Biomedical subjects

Eric Sobel

Publications and source records attributed to Eric Sobel.

13 recordsLinked to original sources

PubMed2006

Lupus-like disease and high interferon levels corresponding to trisomy of the type I interferon cluster on chromosome 9p.

OBJECTIVE: Systemic lupus erythematosus (SLE) is associated with type I interferons (IFNs) and can be induced by IFNalpha treatment. This study looked for evidence of autoimmunity in a pedigree consisting of 4 family members with a balanced translocation 9;21 and 2 members with an unbalanced translocation resulting in trisomy of the short (p) arm and part of the long (q) arm of chromosome 9. These latter 2 subjects had 3 copies of the IFN gene cluster. METHODS: Subjects were evaluated clinically and serologically for autoimmune disease. Expression levels of IFNalpha4, IFNbeta, the type I IFN-inducible gene Mx1, the type I IFN receptor, interleukin-6, and tumor necrosis factor alpha were determined by real-time polymerase chain reaction. Circulating plasmacytoid dendritic cells, the main IFN-producing cells, were quantified by flow cytometry. RESULTS: Both subjects with trisomy of chromosome 9p had a lupus-like syndrome with joint manifestations and antinuclear antibodies: one had anti-RNP and antiphospholipid autoantibodies, and the other had anti-Ro 60. The 3 family members with a balanced translocation 9;21 had no clinical or serologic evidence of autoimmunity, similar to that in relatives who were unaffected by the chromosomal translocation. In the 2 subjects with trisomy of 9p, high levels of IFNalpha/beta (comparable with those found in patients with SLE), increased signaling through the IFN receptor (as indicated by high Mx1 expression), and low levels of circulating plasmacytoid dendritic cells (as observed in patients with SLE) were evident. These abnormalities were not seen in individuals with a balanced translocation. CONCLUSION: Trisomy of the type I IFN cluster of chromosome 9p was associated with lupus-like autoimmunity and increased IFNalpha/beta and IFN receptor signaling. The data support the idea that abnormal regulation of type I IFN production is involved in the pathogenesis of SLE.

Adolescent↗

PubMed2006

Variance component models for X-linked QTLs.

This paper discusses the theory and implementation of a model for mapping X-linked quantitative trait loci (QTL). As a result of X inactivation, a female's body is subdivided into a number of patches. In each patch one of her two X chromosomes is randomly switched off. This smooths the allelic contributions in a heterozygote and implies that females should show less trait variation than males for an X-linked trait. The latest version of the genetic analysis program Mendel incorporates a simple variance component version of this model. An application to head circumference in autistic children illustrates Mendel in action.

Analysis of Variance↗

PubMed2006

Type I interferon production by tertiary lymphoid tissue developing in response to 2,6,10,14-tetramethyl-pentadecane (pristane).

Lymphoid neogenesis is associated with antibody-mediated autoimmune diseases such as Sjogren's syndrome and rheumatoid arthritis. Although systemic lupus erythematosus is the prototypical B-cell-mediated autoimmune disease, the role of lymphoid neogenesis in its pathogenesis is unknown. Intraperitoneal injection of 2,6,10,14-tetramethyl-pentadecane (TMPD, pristane) or mineral oil causes lipogranuloma formation in mice, but only TMPD-treated mice develop lupus. We report that lipogranulomas are a form of lymphoid neogenesis. Immunoperoxidase staining of lipogranulomas revealed B cells, CD4(+) T cells, and dendritic cells and in some cases organization into T- and B-cell zones. Lipogranulomas also expressed the lymphoid chemokines CCL21, CCL19, CXCL13, CXCL12, and CCL22. Expression of the type I interferon (IFN-I)-inducible genes Mx1, IRF7, IP-10, and ISG-15 was greatly increased in TMPD- versus mineral oil-induced lipogranulomas. Dendritic cells from TMPD lipogranulomas underwent activation/maturation with high CD86 and interleukin-12 expression. Magnetic bead depletion of dendritic cells markedly diminished IFN-inducible gene (Mx1) expression. We conclude that TMPD-induced lupus is associated with the formation of ectopic lymphoid tissue containing activated dendritic cells producing IFN-I and interleukin-12. In view of the increased IFN-I production in systemic lupus erythematosus, these studies suggest that IFN-I from ectopic lymphoid tissue could play a role in the pathogenesis of experimental lupus in mice.

