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Results for “Genetic Heterogeneity”

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At least 19 recordsLinked to original sources
PubMed2004

Effects of education, vaccination and treatment on HIV transmission in homosexuals with genetic heterogeneity.

Genetic studies report the existence of a mutant allele Delta32 of CCR5 chemokine receptor gene at high allele frequencies (approximately 10%) in Caucasian populations. The presence of this allele is believed to provide partial or full resistance to HIV. In this study, we look at the impact of education, temporarily effective vaccines and therapies on the dynamics of HIV in homosexually active populations. In our model, it is assumed that some individuals possess one or two mutant alleles (like Delta32 of CCR5) that prevent the successful invasion or replication of HIV. Our model therefore differentiates by genetic and epidemiological status and naturally ignores the reproduction process. Furthermore, HIV infected individuals are classified as rapid, normal or slow progressors. In this complex setting, the basic reproductive number R0 is derived in various situations. The separate or combined effects of therapies, education, vaccines, and genetic resistance are analyzed. Our results support the conclusions of Hsu Schmitz that some integrated intervention strategies are far superior to those based on a single approach. However, treatment programs may have effects which counteract each other, as may genetic resistance.

AIDS Vaccines↗
PubMed1988

Genetic markers in Sjögren's syndrome: the question of its genetic heterogeneity.

Genetic factors may be implicated in the causation of Sjögren's syndrome (SS) as shown by familial clustering of the disease and certain HLA associations. Non-HLA genetic markers in SS have not previously been studied in detail. In this study of 122 unrelated patients with various categories of SS and 104 control subjects, 29 genetic markers were studied (11 blood groups, 5 serum proteins and 13 red-cell enzymes). Almost all systems showed a considerable range of gene frequency among the various subgroups of patients with SS but only a few attained statistical significance (C3 and GPT). Multivariate (kinship) analysis, however, showed clear distinction between the subgroups of SS, suggesting that they are genetically distinct entities.

Alleles↗
PubMed2005

Estimation of the frequency of occult mutations for an autosomal recessive disease in the presence of genetic heterogeneity: application to genetic hearing loss disorders.

The routine testing for pathologic mutation(s) in a patient's DNA has become the foundation of modern molecular genetic diagnosis. It is especially valuable when the phenotype shows genetic heterogeneity, and its importance will grow as treatments become genotype specific. However, the technology of mutation detection is imperfect and mutations are often missed. This can be especially troublesome when dealing with a recessive disorder where the combination of genetic heterogeneity and missed mutation creates an imprecision in the genotypic assessment of individuals who do not appear to have the expected complement of two pathologic mutations. This article describes a statistical approach to the estimation of the likelihood of a genetic diagnosis under these conditions. In addition to providing a means of testing for missed mutations, it also provides a method of estimating and testing for the presence of genetic heterogeneity in the absence of linkage data. Gene frequencies as well as estimates of sensitivity and specificity can be obtained as well. The test is applied to GJB2 recessive nonsyndromic deafness, Usher syndrome types Ib and IIa, and Pendred-enlarged vestibular aqueduct syndrome.

Connexin 26↗
PubMed1986

Strategies for studying heterogeneous genetic traits in humans by using a linkage map of restriction fragment length polymorphisms.

Simple single-gene disorders in humans can be genetically mapped by using traditional methods of linkage analysis and increasingly abundant restriction fragment length polymorphisms (RFLPs). Many human diseases and traits, however, can be expected to be genetically heterogeneous (i.e., caused by any one of several genes), and traditional linkage analysis is much less effective in such circumstances. We present two methods, interval mapping and simultaneous search, designed to exploit the full power of a linkage map of the DNA markers. For the simplest situations, only 1/3 as many affected families are needed to map a heterogeneous trait by using these methods. Only 1/5-1/50 as many are needed to detect that genetic heterogeneity is present.

Chromosome Mapping↗
PubMed2001

[Hereditary cancer: identification, genetic heterogeneity, medico-genetic consult].

The paper deals with a role of inherited factors responsible for the occurrence of malignant tumors. Inherited types of cancer are shown to occur virtually at its sites and averaged 5-15%. Formalized criteria for identifying inherited cancer diseases and their etiological and genetic heterogeneity are presented. A role of genes that genetically predispose to particular forms of cancer is shown, which allows for early (preclinical) diagnosis and prevention of cancer diseases.

