HLA Alleles (hla + allele)

Distribution by Scientific Domains
Distribution within Medical Sciences

Selected Abstracts

The clinical impact of pharmacogenetics on the treatment of epilepsy

EPILEPSIA, Issue 1 2009
Wolfgang Löscher
Summary Drug treatment of epilepsy is characterized by unpredictability of efficacy, adverse drug reactions, and optimal doses in individual patients, which, at least in part, is a consequence of genetic variation. Since genetic variability in drug metabolism was reported to affect the treatment with phenytoin more than 25 years ago, the ultimate goal of pharmacogenetics is to use the genetic makeup of an individual to predict drug response and efficacy, as well as potential adverse drug events. However, determining the practical relevance of pharmacogenetic variants remains difficult, in part because of problems with study design and replication. This article reviews the published work with particular emphasis on pharmacogenetic alterations that may affect efficacy, tolerability, and safety of antiepileptic drugs (AEDs), including variation in genes encoding drug target (SCN1A), drug transport (ABCB1), drug metabolizing (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins. Although the current studies associating particular genes and their variants with seizure control or adverse events have inherent weaknesses and have not provided unifying conclusions, several results, for example that Asian patients with a particular HLA allele, HLA-B*1502, are at a higher risk for Stevens-Johnson syndrome when using carbamazepine, are helpful to increase our knowledge how genetic variation affects the treatment of epilepsy. Although genetic testing raises ethical and social issues, a better understanding of the genetic influences on epilepsy outcome is key to developing the much needed new therapeutic strategies for individuals with epilepsy. [source]

Crystal structure of HLA-A*2402 complexed with a telomerase peptide

Abstract HLA-A*2402 is the most commonly expressed HLA allele in oriental populations. It is also widely expressed in the Caucasian population, making it one of, if not the most abundant HLA,I types. In order to study its structure in terms of overall fold and peptide presentation, a soluble form of this HLA,I (,1, ,2, ,3 and ,2m domains) has been expressed, refolded and crystallized in complex with a cancer-related telomerase peptide (VYGFVRACL), and its structure has been solved to 2.8,Ĺ resolution. The overall structure of HLA-A*2402 is virtually identical to other reported peptide-HLA,I structures. However, there are distinct features observable from this structure at the HLA,I peptide binding pockets. The size and depth of pocket,B makes it highly suitable for binding to large aromatic side chains, which explains the high prevalence of tyrosine at peptide position,2. Also, for HLA binding at peptide position,5, there is an additional anchor point, which allows the proximal amino acids to protrude out, providing a prominent feature for TCR interaction. Finally, pocket,F allows the anchor residue at position,9 to be bound unusually deeply within the HLA structure. [source]

HLA allele and haplotype frequencies in the Albanian population and their relationship with the other European populations

G. Sulcebe
Summary Human leucocyte antigen (HLA) alleles are very interesting markers in identifying population relationships. Moreover, their frequency distribution data are important in the implementation of donor,recipient registry programs for transplantation purposes and also in determining the genetic predisposition for many diseases. For these reasons, we studied the HLA class I and II allele and haplotype frequencies in 160 healthy, unrelated Albanian individuals originating from all regions of the country. The HLA genotyping was performed through a 2-digit resolution SSOP method. The data were analysed with Arlequin and Phylip programs. No deviation was found from the Hardy,Weinberg equilibrium. A total of 17 A*, 30 B*, 12 Cw*, 13 DRB1* and 5 DQB1* alleles were identified. The six most frequent HLA-A-B-DRB1 haplotypes were A*02,B*18,DRB1*11 (5.60%), A*02,B*51,DRB1*16 (4.74%), A*01,B*08,DRB1*03 (3.48%), A*24,B*35,DRB1*11 (2.77%), A*02,B*51,DRB1*13 (2.21%), A*24,B*35,DRB1*14 (1.89%). Interestingly, 12 HLA-A-B-Cw-DRB1-DQB1 haplotypes occurred at a frequency >1%. When compared with the other populations, a close relationship was found with North Greek, Bulgarian, Macedonian, Romanian, Turkish, Cretan, Serbian, Croatian and Italian populations. A higher differentiation in allele frequency level was found with Western Europe populations. These data are the first report of HLA allele and haplotype distribution in an Albanian population inside this country. When compared with other populations, their distribution frequencies show close similarities with neighbouring populations of the entire Balkan area. [source]

