Search PubMed⌕ Search

Biomedical subjects

Glenys Thomson

Publications and source records attributed to Glenys Thomson.

15 recordsLinked to original sources
PubMed2006

Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis.

Variation in major histocompatibility complex genes on chromosome 6p21.3, specifically the human leukocyte antigen HLA-DR2 or DRB1*1501-DQB1*0602 extended haplotype, confers risk for multiple sclerosis (MS). Previous studies of DRB1 variation and both MS susceptibility and phenotypic expression have lacked statistical power to detect modest genotypic influences, and have demonstrated conflicting results. Results derived from analyses of 1339 MS families indicate DRB1 variation influences MS susceptibility in a complex manner. DRB1*15 was strongly associated in families (P=7.8x10(-31)), and a dominant DRB1*15 dose effect was confirmed (OR=7.5, 95% CI=4.4-13.0, P<0.0001). A modest dose effect was also detected for DRB1*03; however, in contrast to DRB1*15, this risk was recessive (OR=1.8, 95% CI=1.1-2.9, P=0.03). Strong evidence for under-transmission of DRB1*14 (P=5.7x10(-6)) even after accounting for DRB1*15 (P=0.03) was present, confirming a protective effect. In addition, a high risk DRB1*15 genotype bearing DRB1*08 was identified (OR=7.7, 95% CI=4.1-14.4, P<0.0001), providing additional evidence for trans DRB1 allelic interactions in MS. Further, a significant DRB1*15 association observed in primary progressive MS families (P=0.0004), similar to relapsing-remitting MS families, suggests that DRB1-related mechanisms are contributing to both phenotypes. In contrast, results obtained from 2201 MS cases argue convincingly that DRB1*15 genotypes do not modulate age of onset, or significantly influence disease severity measured using expanded disease disability score and disease duration. These results contribute substantially to our understanding of the DRB1 locus and MS, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.

Adult↗
PubMed2006

Signatures of demographic history and natural selection in the human major histocompatibility complex Loci.

Many lines of evidence show that several HLA loci have experienced balancing selection. However, distinguishing among demographic and selective explanations for patterns of variation observed with HLA genes remains a challenge. In this study we address this issue using data from a diverse set of human populations at six classical HLA loci and, employing a comparative genomics approach, contrast results for HLA loci to those for non-HLA markers. Using a variety of analytic methods, we confirm and extend evidence for selection acting on several HLA loci. We find that allele frequency distributions for four of the six HLA loci deviate from neutral expectations and show that this is unlikely to be explained solely by demographic factors. Other features of HLA variation are explained in part by demographic history, including decreased heterozygosity and increased LD for populations at greater distances from Africa and a similar apportionment of genetic variation for HLA loci compared to putatively neutral non-HLA loci. On the basis of contrasts among different HLA loci and between HLA and non-HLA loci, we conclude that HLA loci bear detectable signatures of both natural selection and demographic history.

Evolution, Molecular↗
PubMed2005

PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis.

The minor allele of the R620W missense single-nucleotide polymorphism (SNP) (rs2476601) in the hematopoietic-specific protein tyrosine phosphatase gene, PTPN22, has been associated with multiple autoimmune diseases, including rheumatoid arthritis (RA). These genetic data, combined with biochemical evidence that this SNP affects PTPN22 function, suggest that this phosphatase is a key regulator of autoimmunity. To determine whether other genetic variants in PTPN22 contribute to the development of RA, we sequenced the coding regions of this gene in 48 white North American patients with RA and identified 15 previously unreported SNPs, including 2 coding SNPs in the catalytic domain. We then genotyped 37 SNPs in or near PTPN22 in 475 patients with RA and 475 individually matched controls (sample set 1) and selected a subset of markers for replication in an additional 661 patients with RA and 1,322 individually matched controls (sample set 2). Analyses of these results predict 10 common (frequency >1%) PTPN22 haplotypes in white North Americans. The sole haplotype found to carry the previously identified W620 risk allele was strongly associated with disease in both sample sets, whereas another haplotype, identical at all other SNPs but carrying the R620 allele, showed no association. R620W, however, does not fully explain the association between PTPN22 and RA, since significant differences between cases and controls persisted in both sample sets after the haplotype data were stratified by R620W. Additional analyses identified two SNPs on a single common haplotype that are associated with RA independent of R620W, suggesting that R620W and at least one additional variant in the PTPN22 gene region influence RA susceptibility.

