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R C Elston

Publications and source records attributed to R C Elston.

At least 91 records · Page 5Linked to original sources
PubMed1998

The identification of a conserved binding motif within human papillomavirus type 16 E6 binding peptides, E6AP and E6BP.

A 16-mer peptide library was screened using the yeast two-hybrid system to identify peptides which specifically interact with the human papillomavirus type 16 (HPV-16) E6 protein. Four different peptides were identified, three of which contained an E-L-L/V-G motif. A fifth E6 binding peptide, derived from the putative tumour suppressor protein tuberin, was identified during a two-hybrid screen of a HeLa cDNA expression library. This peptide contained a D-I-L-G motif. Homology to the peptides was found within the E6 binding proteins E6-AP and E6-BP. A synthetic peptide containing the ELLG motif blocked the interaction of E6 with both E6-AP and E6-BP. The data suggest that E6 interacts through a structurally similar binding domain present within a number of cellular proteins.

Amino Acid Sequence↗
PubMed1997

Alternative test for linkage between two loci.

When using the maximum likelihood method to test for linkage it is traditionally assumed that the female (theta f) and male (theta m) recombination fractions are equal. However, this assumption is not always realistic. In this paper we present a testing for linkage that does not require this assumption. Specifically, we propose testing for linkage by testing the null hypothesis H0: theta f + theta m = 1 vs. the alternative HA: theta f + theta m < 1, treating theta f - theta m as a nuisance parameter. This leads to a likelihood ratio test statistic that is asymptotically distributed as a chi-square with one degree of freedom. By examining the expected values of the maximum lod scores, we show that for data from phase-known meioses this test can provide a more powerful test for linkage-especially so when theta f not equal to theta m-unless the recombination fraction is zero. For data from phase-unknown meioses, the proposed test is a more powerful test for linkage only for large values of theta f - theta m; otherwise, the traditional test has higher power. Thus, the proposed test can lead to gain in power for detecting linkage when either phase is known for most meioses or when there is a large absolute difference between the male and female recombination fractions.

Chromosome Mapping↗
PubMed1997

Population-based family study designs: an interdisciplinary research framework for genetic epidemiology.

Most complex traits such as cancer and coronary heart diseases are attributed either to heritable factors or to environmental factors or to both. Dissecting the genetic and environmental etiology of complex traits thus requires an interdisciplinary research strategy. Genetic studies generally involve families and investigate familial aggregations of traits, segregation of major disease genes, and locations of disease genes on the human genome, the latter of which can be identified via linkage analysis. Epidemiologic studies often use population-based case-control studies to establish the role of specific environmental factors. Integrating both objectives, genetic epidemiology is to assess the associations of environmental factors with disease status, to quantify the aggregation of cases within families, to characterize putative disease genes via segregation analysis, and to localize disease genes via linkage analysis with genetic markers. To accomplish these objectives through designed studies, we propose a class of population-based family study designs, which are formed by choosing among sampling designs at three stages. The objectives of sampling at these three stages are 1) combined aggregation and association analysis, 2) combined segregation, aggregation, and association analysis, and 3) combined linkage, segregation, aggregation, and association analysis. These designs form an interdisciplinary research framework for genetic epidemiology. Our preliminary exploration of this framework and related analytic methods indicates that population-based family study designs retain the efficiency of linkage analysis for localizing disease genes without losing the property of being population-based, and they will therefore allow an assessment of a joint contribution of genetic and environmental factors to complex traits.

Case-Control Studies↗
PubMed1997

Deriving components of genetic variance for multilocus models.

Several authors have considered two-locus models as a basis for the inheritance of complex diseases. The purpose of this paper is to give a simple general formulation to derive the additive, dominant, and epistatic effects, and hence the corresponding variance components, for any multilocus model. These variance components should be useful for investigating the power of model-free linkage analysis to detect various modes of multilocus inheritance.

Alleles↗
PubMed1997

A new test statistic for linkage applied to bipolar disorder and marker D18S41.