Identification of naturally processed CD8 T,cell epitopes from prostein, a prostate tissue-specific vaccine candidate

Abstract Prostein is a prostate tissue-specific protein that is uniquely and abundantly expressed in normal and cancerous prostate tissues. Due to this expression profile, we examined the immunogenicity of prostein as a potential vaccine candidate for prostate cancer. To determine the presence of CD8 T,cells specific for naturally processed prostein-derived epitopes in healthy individuals, we developed and applied an in vitro stimulation protocol. Using this protocol, we identified CD8 T,cells specific for prostein in the peripheral blood of a male and a female donor. Prostein-specific CD8 T,cell clones specifically recognized prostein-expressing targets, including prostate tumor cell lines expressing the relevant HLA alleles. CD8 T,cell clones isolated from the male donor were significantly less effective in recognizing target cells compared to cells isolated from the female donor and appeared to recognize subdominant epitopes. The identification of a prostein-specificCD8 T,cell repertoire supports the development of prostein in vaccination strategies against prostate cancer. Furthermore, the naturally processed peptide epitopes identified provide tools for the development of peptide-based vaccination strategies against prostate cancer and for monitoring of prostein-specific responses in vaccinated patients. [source]

Characterization of HLA DR3/DQ2 transgenic mice: a potential humanized animal model for autoimmune disease studies

Dan Chen
Abstract Linkage studies indicate close associations of certain HLA alleles with autoimmune diseases. To better understand how specific HLA alleles are related to disease pathogenesis, we have generated an HLA DR3/DQ2 transgenic mouse utilizing a 550-kb yeast artificial chromosome (YAC) construct containing the complete DR,, DR,1, DR,3, DQ,, and DQ, regions. The transgenic mouse (4D1/C2D) in an I-A,o background appears healthy with no signs of autoimmune diseases. Lymphoid tissues as well as CD4+ T cells develop normally. Characterization of the transgene expression demonstrates that ,90% of B cells express high levels of DR3 and 50,70% of B cells express DQ2. CD11c+ dendritic cells express high levels of DR and DQ. Approximately12,18% of resting T cells are positive for DR expression, and further up-regulation to 40,50% expression is seen upon activation with anti-CD3/anti-CD28 mAb. These results suggest that the transgenic construct confers a high fidelity to the normal human temporal and spatial expression profile. Analysis of T cell receptor repertoire in transgenic mice confirms that DR3/DQ2 are able to mediate thymic selection. Furthermore, transgenic mice respond to a DR3-restricted antigen, demonstrating antigen processing and presentation by antigen-presenting cells (APC). Purified T cells from ovalbumin (OVA)-immunized 4D1 mice respond to human APC co-cultured with OVA, suggesting appropriate antigen/DR3 or DQ2 recognition by murine T cells. Immunoglobulin isotype switching is also observed, indicating functional T-B cognate interactions. Thus, the DR3/DQ2 transgenic mouse has normal lymphoid development and functionality that are mediated by HLA transgenes and can be used to investigate HLA-associated immunological questions. [source]

Specific human leukocyte antigen class I and II alleles associated with hepatitis C virus viremia,,§