Arthritis, Rheumatoid↗
PubMed2005

Hardy-Weinberg testing of a single homozygous genotype.

No proper statistical test is available for the evaluation of deviation of a single homozygous genotype from Hardy-Weinberg equilibrium (HWE) proportion. We propose a 1-d.f. chi2-test. The power of the proposed test is favorable compared to existing HWE testing procedures. The applications of this test are discussed.

Gene Frequency↗
PubMed2004

Impact of shared epitope genotype and ethnicity on erosive disease: a meta-analysis of 3,240 rheumatoid arthritis patients.

OBJECTIVE: The strongest known genetic association in rheumatoid arthritis (RA) is with HLA-DRB1 alleles that share a similar amino acid sequence, termed the shared epitope (SE). Although many studies have examined the association of the SE with disease severity, the results have been inconsistent, which may reflect the relatively small sample sizes or ethnic differences. The aim of this study was to assess the association of HLA-DRB1 SE alleles and genotype with the development of bony erosions in RA by meta-analysis. METHODS: We identified English-language articles published between January 1, 1987 and June 1, 1999 through Medline, EMBase, and manual searches of 6 relevant journals. Included were studies in which molecular typing of HLA-DRB1 alleles was performed and in which the presence or absence of bony erosions was reported. Data were extracted from the studies, and erosions were coded as present or absent. Authors were contacted for missing information and data on individual patients. RESULTS: A total of 29 studies and 3,240 patients were available for analysis. The summary odds ratios (ORs), when all patients were evaluated as a single group, demonstrated a significant association of the presence of the SE (2 or 1 versus 0 SE alleles) with erosions (OR 2.0; 95% confidence interval [95% CI] 1.8-2.2), although significant heterogeneity was present (P = 0.002). Subgroup analyses demonstrated the important influence of ethnic background. For example, no association of the SE with erosions was demonstrated in Greeks (OR 0.8 [95% CI 0.2-1.5]). In contrast, there was a striking dose-dependent relationship in southern European Caucasians and Asians, with ORs as high as 6.2 and 5.4, respectively, in patients with 2 SE alleles. Although our ability to assess the relationship between SE genotype and erosions was limited, particular importance of the DRB1*0401 SE allele was suggested in an analysis restricted to northern European Caucasians. CONCLUSION: The SE is associated with the development of erosive disease in many ethnic groups; however, striking exceptions exist. These variations may be due to allele differences between populations, such as the frequency of DRB1*0401 among different ethnic groups. Further study to better understand the genetic and environmental differences between these populations may provide insight into mechanisms that influence the clinical expression of RA.

Arthritis, Rheumatoid↗
PubMed2004

High resolution HLA-DRB1 identification of a Caucasian population.

Polymerase chain reaction-sequence-specific oligonucleotide probes typing methods have been applied to 1000 individuals from the Northern Ireland population to give human leukocyte antigen DRB1 (HLA-DRB1) allele assignment. HLA-DRB1 allele frequencies and four-locus haplotypes (A/B/C/DR) for this Caucasian population, based on HLA class I and class II allele assignment, are now presented. No significant deviations from Hardy-Weinberg proportions were observed. The HLA-C locus exhibited marginal evidence of selection (p<0.03, uncorrected one-sided test) in the direction of balancing selection; the HLA-A, -B, and -DRB1 allele frequency distributions were compatible with expectations under a neutral model (which does not mean that selection is not operating). Evidence for selection was seen on haplotypes HLA-A*010101-B*0801-DRB1*030101 and HLA-A*290201-B*440301-DRB1*070101 based on their patterns of linkage disequilibrium.

Alleles↗
PubMed2004

Absolute risk of childhood-onset type 1 diabetes defined by human leukocyte antigen class II genotype: a population-based study in the United Kingdom.

The autoimmune disease process leading to childhood-onset type 1 diabetes appears to start in infancy, and decisions on treatment to prevent initiation of autoimmunity will need to be based on genetic susceptibility alone. We set out to quantify the absolute risk associated with human leukocyte antigen (HLA) DRB1-DQA1-DQB1 class II genotypes and to develop strategies for recruitment into primary prevention trials. HLA class II haplotype- and genotype-specific risks were derived from 753 United Kingdom families from the Bart's-Oxford population-based study of type 1 diabetes and combined with incidence data from the region to calculate the absolute risk of development of diabetes. A hierarchy of susceptibility was established for both HLA class II haplotypes and genotypes, and the sensitivity and specificity of each genotype was established relative to age at disease onset. Highest risk was conferred by the genotype DRB1*03-DQA1*0501-DQB1*0201/DRB1*0401-DQA1*0301-DQB1*0302 (5% absolute risk of diabetes by age 15 yr), although sensitivity was only 22.6%. Combining the six highest risk genotypes conferred similar risk but increased sensitivity to 36.6% and was most sensitive for diagnosis of diabetes before age 5 yr (48.4%), whereas inclusion of 11 genotypes achieved the same sensitivity for diagnosis for ages 10-14 yr. Analysis of genotype-specific risk should form the basis for design of future primary prevention trials in the general population.