Genetic Counseling↗
PubMed1992

Atypical reactions to halothane in a subgroup of homozygous malignant hyperthermia(MH)-susceptible pigs: indication of a heterogenous genetic basis for the porcine syndrome.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle. In genetically susceptible pigs, MH can be induced by volatile, halogenated anaesthetics such as halothane. Within a series of pharmacological investigations, a fulminant MH could be induced in 59 of 66 homozygous halothane-susceptible pigs by a challenge with 3% halothane for 15 minutes. The typical MH was characterized by sudden appearance of tachycardia, muscle rigidity with typical extension of the hindlimbs, increase of body temperature, acidosis-caused by rapid increase of CO2 and lactate production-, hyperkalaemia and increased activity of creatine kinase (CK) and aspartate transaminase (AST). In seven homozygous MH-susceptible pigs, this typical MH could not be induced by halothane. These animals responded with sudden appearance of bradyarrhythmia and decrease of arterial pressure. In these MH-atypical pigs (MHA) neither the typical extension of hindlimbs nor a hyperthermia occurred. Compared to a group of 6 MH-susceptible pigs with typical reactions to halothane (MHS), the biochemical alterations were significantly retarded in MHA-pigs. These atypical reactions to halothane could be the effect of decreased cardiac output. Concerning the atypical reactions, we observed a familiar predisposition in MH-susceptible pigs. Although atypical reactions were not found in a group of homozygous halothane-nonsusceptible pigs (MHN), a possible explanation for atypical reactions could be a MH-independent halothane-susceptibility of the myocardium+ in MHA-pigs. On the other side the data may indicate that a primary defect in both the skeletal muscle and also the myocardium is involved in MH. The different reactions to halothane in MH-susceptible pigs could point to a genetic heterogeneity.

Animals↗
PubMed1993

Ulcerative colitis: a genetically heterogeneous disorder defined by genetic (HLA class II) and subclinical (antineutrophil cytoplasmic antibodies) markers.

Newly described distinct associations of HLA class II genes with ulcerative colitis (UC) (DR2) and Crohn's disease (CD) (DR1/DQ5) provide strong evidence for genetic heterogeneity of susceptibility between these two forms of inflammatory bowel disease. A familial distribution of antineutrophil cytoplasmic antibodies (ANCAs, a subclinical marker of UC) in UC families has further implied the existence of heterogeneity within UC. To test the hypothesis that the heterogeneity within UC indicated by ANCAs has a genetic basis that resides within the HLA region, we studied 89 UC cases and an ethnically matched control group (n = 50). Serological and molecular typing techniques were applied to define HLA class II genes (DR, DQ). ANCAs were detected using an enzyme-linked immunosorbent assay, and positive values were confirmed by indirect immunofluorescence. We observed that ANCA-positive UC patients (n = 70) had a significantly increased frequency of DR2 compared with ANCA-negative controls (n = 46) (44% vs 22%, P = 0.01). In contrast, the frequency of DR2 in ANCA-negative UC cases (21%) was virtually identical to that in controls (22%, P = 0.9). Furthermore, the ANCA-negative UC patients had an increase in the DR4 allele compared with ANCA-positive UC (P = 0.004). Thus, with the combination of a subclinical marker (ANCAs) and molecular genetic markers, genetic heterogeneity has been demonstrated within UC: ANCA-positive UC associated with DR2, and ANCA-negative UC likely associated with DR4.

Adult↗
PubMed1992

Detection of genetic heterogeneity for complex quantitative phenotypes.

Statistically characterizing factors responsible for quantitative phenotype expression (e.g., polygenes, major genes, shared household factors, etc.) through model selection strategies is a difficult task. A great deal of effort has been expended on refining mathematical and computational aspects of various segregation models used to characterize unique expressions of quantitative phenotypes in an effort to make these models easier to implement and evaluate for a given set of data. In this paper a slightly different angle is emphasized: namely, the explicit modeling of the potentially numerous heterogeneous genetic and environmental processes (i.e., segregation patterns, household aggregations, etiologic processes, etc.) that could contribute to the overall variation of a quantitative trait. As such, this paper describes tools for detecting quantitative trait heterogeneity that are meant to answer such questions as "are there pedigrees among a great many that show a pattern consistent with a possibly very specific single locus segregation pattern while the rest show compatibility with a polygenic or purely environmental pattern?" Methods for determining the significance of such heterogeneity are also discussed, as are the results of numerous examples and simulation studies carried out in an effort to validate and further elaborate aspects of the proposed techniques.