Animals↗

PubMed2005

Fine mapping of the multiple sclerosis susceptibility locus on 5p14-p12.

Linkage analyses have identified four major MS susceptibility loci in Finns. Here we have fine mapped the region on chromosome 5p in 28 Finnish MS families. Marker D5S416 provided the highest pairwise LOD score, and multipoint and haplotype analyses restrict the critical region to about 5.3 Mb on 5p15 between markers D5S1987 and D5S416. Ascertaining for HLA type and geographical origin indicated that families with and without the HLA DR15 risk haplotype, as well as families within and outside an internal high-risk region, contributed to the linkage to 5p, implying the general significance for this locus in Finnish MS families.

Chromosome Mapping↗

PubMed2005

Association of anti-nucleoprotein autoantibodies with upregulation of Type I interferon-inducible gene transcripts and dendritic cell maturation in systemic lupus erythematosus.

Lupus patients selectively produce autoantibodies against nucleoproteins. Since the RNA/DNA components of these autoantigens are endogenous TLR ligands capable of stimulating Type I interferon (IFN-I) production, we asked whether autoantibodies against the ribonucleoproteins Sm/RNP and Ro60 and double-stranded DNA are associated with high levels of IFN-I. IFN-I levels were increased in SLE (n = 88) vs. other autoimmune diseases (n = 82) and controls (n = 57) (P < 0.0001) and were associated positively with autoantibodies against Sm/RNP, Ro60/La, and dsDNA but negatively with anti-phospholipid. Low numbers of circulating plasmacytoid and myeloid dendritic cells also were associated with these autoantibodies. The IFN-I and dendritic cell abnormalities correlated with disease severity and were not therapy-related. These findings suggest that immunostimulatory nucleic acid components of autoantigens may act as endogenous adjuvants by promoting IFN-I production and dendritic cell maturation, helping to explain the high prevalence of autoantibodies against nucleoprotein antigens in SLE.

Antibodies, Antinuclear↗

PubMed2005

Association testing with Mendel.

This report presents an overview of association testing strategies from a user's perspective, with particular attention to the capabilities of the computer program Mendel. Association testing is driven by the nature of the study sample, the nature of the disease trait, and the kind of markers employed. The practicing statistician must also choose whether to conduct parametric or nonparametric tests. Because of the complexities involved, Mendel offers users several analysis options. The different options are tied together by shared input and output conventions and a shared language for defining models. Mendel also features new statistics and theory found in no other genetics software. The most important innovations include: association testing by penetrance estimation, expansion of matched-pair designs to permutation unit designs, and a rigorous implementation of the measured genotype approach for quantitative trait loci. This report explains how Mendel imputes allele counts and conducts both asymptotic and permutation tests in the measured genotype framework.

Analysis of Variance↗

PubMed2004

Locus for quantitative HDL-cholesterol on chromosome 10q in Finnish families with dyslipidemia.

Decreased HDL-cholesterol (HDL-C) and familial combined hyperlipidemia (FCHL) are the two most common familial dyslipidemias predisposing to premature coronary heart disease (CHD). These dyslipidemias share many phenotypic features, suggesting a partially overlapping molecular pathogenesis. This was supported by our previous pooled data analysis of the genome scans for low HDL-C and FCHL, which identified three shared chromosomal regions for a qualitative HDL-C trait on 8q23.1, 16q23.3, and 20q13.32. This study further investigates these regions as well as two other loci we identified earlier for premature CHD on 2q31 and Xq24 and a locus for high serum triglycerides (TGs) on 10q11. We analyzed 67 microsatellite markers in an extended study sample of 1,109 individuals from 92 low HDL-C or FCHL families using both qualitative and quantitative lipid phenotypes. These analyses provided evidence for linkage (a logarithm of odds score of 3.2) on 10q11 using a quantitative HDL-C trait. Importantly, this region, previously linked to TGs, body mass index, and obesity, provided evidence for association for quantitative TGs (P = 0.0006) and for a combined trait of HDL-C and TGs (P = 0.008) with marker D10S546. Suggestive evidence for linkage also emerged for HDL-C on 2q31 and for TGs on 20q13.32. Finnish families ascertained for dyslipidemias thus suggest that 10q11, 2q31, and 20q13.32 harbor loci for HDL-C and TGs.