Age of Onset↗
PubMed2003

Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans.

An underlying complex genetic susceptibility exists in multiple sclerosis (MS), and an association with the HLA-DRB1*1501-DQB1*0602 haplotype has been repeatedly demonstrated in high-risk (northern European) populations. It is unknown whether the effect is explained by the HLA-DRB1 or the HLA-DQB1 gene within the susceptibility haplotype, which are in strong linkage disequilibrium (LD). African populations are characterized by greater haplotypic diversity and distinct patterns of LD compared with northern Europeans. To better localize the HLA gene responsible for MS susceptibility, case-control and family-based association studies were performed for DRB1 and DQB1 loci in a large and well-characterized African American data set. A selective association with HLA-DRB1*15 was revealed, indicating a primary role for the DRB1 locus in MS independent of DQB1*0602. This finding is unlikely to be solely explained by admixture, since a substantial proportion of the susceptibility chromosomes from African American patients with MS displayed haplotypes consistent with an African origin.

Alleles↗
PubMed2003

An integrated haplotype map of the human major histocompatibility complex.

Numerous studies have clearly indicated a role for the major histocompatibility complex (MHC) in susceptibility to autoimmune diseases. Such studies have focused on the genetic variation of a small number of classical human-leukocyte-antigen (HLA) genes in the region. Although these genes represent good candidates, given their immunological roles, linkage disequilibrium (LD) surrounding these genes has made it difficult to rule out neighboring genes, many with immune function, as influencing disease susceptibility. It is likely that a comprehensive analysis of the patterns of LD and variation, by using a high-density map of single-nucleotide polymorphisms (SNPs), would enable a greater understanding of the nature of the observed associations, as well as lead to the identification of causal variation. We present herein an initial analysis of this region, using 201 SNPs, nine classical HLA loci, two TAP genes, and 18 microsatellites. This analysis suggests that LD and variation in the MHC, aside from the classical HLA loci, are essentially no different from those in the rest of the genome. Furthermore, these data show that multi-SNP haplotypes will likely be a valuable means for refining association signals in this region.

Chromosome Mapping↗
PubMed2003

PyPop: a software framework for population genomics: analyzing large-scale multi-locus genotype data.

Software to analyze multi-locus genotype data for entire populations is useful for estimating haplotype frequencies, deviation from Hardy-Weinberg equilibrium and patterns of linkage disequilibrium. These statistical results are important to both those interested in human genome variation and disease predisposition as well as evolutionary genetics. As part of the 13th International Histocompatibility and Immunogenetics Working Group (IHWG), we have developed a software framework (PyPop). The primary novelty of this package is that it allows integration of statistics across large numbers of data-sets by heavily utilizing the XML file format and the R statistical package to view graphical output, while retaining the ability to inter-operate with existing software. Largely developed to address human population data, it can, however, be used for population based data for any organism. We tested our software on the data from the 13th IHWG which involved data sets from at least 50 laboratories each of up to 1000 individuals with 9 MHC loci (both class I and class II) and found that it scales to large numbers of data sets well.

Computational Biology↗
PubMed2002

An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections.

The role of host genetic factors in conferring predisposition or protection in infectious diseases has become evident. Infection with group A streptococci causes a wide spectrum of disease ranging from pharyngitis to streptococcal toxic shock syndrome. The release of inflammatory cytokines triggered by streptococcal superantigens has a pivotal role in invasive streptococcal disease. However, individuals infected with the same strain can develop very different manifestations. We report here that the immunogenetics of the host influence the outcome of invasive streptococcal infection, and demonstrate the underlying mechanism for these genetic associations. Specific human leukocyte antigen class II haplotypes conferred strong protection from severe systemic disease, whereas others increased the risk of severe disease. Patients with the DRB1*1501/DQB1*0602 haplotype mounted significantly reduced responses and were less likely to develop severe systemic disease (P < 0.0001). We propose that human leukocyte antigen class II allelic variation contributes to differences in severity of invasive streptococcal infections through their ability to regulate cytokine responses triggered by streptococcal superantigens.