We applied a new test statistic for linkage that removes the traditional assumption of equal female (theta f) and male (theta m) recombination fractions by testing Ho: theta f + theta m = 1 vs. HA: theta f + theta m < 1 to GAW10 Problem 1. Specifically we reanalyzed the reported possible linkage between a suggested susceptibility locus for bipolar affective disorder and marker D18S41 on chromosome 18 [Stine et al., 1995]. We used penetrance functions fitting the description of those used by Stine et al. [1995] assuming a continuous age-dependent logistic distribution. Maximum likelihood marker allele frequencies were estimated assuming Hardy-Weinberg equilibrium. Results from the traditional lod-score analyses do not strongly support the existence of linkage between the disease locus and marker D18S41. Similarly, the new test statistic for linkage failed to provide evidence in support of linkage. This was true whether dominant or recessive models of inheritance were assumed, and whether the analyses included all available pedigrees or were confined to paternally transmitted pedigrees. The appreciable difference found between our lod scores and those obtained by Stine et al. [1995] can be attributed to differences in the assumptions made regarding the age-dependent penetrance function, the marker allele frequencies, or both.

Alleles↗
PubMed1997

Modeling age of onset and residual familial correlations for the linkage analysis of bipolar disorder.

We applied regressive modeling to the data described by Stine et al. [1995] and further explored the possible linkage of bipolar disorder to marker D18S41 on chromosome 18. We performed analyses to determine age-dependent penetrance functions that best fit the data and that allow for residual familial correlations. Specifically, we introduce here a simple method to allow for a sibling correlations. that is not due to segregation at the linked locus, and then extend the results of Stine et al. [1995] by using the best fitting "regressive" model of this kind as input into a lod score linkage analysis. Although a formal segregation analysis was not attempted, a surprising finding was that, except for doubtful linkage to D18S41, there is little evidence for genetic transmission of bipolar disorder in these families.

Age of Onset↗
PubMed1997

Model-free age-of-onset methods applied to the linkage of bipolar disorder.

We performed Haseman-Elston regression on a set of bipolar pedigrees using each of three dependent variables: a binary trait indicating disease concordance or discordance, a binary trait adjusted for age-of-onset, and the residuals from a survival analysis. The latter two methods, which both adjust for age-of-onset, gave smaller p-values when previous analyses suggested linkage between disease and marker, but not when previous analyses were not suggestive of linkage.

Age of Onset↗
PubMed1997

False discoveries in genome scanning.

Methods of multiple comparisons were applied to linkage analysis in the case of genome scanning. Data for Problem 2A were used. p-Values were calculated for all 440,400 possible tests of linkage. Plots of distribution functions and false discovery rate are shown.

Chromosome Mapping↗
PubMed1997

Probabilities of identity-by-descent patterns in sibships when the parents are not genotyped.

An assumption-free algorithm has been applied to compute the probabilities of all possible identity-by-descent (IBD) configurations when the parents have not been genotyped. These probabilities can be used to determine the amount of information that a particular sibship will bring to a nonparametric linkage analysis. It is shown that the number of possible configurations can be extremely large even when the markers are closely spaced and are rather polymorphic. Further, it is not always possible to reduce this number to a manageable one simply by consideration of the relative probabilities of the configurations.

Algorithms↗
PubMed1997

Linkage of multilocus components of variance to polymorphic markers.

Haseman & Elston (1972) introduced a sib pair method using classical regression analysis to detect linkage between a polymorphic marker locus and any quantitative trait locus. Most of the diseases mapped to date follow simple Mendelian, single locus transmission. But there are many familial diseases that do not follow simple Mendelian segregation, for example diabetes, several forms of cancer, etc. In this paper, we extend Haseman and Elston's sib pair method to two unlinked quantitative trait loci each linked to one of two unlinked polymorphic marker loci. For the two-locus epistatic model, we give a general formulation of the complete regression model and details of the regression coefficients in terms of variance components.

