduction are discussed. Frequently used terms are defined (eg, genotype, haplotype, polymorphism, single nucleotide polymorphism, linkage disequilibrium). Guidelines are proposed for the evaluation of reports of genetic association studies (including selection of polymorphisms for study, study design, assay characteristics, sample size, multiple testing, and multivariable analysis). The potential value of this type of investigation in elucidating the mechanisms of disease in reproduction is illustrated.
Genetic Diseases, Inborn↗