Genetic Linkage↗
PubMed1982

Empirical risk for insulin-dependent diabetes (IDD) in sibs. Further definition of genetic heterogeneity.

We have studied the effect of age at diagnosis in the proband and parental status [normal versus non-insulin-dependent diabetes (NIDD)] on the cumulative risk to age 40 (CR40) for insulin-dependent diabetes (IDD) in sibs of IDD probands in 493 families. We found a significantly increased cumulative risk to age 40 fro IDD in sibs of probands with disease diagnosed before age 10 (8.5 +/- 2.0%) as compared with that in sibs of probands with disease diagnosed after age 10 (4.6 +/- 0.8%) (X2 = 7.6, P = 0.006). Within the family subset with probands of earlier IDD onset (before age 10) we also found an increased CR40 for IDD in the sibs of the probands in families with an NIDD parent (with NIDD parent: CR40 = 7..5 +/- 2.0%, X2 = 12.8, P less than 0.0005). These data are compatible with the theory of heterogeneity (genetic and/or environmental) of IDD and a possible relationship between IDD and NIDD.

Adolescent↗
PubMed2004

Phenotypic variation resulting from a deficiency of epidermal growth factor receptor in mice is caused by extensive genetic heterogeneity that can be genetically and molecularly partitioned.

The timing of lethality caused by homozygosity for a null allele of the epidermal growth factor receptor (Egfrtm1Mag) in mice is strongly dependent on genetic background. Initial attempts to genetically map background modifiers using Swiss-derived, outbred CD-1 mice were unsuccessful. To investigate the genetic architecture contributing to survival of Egfrtm1Mag homozygous embryos, the genetic variability segregating within the outbred population was partitioned by surveying viability of Egfrtm1Mag mutants using intercrosses between 129S6/SvEvTAC-Egfrtm1Mag and nine Swiss-derived, inbred strains: ALR/LtJ, ALS/LtJ, APN, APS, ICR/HaRos, NOD/LtJ, NON/LtJ, SJL/J, and SWR/J. The observations showed that these strains support varying levels of survival of Egfrtm1Mag homozygous embryos, suggesting that genetic heterogeneity within the CD-1 stock contributed to the original lack of Egfrtm1Mag modifier detection. Similar to the Swiss-derived intercrosses, nine congenic strains, derived from 129S6/SvEvTAC, AKR/J, APN, BALB/cJ, BTBR-T+ tf/tf, C3H/HeJ, C57BL/6J, DBA/2J, and FVB/NJ inbred backgrounds, also supported varying levels of survival of Egfrtm1Mag mutants. By intercrossing the congenic lines to create hybrid F1 embryos, different genetic backgrounds were found to have complementary modifiers. Analysis of the congenic lines argues against heterosis of outbred backgrounds contributing to Egfrtm1Mag phenotypic variability. A detailed analysis of the crosses suggests that modifiers function at three distinct stages of development. One class of modifiers supports survival of Egfrtm1Mag homozygous embryos to mid-gestation, another class supports development through the mid-gestation transition from yolk-sac to placental-derived nutrient sources, and a third class supports survival through later stages of gestation. Data from microarray analysis using RNA from wild-type and Egfrtm1Mag mutant placentas support the existence of extensive genetic heterogeneity and suggest that it can be molecularly partitioned. This method should be generally useful to partition heterogeneity contributing to other complex traits.

Animals↗
PubMed1998

Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity.