HEPATOLOGY, Issue 5 2010
Mark H. Kuniholm
Studies of human leukocyte antigen (HLA) alleles and their relation with hepatitis C virus (HCV) viremia have had conflicting results. However, these studies have varied in size and methods, and few large studies assessed HLA class I alleles. Only one study conducted high-resolution class I genotyping. The current investigation therefore involved high-resolution HLA class I and II genotyping of a large multiracial cohort of U.S. women with a high prevalence of HCV and HIV. Our primary analyses evaluated associations between 12 HLA alleles identified through a critical review of the literature and HCV viremia in 758 HCV-seropositive women. Other alleles with >5% prevalence were also assessed; previously unreported associations were corrected for multiple comparisons. DRB1*0101 (prevalence ratio [PR] = 1.7; 95% confidence interval [CI] = 1.1,2.6), B*5701 (PR=2.0; 95% CI = 1.0,3.1), B*5703 (PR = 1.7; 95% CI = 1.0,2.5), and Cw*0102 (PR = 1.9; 95% CI = 1.0,3.0) were associated with the absence of HCV RNA (i.e., HCV clearance), whereas DRB1*0301 (PR = 0.4; 95% CI = 0.2,0.7) was associated with HCV RNA positivity. DQB1*0301 was also associated with the absence of HCV RNA but only among HIV-seronegative women (PR = 3.4; 95% CI = 1.2,11.8). Each of these associations was among those predicted. We additionally studied the relation of HLA alleles with HCV infection (serostatus) in women at high risk of HCV from injection drug use (N = 838), but no significant relationships were observed. Conclusion: HLA genotype influences the host capacity to clear HCV viremia. The specific HLA associations observed in the current study are unlikely to be due to chance because they were a priori hypothesized. (HEPATOLOGY 2010.) [source]

The peopling of Madeira archipelago (Portugal) according to HLA genes

A. Arnaiz-Villena
Summary The Madeira-Porto Santo Archipelago was officially colonized in 1420 by Portuguese settlers. Its importance in Columbus' information for the American discovery and for slave traffic across the Atlantic is unquestionable. Thus, a complex peopling may have given rise to a present-day high admixture of ethnicities according to HLA genes. A sample of 173 healthy unrelated Madeirans was analysed and compared with 6986 HLA chromosomes from other worldwide populations. Genetic distances, neighbour-joining dendrograms and correspondence analyses were used for comparisons. Southern European, North African (including Canary Islands), Jewish and Mediterranean typical HLA alleles were found and genetic distances from Madeirans to these populations were the closest ones. In addition A*24-B*65-DRB1*0102-DQB1*0501 and A*68-B*08-DRB1*0301-DQB1*0201 haplotypes were newly found in Madeira and not found in any other population. Jewish-Armenian-Middle East haplotype (A*33-B*65-DRB1*0102-DQB1*0501) is one of the most common haplotypes; this haplotype is also present in Spaniards and North Africans. Quantitatively, Portuguese, North Africans (Algerians), Spaniards and Canary Islanders (in this order) are the most important parental populations to Madeirans. Results are discussed on the basis of the recorded historical peopling which does not show a noticeable African gene input in present-day Madeiran population according to our data; one of the closest related populations found is the Canary Islanders, suggesting that Guanche (Canary Islands first inhabitants) slaves gene flow is still noticed at present, both in Madeira and in Canary Islands populations. [source]

Lack of association between HLA-A, -B and -DRB1 alleles and the development of SARS: a cohort of 95 SARS-recovered individuals in a population of Guangdong, southern China

P. Xiong
Summary Severe acute respiratory syndrome (SARS), caused by infection with a novel coronavirus (SARS-CoV), was the first major novel infectious disease at the beginning of the 21st century, with China especially affected. SARS was characterized by high infectivity, morbidity and mortality, and the confined pattern of the disease spreading among the countries of South-East and East Asia suggested the existence of susceptible factor(s) in these populations. Studies in the populations of Hong Kong and Taiwan showed an association of human leucocyte antigen (HLA) polymorphisms with the development and/or severity of SARS, respectively. The aim of the present study was to define the genotypic patterns of HLA-A, -B and -DRB1 loci in SARS patients and a co-resident population of Guangdong province, southern China, where the first SARS case was reported. The samples comprised 95 cases of recovered SARS patients and 403 unrelated healthy controls. HLA -A, -B and -DRB1 alleles were genotyped using polymerase chain reaction with sequence-specific primers. The severity of the disease was assessed according to the history of lung infiltration, usage of assisted ventilation and occurrence of lymphocytopenia. Although the allelic frequencies of A23, A34, B60, DRB1*12 in the SARS group were slightly higher, and A33, -B58 and -B61 were lower than in the controls, no statistical significance was found when the Pc value was considered. Similarly, no association of HLA alleles with the severity of the disease was detected. Thus, variations in the major histocompatibility complex are unlikely to have contributed significantly to either the susceptibility or the severity of SARS in the population of Guangdong. [source]