Adult↗

PubMed2004

Efficient simulation of P values for linkage analysis.

In many genetic linkage analyses, the P value is obtained through simulation since the underlying distribution of the test statistic is complex and unknown. However, this can be very computationally intensive. A "bootstrap/replicate pool" approach has been suggested that generates P values more efficiently in terms of computation by resampling sums from a small set of simulated replicates for each pedigree. The replicate pool idea has been successfully applied, but, to our knowledge, has never been theoretically studied. An entirely different method for increasing the computational efficiency of P value simulation is Besag and Clifford's sequential sampling method. We propose an algorithm which combines Besag and Clifford's method with the replicate pool method to efficiently estimate P values for linkage studies. We derive variance expressions for the P value estimates from the replicate pool method and from our proposed hybrid method, and use these to show that the hybrid estimator has a substantial advantage over the other methods in most situations.

Algorithms↗

PubMed2002

Fine mapping of a multiple sclerosis locus to 2.5 Mb on chromosome 17q22-q24.

Genome-wide linkage analyses performed in a Finnish study sample have identified four potential predisposing loci for multiple sclerosis (MS). Here we made an effort to restrict the wide linkage region on chromosome 17 with a dense set of 31 markers using multipoint linkage analyses and monitoring for shared marker alleles in MS chromosomes. We carried out the linkage analyses in 22 Finnish multiplex MS families originating from a regional subisolate that shows an exceptionally high prevalence of MS in order to minimize the genetic and environmental heterogeneity of the study sample. Thirty markers on the 23 cM initial interval gave positive pairwise LOD scores. We monitored for shared haplotypes among affected family members within a family, and identified an approximately 4 cM region flanked by the markers D17S1792 and ATA43A10 in 17 out of the 22 families (77.3%). The multipoint linkage analyses using Genehunter and SIMWALK 2.40 provided further evidence for the same 4 cM region, for example a maximal multipoint NPL score of 5.98 (P<0.0002). We observed nominal evidence for association to MS, with one marker flanking the shared region, and this association was replicated in the additional set of families. Using the combined power of linkage, association and shared haplotype analyses, we were thus able to restrict the MS locus on chromosome 17q from 23 cM to a 4 cM region covering a physical interval of approximately 2.5 Mb. Thus, this study describes the restriction of an MS locus outside the HLA region into a segment approachable by molecular tools.

Chromosomes, Human, Pair 17↗

PubMed2002

A susceptibility locus for migraine with aura, on chromosome 4q24.

Migraine is a complex neurovascular disorder with substantial evidence supporting a genetic contribution. Prior attempts to localize susceptibility loci for common forms of migraine have not produced conclusive evidence of linkage or association. To date, no genomewide screen for migraine has been published. We report results from a genomewide screen of 50 multigenerational, clinically well-defined Finnish families showing intergenerational transmission of migraine with aura (MA). The families were screened using 350 polymorphic microsatellite markers, with an average intermarker distance of 11 cM. Significant evidence of linkage was found between the MA phenotype and marker D4S1647 on 4q24. Using parametric two-point linkage analysis and assuming a dominant mode of inheritance, we found for this marker a maximum LOD score of 4.20 under locus homogeneity (P=.000006) or locus heterogeneity (P=.000011). Multipoint parametric (HLOD = 4.45; P=.0000058) and nonparametric (NPL(all) = 3.43; P=.0007) analyses support linkage in this region. Statistically significant linkage was not observed in any other chromosomal region.

Chromosome Mapping↗

PubMed2002

Detection and integration of genotyping errors in statistical genetics.