Maturity-onset diabetes of the young (MODY) can be defined by the clinical characteristics of early-onset Type 2 (non-insulin-dependent) diabetes and autosomal dominant inheritance. Mutations in four genes have been shown to cause MODY: glucokinase, hepatic nuclear factor 1 alpha (HNF1alpha), hepatic nuclear factor 4 alpha (HNF4alpha) and insulin promoter [corrected] factor 1 (IPF1). In white Caucasians it is now possible to define the gene in most patients with a clinical diagnosis of MODY. Each gene involved in MODY has its own specific clinical and physiological characteristics. Patients with mutations of the glucokinase gene have mild fasting hyperglycaemia throughout life, and rarely require medication or develop microvascular complications. The principle pathophysiology is stable beta-cell dysfunction characterized by reduced sensing of glucose by the pancreas. Patients with mutations in HNF1alpha have normal glucose tolerance in early childhood and usually present with symptomatic diabetes in their late teens or early adulthood. They show increasing hyperglycaemia and treatment requirements with frequent microvascular complications. The underlying defect is progressive beta-cell failure, with the early lesion characterized by failure to increase insulin secretion with increasing glucose levels. Patients with HNF4alpha and IPF1 mutations show a similar clinical picture to HNF1alpha although diabetes may be diagnosed later. There are other patients with MODY in whom the genetic defect is still unknown. Molecular genetic testing in patients with diabetes offers the possibility of making a firm diagnosis of MODY and allows prediction of the future clinical course. The role of predictive testing in non-diabetic subjects within families is uncertain at present. Preliminary evidence suggests that maintaining insulin sensitivity by avoiding obesity and regular physical exercise may help delay the onset of diabetes.

Adolescent↗
PubMed2026

Genetic heterogeneity affects the risk of incident depression, comorbidity, and response to environment: A prospective trajectory study.

BACKGROUND: Depression exhibits significant heterogeneity in its genetic underpinnings. The role of genetic components in the development of depression and its comorbidities remains insufficiently explored. METHODS: First, depression risk loci from a large-scale genome-wide meta-analysis were annotated to Gene Ontology (GO) terms by functional enrichment. GO-based polygenic risk scores (GO-PRS) were then calculated for individuals in the UK Biobank. Principal component analysis (PCA) was applied for dimensionality reduction, followed by cluster analysis to identify genetic subtypes of depression. Multistate models were applied to assess the impact of genetic patterns on the trajectory from healthy status to incident depression, and depression to 26 subsequent diseases, as well as the associations between environmental factors and disease trajectories across genetic subtypes. RESULTS: Participants were categorized into three genetic subtypes: immune-dominant, neuro-dominant, and comprehensive-risk. Significant differences in risk of depression and subsequent diseases, and susceptibility to environmental factors were observed across subtypes. Comprehensive-risk subtype showed higher risks of depression compared to immune-dominant (HR: 1.10, 95% CI: 1.05-1.15) and neuro-dominant subtype (HR: 1.12, 95% CI: 1.08-1.16). Comprehensive-risk subtype exhibited higher risks of transition from depression to subsequent diseases, such as anemia compared to immune-dominant subtype, and diseases of the digestive system compared to neuro-dominant subtype. Environmental factors were more strongly associated with the transition from depression to subsequent diseases in immune-dominant and comprehensive-risk subtypes, including cardiovascular, respiratory, and metabolic diseases. CONCLUSIONS: Our findings highlight the genetic heterogeneity of depression and comorbidities, and shed light on how genetic components modulate responses to environmental factors.

Humans↗
PubMed1991

Power of the admixture test to detect genetic heterogeneity.

Several dominant genetic diseases which appear to be homogeneous are the expression of genetic mutations at several loci. The power to detect linkage by likelihood methods is diminished for heterogeneous, as compared to genetically homogeneous, disorders. Using a simulation approach and two pedigrees typical of those available for the study of a dominant disease (with expected lod scores of 0.43 and 1.00 at theta = 0.05 and PIC = .59), I have evaluated the power to detect genetic heterogeneity by using the admixture test. Linkage power was determined by varying the number of families available for study, the recombination fraction (theta), the informativity of the hypothetical marker, and the proportion of linked families, alpha. For moderate and small values of alpha it is feasible to detect genetic heterogeneity once linkage has been established; rarely will it be possible to detect linkage and heterogeneity simultaneously given a limited number of small or moderate pedigrees.

Epidemiologic Methods↗
PubMedDate not supplied

DNA linkage studies in the fragile X syndrome suggest genetic heterogeneity.