Identification of novel single nucleotide polymorphisms within the NOTCH4 gene and determination of association with MHC alleles

R. Tazi-Ahnini
Summary Mapping of disease susceptibility loci within the MHC has been partly hampered by the high degree of polymorphism of the HLA genes and the high level of linkage disequilibrium (LD) between markers within the MHC region. It is therefore important to identify new markers and determine the level of LD between HLA alleles and non-HLA genes. The NOTCH4 gene lies at the centromeric end of the MHC class III region, approximately 335 kb telomeric of the DRB1 locus. The encoded protein is an oncogene that is important in regulating vascular development and remodelling. A recent report has linked polymorphisms within NOTCH4 with risk of developing schizophrenia. We have investigated if coding polymorphisms exist within this gene and have identified three single nucleotide polymorphisms; a synonomous T to C transition at +1297 (HGBASE accession number SNP000064386), a synonomous A to G transition at +3061 (SNP000064387) and an A to G transition at +3063 which results in a replacement of glycine with aspartic acid at amino acid 279 (SNP000064388). The allele frequencies of +1297T, +3061A and +3063G were 0.65, 0.66 and 0.66, respectively. Linkage disequilibrium was detected both between these markers and with MHC alleles. These findings can be used in the fine mapping of disease susceptibility alleles within the MHC. [source]

Associations of HLA class II alleles with pulmonary tuberculosis in Thais

S. Vejbaesya
Summary Tuberculosis is an important infectious disease in Thailand. Susceptibility to tuberculosis is influenced not only by the environment but also by host genetic factors. In this study, we investigated HLA alleles in 82 patients with tuberculosis from Bangkok and in 160 normal controls. HLA-DRB1, DQA1 and DQB1 genotyping was performed by the PCR-SSO method. The frequency of HLA-DQB1*0502 was increased in tuberculosis patients compared to the normal controls (P = 0.01, OR = 2.06). In contrast, the frequencies of DQA1*0601 and DQB1*0301 were decreased in tuberculosis patients compared to the controls (P = 0.02 and P = 0.01, respect­ively). Our results suggest that HLA-DQB1*0502 may be involved in the development of pulmonary tuberculosis, whereas HLA-DQA1*0601 and DQB1*0301 may be associated with protection against tuberculosis. [source]

Geographical differences within Finland in the frequency of HLA-DQ genotypes associated with Type 1 diabetes susceptibility

J. Ilonen
Geographical variations in the HLA-DQ genotypes associated with risk for type 1 diabetes were evaluated in Finland. Samples of 280 diabetic children diagnosed in Turku (south-west of the country) and 405 in Oulu (north of the country) were studied as well as a series of 14 096 and 10 016 newborns collected from the same hospitals. There were no major differences in the risk or protection conferred by various HLA-DQB1 genotypes between south-western and northern parts of the country when genotypes of children with type 1 diabetes from these two centres were compared with those of newborns, representing the background populations. However, the distribution of various genotypes was different, both in diabetic children and in newborns, when compared between the two regions (P < 0.0001, ,2 test). These differences reflected the allele frequencies in newborn cohorts in which HLA-DQB1*02 and DQB1*0301 were found more often in Turku and DQB1*0302 more often in Oulu (P < 0.0001 for all differences). Similar types of differences were detected when children who were diagnosed as having diabetes during the national ,Childhood Diabetes in Finland' (DiMe) study between the years 1986,1989 were compared according to their residence. The observed differences in genotype and allele frequencies demonstrate the heterogeneity for HLA alleles even in a population that is generally regarded as highly homogeneous. These differences also affect the sensitivity and efficiency of the screening programme used for identifying infants with genetic susceptibility to IDDM in the ongoing Finnish Diabetes Prediction and Prevention Study. [source]

Changes in impact of HLA class I allele expression on HIV-1 plasma virus loads at a population level over time