Analysis of Variance↗
PubMed1996

Familial uveal melanoma, III. Is the occurrence of familial uveal melanoma coincidental?.

OBJECTIVE: To ascertain whether the familial occurrence of uveal melanoma was coincidental in kindreds in which 1 first-degree relative of the proband had also been affected with primary uveal melanoma. PATIENTS: In a series of 4500 patients with primary uveal melanoma, 17 kindreds were identified in which a first-degree relative of the proband had also been affected with primary uveal melanoma. DESIGN: In the 17 families in which a first-degree relative of the proband had been affected, primary uveal melanoma was classified as familial. In the remaining 4483 families, primary uveal melanoma was classified as sporadic. The expected number of affected first-degree relatives of probands for a family was estimated, assuming an incidence rate of 6 cases per million population per year in each type of family. RESULTS: The expected number of affected first-degree relatives was calculated to be 0.81, with an SE of 0.08, compared with 17 observed affected first-degree relatives (P < .001). CONCLUSION: Our study provides strong statistical evidence that occurrence of familial uveal melanoma is not coincidental.

Adolescent↗
PubMed1996

Association within twin pairs for a dichotomous trait.

We propose an odds-ratio measure of twin association for a dichotomous trait. This odds ratio can be estimated without arbitrarily specifying an index twin and without estimating additional nuisance parameters. Tests of association and confidence intervals may be computed easily, in contrast to those proposed previously [Donner et al. (1995) Genet Epidemiol 12:267-277] for a correlation measure of association. For testing homogeneity of association in two samples of twins, monozygotic and dizygotic, we propose a large-sample test and an exact test, both based on the odds-ratio parameterization. Large-sample tests of homogeneity are slightly anticonservative when some cell counts are small, and the exact test may be preferred in these situations. We also propose a long-linear parameterization useful for modeling more complex data sets.

Attention↗
PubMed1996

Two-stage global search designs for linkage analysis using pairs of affected relatives.

We investigate the two-stage procedure proposed by Elston [(1992) Proceedings of the XVIth International Biometric Conference, Hamilton, New Zealand, December 7-11, 1992, pp 39-51, and (1994) "Genetic Approaches to Mental Disorders." Washington, DC: American Psychiatric Press, pp 3-21] for performing a global search of the genome to locate disease genes by linkage analysis using affected relative pairs. The optimal design depends on the type of pairs studied, the effect of the disease locus, the relative costs of recruiting affected persons and typing markers, how informative the markers are, and the amount of genetic heterogeneity. It is specified by the initial number of markers to use, the number of affected relative pairs to study, the initial significance level alpha* to use at the first stage, and the number of flanking markers to use at the second stage around markers significant at the first stage. Asymptotically, the optimal design does not depend separately on either the desired final significance level or power, but rather on a function of the two. Both as the effect of the disease locus increases and as the relative cost of recruiting a subject increases, the optimal number of initial markers increases and the optimal number of pairs decreases. The expected cost of the study decreases as the effect of the disease locus increases, but increases as the relative cost of recruiting a subject increases. The optimal initial number of markers decreases but the number of pairs increases when there is genetic heterogeneity present; conversely, the optimal initial number of markers increases when markers are less than fully informative. Compared to a one-stage procedure, a two-stage procedure typically halves the cost of a study.

Epidemiologic Methods↗
PubMed1996

An autosomal screen for genes that predispose to celiac disease in the western counties of Ireland.

Celiac disease is a strongly heritable gastrointestinal illness that is an especially important model of the genetically complex multifactorial immune mediated diseases. The HLA component of celiac disease (a specific HLA-DQ heterodimer)is largely established and is relatively uncomplicated, and the environmental component (gluten and related grain storage proteins in the diet) is remarkably well understood. Previous family studies of celiac disease suggested that there is at least one important non-HLA locus. This locus may be a stronger genetic factor than HLA, and it apparently has a recessive mode of inheritance. We used a three step genome screening protocol to identify loci that contribute to celiac disease in the western counties of ireland, a region with the highest prevalence of celiac disease in the world. The most significant of several possible non-HLA loci that we found was on chromosome 6p about 30 cM telomeric from HLA. It has a multipoint maximum lod score of 4.66 (compared with 4.44 for HLA-DQ) and appears to have a recessive mode of inheritance. Our study localizes and provides strong evidence for linkage of at least one non-HLA locus to celiac disease and may serve as a prototype for an efficient approach to screening the human genome for loci that contribute to complex diseases.