Fasciitis, Necrotizing↗
PubMed2002

Haplotype frequency estimation in patient populations: the effect of departures from Hardy-Weinberg proportions and collapsing over a locus in the HLA region.

Haplotype analyses are an important area in the study of the genetic components of human disease. Associations between markers and disease loci that are not evident with a single marker locus may be identified in multi-locus marker analyses using estimated haplotype frequencies (HFs). Procedures that make use of the expectation-maximization (EM) algorithm to estimate HFs from unphased genotype data are in common use in genetic studies. The EM algorithm uses these unphased genotype frequencies along with the assumption of Hardy-Weinberg proportions (HWP) to converge on HF estimates. In this paper, we assess the accuracy of EM estimates of HFs in patients with type I diabetes for whom the true haplotypes are known, but the data are analyzed ignoring family information to allow comparison between estimated and true frequencies. The data consist of six HLA loci with high levels of polymorphism and a range of departures from HWP and linkage equilibrium. While the overall accuracy of the EM estimates is good, there can be large over- and underestimates of particular HFs, even for common haplotypes, especially when the loci involved deviate significantly from HWP. Estimating HFs for three or more loci and then collapsing over loci so as to generate two locus haplotypes can improve the accuracy of the estimation. The collapsing procedure is most beneficial when one of the loci in the two-locus haplotype of interest deviates significantly from HWP and the locus collapsed over is in linkage disequilibrium with the other loci.

Algorithms↗
PubMed2002

The HLA class I A locus affects susceptibility to type 1 diabetes.

Human leukocyte antigen A (HLA-A) genotypes were determined for samples from 283 multiplex, Caucasian, type 1 diabetes families from the Human Biological Data Interchange (HBDI) using an immobilized probe assay. Distribution of HLA-A alleles transmitted to patients was significantly different from that in affected family-based controls (AFBAC) (p = 0.004). Transmission disequilibrium test (TDT) analysis revealed differential transmission of several HLA-A alleles from parents to affected offspring. HLA class II DRB1 and DQB1 loci were also typed, allowing assignment of HLA-A alleles to haplotypes and calculation of linkage disequilibrium values. Some of the apparent effects of HLA-A alleles on type 1 diabetes susceptibility were attributable to linkage disequilibrium with DR and DQ alleles, although others were not. The differences in frequencies between patients and controls of alleles A*0101, A*2402, and A*3002 could not be explained by linkage disequilibrium alone. Our results suggest an important role for class I antigens in modulating susceptibility to type 1 diabetes.

Alleles↗
PubMed2002

Clinical usefulness of genetic information for predicting radiographic damage in rheumatoid arthritis.

OBJECTIVE: To determine whether knowledge of genetic information aids the prediction of radiographic damage for patients with rheumatoid arthritis (RA) in whom extensive sociodemographic, family history, clinical, and immunologic information is available. METHODS: Subjects included 146 Caucasian women who were participants in a community based longitudinal study of RA. Our primary outcome measure was the severity of erosive disease. Nongenetic covariates included age at RA onset, disease duration, family history of RA, education level, family income, baseline values of function, painful and swollen joint groups and pain rating, and rheumatoid factor positivity. All women were genotyped for the HLA-DRB1 shared epitope (SE) and the tumor necrosis factor a (TNFa) microsatellite. Likelihood ratio tests (LRT) were performed to evaluate the usefulness of genetic information for predicting radiographic damage in RA, after adjusting for nongenetic covariates. Receiver operating characteristic (ROC) curves displaying the sensitivity and specificity of combinations of nongenetic and genetic information were derived, and the areas under the curves (AUC) were compared. RESULTS: Genetic information contributed significantly to the prediction of radiographic damage in RA even after adjusting for all nongenetic covariates (p value for LRT = 0.0019). The odds ratio describing the risk of severe erosive disease among individuals who had inherited both the SE and TNFa allele 11 (TNFa11) was 7.6 compared to individuals who were SE and TNFa11 negative. Analysis of ROC curves confirmed the usefulness of genetic information. CONCLUSION: Genetic information is useful for predicting radiographic damage in RA even for patients in whom extensive sociodemographic, family history, clinical, and immunologic information is available.

Adult↗