Michiko Koga
ABSTRACT HLA class I allele types have differential impacts on the level of the pVL and outcome of HIV-1 infection. While accumulations of CTL escape mutations at population levels have been reported, their actual impact on the level of the pVL remains unknown. In this study HLA class I types from 141 untreated, chronically HIV-1 infected Japanese patients diagnosed from 1995,2007 were determined, and the associations between expression of individual HLA alleles and level of pVL analyzed. It was found that the Japanese population has an extremely narrow HLA distribution compared to other ethnic groups, which may facilitate accumulation of CTL escape mutations at the population level. Moreover while they uniquely lack the most protective HLA-B27/B57, they commonly express the alleles that are protective in Caucasians (A11:10.4%, A26:11.55%, B51:8.6% and Cw14:12.7%). Cross-sectional analyses revealed no significant associations between expression of individual alleles and the level of the pVL. The patients were then stratified by the date of HIV diagnosis and the analyses repeated. It was found that, before 2001, B51+ individuals displayed significantly lower pVL than the other patients (median: 5150 vs. 18 000 RNA copies/ml, P= 0.048); however thereafter this protective effect waned and disappeared, whereas no changes were observed for any other alleles over time. These results indicate that, at a population level, some HLA alleles have been losing their beneficial effects against HIV disease progression over time, thereby possibly posing a significant challenge for HIV vaccine development. However such detrimental effects may be limited to particular HLA class I alleles. [source]

Association of HLA subtype DRB1*0407 in Colombian patients with actinic prurigo

Alfonso Suárez
Background: Human leukocyte antigen (HLA) DRB1*0407 had been associated with actinic prurigo in different populations. This class II HLA-DR subtype had not been studied in Colombia. Objective: The objective of this study was to establish whether there was an association of actinic prurigo with HLA DR in a Colombian population. Materials and methods: Forty patients with a clinical diagnosis of actinic prurigo and 40 healthy subjects, paired by age, sex and birthplace, were studied. HLA typing for HLA DRB1 and DRB1*04, if necessary, was performed by the PCR-SSP method using blood samples. Results: A high frequency of HLA DRB1*0407 was found in the patients (97.5% vs. 30%; P< 0.00001). The allelic frequency of HLA DRB1*0407 was 63.8% in the case group, and 14.5% in the controls (P<0.00001). In the control group, there was a higher frequency of the alleles DRB1*01 (14.5% vs. 1.25%; P=0.0027) and DRB1*13 (23.7% vs. 2.5%; P=0.00013). Limitations: The small number of controls does not allow us to drive conclusions about other HLA alleles. Conclusions: HLA subtype DRB1*0407, found in actinic prurigo patients in studies conducted in England, Scotland, Ireland and Mexico, was also associated in Colombian patients. This finding, concordant in patients from different ethnic groups, could be helpful in the diagnosis of this disease and probably important in its pathogenesis. DRB1*01 and DRB1*13 alleles were more frequent in controls than in patients; we do not know whether they play any role in the resistance to the disease. [source]

Enhancement of immunogenicity of JEG-3 Cells by ectopic expression of HLA-A*0201 and CD80

Serpil Koc
The chorioncarcinoma cell line JEG-3 escapes immunity by secretion of leukocyte inhibitory factor suppressing leukocyte proliferation. The cells lack expression of classical HLA alleles but express nonclassical HLA-G, which binds to killer inhibitory receptor of natural killer cells, preventing cytolysis. We investigated whether JEG-3 cells are capable of immune stimulation after introduction of classical HLA and T-cell costimulatory signals. JEG-3 cells were transduced with vectors for HLA-A*0201 and/or CD80. Parental JEG-3, or JEG-3/A2, JEG-3/CD80, or JEG-3/A2/CD80 were used to stimulate allogeneic T cells. While parental JEG-3 cells induced only marginal proliferation of resting T cells, HLA-A2 or CD80 expressing JEG-3 induced enhanced proliferation. Double transfectants were most efficient. This difference was more obvious when T cells were preactivated by PHA. T cell lines restimulated with JEG-3 transfectants were characterized for expansion, phenotypes, and cytolytic activity. HLA-A2 matched and nonmatched donors were compared. T cells stimulated with JEG-3/A2 or JEG-3/CD80 were cytolytic towards parental JEG-3 cells. Again double positive JEG-3/A2/CD80 induced highest cytolytic activity, most obvious in HLA-nonmatched donors suggesting alloreactivity to HLA. Our data suggest that, in spite of immunosuppressive mechanisms, proliferative and cytolytic T cell responses are induced by JEG-3 cells when classical HLA and/or costimulatory signals are present on the cells. [source]

Does pregnancy provide vaccine-like protection against rheumatoid arthritis?