Detection of genotyping errors and integration of such errors in statistical analysis are relatively neglected topics, given their importance in gene mapping. A few inopportunely placed errors, if ignored, can tremendously affect evidence for linkage. The present study takes a fresh look at the calculation of pedigree likelihoods in the presence of genotyping error. To accommodate genotyping error, we present extensions to the Lander-Green-Kruglyak deterministic algorithm for small pedigrees and to the Markov-chain Monte Carlo stochastic algorithm for large pedigrees. These extensions can accommodate a variety of error models and refrain from simplifying assumptions, such as allowing, at most, one error per pedigree. In principle, almost any statistical genetic analysis can be performed taking errors into account, without actually correcting or deleting suspect genotypes. Three examples illustrate the possibilities. These examples make use of the full pedigree data, multiple linked markers, and a prior error model. The first example is the estimation of genotyping error rates from pedigree data. The second-and currently most useful-example is the computation of posterior mistyping probabilities. These probabilities cover both Mendelian-consistent and Mendelian-inconsistent errors. The third example is the selection of the true pedigree structure connecting a group of people from among several competing pedigree structures. Paternity testing and twin zygosity testing are typical applications.

Algorithms↗

PubMedDate not supplied

Diagnostic accuracy for lupus and other systemic autoimmune diseases in the community setting.

BACKGROUND: Most individuals with autoimmune and other immune disorders undergo initial evaluation in the community setting. Since misdiagnosis of systemic autoimmune diseases can have serious consequences, we evaluated community physicians' accuracy in diagnosing autoimmune diseases and the consequences of misdiagnosis. METHODS: We studied the patients referred to our Autoimmune Disease Center for 13 months (n = 476). We estimated the degree of agreement with the final diagnosis (kappa statistic) and the accuracy indexes (sensitivity, specificity, and predictive values) of the referring physicians' diagnoses. RESULTS: We found a 49% agreement between the referring and final diagnoses (kappa = 0.36). Of 263 patients referred with a presumptive diagnosis of systemic lupus erythematosus (SLE), 125 received a diagnosis of other conditions (kappa = 0.34). Of those referred with SLE, 76 (29%) were seropositive for antinuclear antibodies but did not have autoimmune disease. The degree of agreement for referring rheumatologists (kappa = 0.55) was better than that for nonrheumatologists (kappa = 0.32). Stepwise logistic regression indicated that rheumatologists were 4 times more likely to make an accurate diagnosis of SLE than were nonrheumatologists (P<.003). Thirty-nine patients who were seropositive for antinuclear antibodies but had no autoimmune disease had been treated with corticosteroids at dosages as high as 60 mg/d. CONCLUSIONS: Many patients with a positive antinuclear antibody test are incorrectly given a diagnosis of SLE and sometimes treated with toxic medications. The data support the importance of continuing medical education for community physicians in screening for autoimmune diseases and identifying patients who may benefit from early referral to a specialist.

Adrenal Cortex Hormones↗

PubMedDate not supplied

Merging microsatellite data.

Genotype calling procedures vary from laboratory to laboratory for many microsatellite markers. Even within the same laboratory, application of different experimental protocols often leads to ambiguities. The impact of these ambiguities ranges from irksome to devastating. Resolving the ambiguities can increase effective sample size and preserve evidence in favor of disease-marker associations. Because different data sets may contain different numbers of alleles, merging is unfortunately not a simple process of matching alleles one to one. Merging data sets manually is difficult, time-consuming, and error-prone due to differences in genotyping hardware, binning methods, molecular weight standards, and curve fitting algorithms. Merging is particularly difficult if few or no samples occur in common, or if samples are drawn from ethnic groups with widely varying allele frequencies. It is dangerous to align alleles simply by adding a constant number of base pairs to the alleles of one of the data sets. To address these issues, we have developed a Bayesian model and a Markov chain Monte Carlo (MCMC) algorithm for sampling the posterior distribution under the model. Our computer program, MicroMerge, implements the algorithm and almost always accurately and efficiently finds the most likely correct alignment. Common allele frequencies across laboratories in the same ethnic group are the single most important cue in the model. MicroMerge computes the allelic alignments with the greatest posterior probabilities under several merging options. It also reports when data sets cannot be confidently merged. These features are emphasized in our analysis of simulated and real data.

Algorithms↗