Previously, we showed genetic heterogeneity for linkage between the fra(X) locus and a factor IX DNA RFLP (Brown et al, 1985). When fra(X) families were predivided into two classes, one containing those with non-penetrant (NP) males and one with apparent full penetrance (P), evidence of significant heterogeneity was present. We have now extended this analysis by adding DNA linkage information on 2 additional probes, 52A and ST14, studied in 16 fra(X) kindreds. These data were combined with information on 16 published fra(X) families. There were 7 NP families and 25 P families. We confirmed our previous findings of a higher recombination fraction between factor IX and fra(X) in P families (0 = .32 with lod of .67) compared to as NP families (0 = .06 with lod of 6.11) which was significant at p less than .01. In comparing recombination fractions for the additional probes, more recombination between 52A and the other loci was consistently seen in P compared to NP families which suggested that there may be a higher rate of recombination proximal to the fra(X) locus in P kindreds. A strikingly higher recombination fraction between 52A and factor IX was present in comparing all fra(X) families (.18) to normal families (.02) which was significant at p less than .001. These results suggest genetic heterogeneity with respect to recombination is present both among fra(X) pedigrees and between fra(X) and normal pedigrees.

DNA↗
PubMed1987

Transfusion-associated AIDS: donor-recipient human immunodeficiency virus exhibits genetic heterogeneity.

The genetic diversity of the human immunodeficiency virus (HIV) isolated from transfusion-associated AIDS patients has been examined. Restriction enzyme mapping studies of integrated proviral DNA of donor and recipient origin demonstrated genomic variation between isolates. Analysis of the molecularly cloned viral genomes of one donor-recipient pair showed that virus from the recipient had restriction enzyme site differences from the donor, noticeably clustered in the env and orf-2 regions, and also had a greater number of restriction sites in common with the donor as well. These results suggest that HIV may undergo genomic variation in vivo. Comparison of donor-recipient viruses may further the understanding of the molecular basis for AIDS pathogenesis.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Evolution of intratumoral genetic heterogeneity during colorectal cancer progression.

Evolution of intratumoral genetic heterogeneity during colorectal tumor progression has not been investigated so far. Multiple sample areas in colorectal adenocarcinoma at early and advanced stages and in metastases were studied for the well-known genetic alterations: K-ras and p53 point mutations and loss of heterozygosity (LOH) on chromosomes 5q and 18q. In primary colorectal cancers (CRCs), intratumoral genetic heterogeneity was more often observed in early than in advanced stages, at 90 and 67%, respectively. All but one of the advanced CRCs were composed of one predominant clone and other minor clones, whereas no predominant clone has been identified in half of the early cancers. At the early stage, the last events that were produced, the p53 mutation and LOH of 18q, were also the most heterogeneous. At the advanced stage, the LOH of 5q and 18q were the most frequent heterogeneous events (67 and 58%, respectively). The intratumoral heterogeneity for mutations was significantly reduced, from the early to the advanced stages (from 60 to 20% for K-ras and from 70 to 20% for p53). On the other hand, a quasi absence of intratumoral genetic heterogeneity was observed for K-ras and p53 in distant metastasis. In conclusion, colorectal adenocarcinomas are characterized by marked intratumoral genetic heterogeneity. A reduction of the intratumoral genetic heterogeneity for point mutations and a relative stability of the heterogeneity for allelic losses indicate that, during the progression of CRC, clonal selection and chromosome instability continue, while an increase cannot be proven.

Colorectal Neoplasms↗
PubMed1995

Genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy in a genetic isolate (Amish) and evidence for a new locus.

Limb-girdle muscular dystrophy (LGMD) is a hereditary myopathy presenting clinical and genetic heterogeneity. In 1991, a recessive form (LGMD2A) was linked to chromosome 15q in a genetic isolate from the Isle of La Réunion. Confirmation of this localization was subsequently reported in Brazilian and northern Indiana Amish pedigrees. Here we report the exclusion of the LGMD2A locus in six Amish kindreds from southern Indiana that are related by multiple consanguineous links to the same northern Indiana families in which the involvement of the chromosome 15 locus was previously demonstrated. These findings indicate unexpected genetic heterogeneity of LGMD in an Indiana Amish isolate. Furthermore, genetic analyses also ruled out the possible involvement of the chromosome 2 locus recently described (LGMD2B), thus demonstrating that a mutation within at least one additional locus leads to this condition. Several candidate genes putatively involved in neuromuscular disorders were also excluded.

Chromosomes, Human, Pair 15↗