Adolescent↗
PubMed1996

Delayed hypersensitivity skin tests and subsequent renal transplant outcome.

BACKGROUND: Some studies in the literature have supported, while others have denied, the relationship between results of delayed hypersensitivity skin tests (DHST), renal allograft and patient survival rates. Several factors contribute to the unreliability of these studies. For example, most of these studies were performed in the precyclosporine era, furthermore, other variables which influence renal allografts and patient survival rates were not controlled in those studies. OBJECTIVE: The purpose of this study was to investigate the relationship between results of DHST performed in the pretransplant period with the subsequent renal transplant outcome in the cyclosporine era. METHODS: The study included 103 first cadaveric renal transplant recipients. DHST were performed during pretransplant evaluation by intradermal injections of a battery of recall antigens. Based on skin-test results, the patients were assigned to two groups--those with a positive skin test (STP+) and those with a negative (anergic) skin test. These two groups were compared with each other regarding allograft survival, patient survival, and other variables known to influence survival rates. RESULTS: The mean age, sex and racial distribution, degree of HLA matches between recipients and donors, number of acute rejection episodes, and number of patients with acute tubular necrosis were similar between the two groups. Renal allograft survival rates in the anergic group at 6 months, 1 year, 2 years, and 3 years were 97%, 90%, 84%, and 57%, respectively. The survival rate for renal allografts in the STP+ group for the same time points was 90%, 86%, 80%, and 72%, respectively. Patient survival rates for the anergic group at 6 months, 1 year, 2 years, and 3 years were 95%, 94%, 89%, and 85%, respectively, while those for the STP+ group were 98%, 98%, 98%, and 97% respectively. Differences between the STP+ and anergic groups, with regard to patient and allograft survival rates, were not significant. CONCLUSION: We conclude that DHST is not helpful in predicting outcome of patient or renal allograft survival rates over a 3-year time period.

Adult↗
PubMed1996

HLA-DR, DQ genotypes of celiac disease patients and healthy subjects from the West of Ireland.

Celiac disease (CD) has one of the strongest class II HLA associations of any human illness. We used DNA-RFLP typing to study the class II HLA genotypes of celiac disease patients from the West of Ireland, the geographic area with the highest rate of celiac disease in the world. We confirmed the high frequency of HLA-DR3 in this population, and we were also able to demonstrate the additional risk of developing celiac disease imparted by HLA-DR7. This was done by clearly distinguishing DR7,DQ2 haplotypes from DR7,DQ9 haplotypes, and by "subtraction analysis" of haplotype frequencies. As reported in other populations, most of the patients without DR3 were heterozygous for DR7 and DR11 or 12 (DR5), or had DR4. We used PCR-RFLP and direct sequencing of amplified DNA to examine HLA-DR4 subtypes. The frequency of HLA-DR4 was markedly decreased in patients compared with controls (p = 0.000001) and there was a significant alteration of DR4 subtypes of the patients compared with controls (p = 0.0227). Moreover, all of the CD patients (5 of 5) with DR4 had a haplotype associated with the DQB1*0302 allele compared with only 11 of 23 control subjects with DR4. Our results in this population with exceptionally high risk of CD strongly support the DQ heterodimer hypothesis and suggest that the recently described sequence difference between the DQB1*02 alleles of DR3 and DR7 may contribute to a synergistic increased risk when these haplotypes are inherited together. In addition, our findings suggest a role for HLA-DQ in DR4-associated CD.

Celiac Disease↗