Katherine A. Guthrie
Objective Previous studies have evaluated the correlation between rheumatoid arthritis (RA) risk and pregnancy history, with conflicting results. Fetal cells acquired during pregnancy provide a potential explanation for modulation of RA risk by pregnancy. The present study was undertaken to examine the effect of parity on RA risk. Methods We examined parity and RA risk using results from a population-based prospective study in Seattle, Washington and the surrounding area and compared women who were recently diagnosed as having RA (n = 310) with controls (n = 1,418). We also evaluated the distribution of parity in cases according to HLA genotype. Results We found a significant reduction of RA risk associated with parity (relative risk [RR] 0.61 [95% confidence interval 0.43,0.86], P = 0.005). RA risk reduction in parous women was strongest among those who were younger. Most striking was that RA risk reduction correlated with the time that had elapsed since the last time a woman had given birth. RA risk was lowest among women whose last birth occurred 1,5 years previously (RR 0.29), with risk reduction lessening progressively as the time since the last birth increased (for those 5,15 years since last birth, RR 0.51; for those >15 years, RR 0.76), compared with nulliparous women (P for trend = 0.007). No correlation was observed between RA risk and either age at the time a woman first gave birth or a woman's total number of births. Among cases with the highest genetic risk of RA (i.e., those with 2 copies of RA-associated HLA alleles), a significant underrepresentation of parous women versus nulliparous women was observed (P = 0.02). Conclusion In the present study, there was a significantly lower risk of RA in parous women that was strongly correlated with the time elapsed since a woman had last given birth. While the explanation for our findings is not known, HLA-disparate fetal microchimerism can persist many years after a birth and could confer temporary protection against RA. [source]

HLA type and immune response to Borrelia burgdorferi outer surface protein a in people in whom arthritis developed after Lyme disease vaccination

Robert Ball
Objective To investigate whether persons with treatment-resistant Lyme arthritis,associated HLA alleles might develop arthritis as a result of an autoimmune reaction triggered by Borrelia burgdorferi outer surface protein A (OspA), the Lyme disease vaccine antigen. Methods Persons in whom inflammatory arthritis had developed after Lyme disease vaccine (cases) were compared with 3 control groups: 1) inflammatory arthritis but not Lyme disease vaccine (arthritis controls), 2) Lyme disease vaccine but not inflammatory arthritis (vaccine controls), and 3) neither Lyme disease vaccine nor inflammatory arthritis (normal controls). HLA,DRB1 allele typing, Western blotting for Lyme antigen, and T cell reactivity testing were performed. Results Twenty-seven cases were matched with 162 controls (54 in each control group). Odds ratios (ORs) for the presence of 1 or 2 treatment-resistant Lyme arthritis alleles were 0.8 (95% confidence interval [95% CI] 0.3-2.1), 1.6 (95% CI 0.5,4.4), and 1.75 (95% CI 0.6,5.3) in cases versus arthritis controls, vaccine controls, and normal controls, respectively. There were no significant differences in the frequency of DRB1 alleles. T cell response to OspA was similar between cases and vaccine controls, as measured using the stimulation index (OR 1.6 [95% CI 0.5,5.1]) or change in uptake of tritiated thymidine (counts per minute) (OR 0.7 [95% CI 0.2,2.3]), but cases were less likely to have IgG antibodies to OspA (OR 0.3 [95% CI 0.1,0.8]). Cases were sampled closer to the time of vaccination (median 3.59 years versus 5.48 years), and fewer cases had received 3 doses of vaccine (37% versus 93%). Conclusion Treatment-resistant Lyme arthritis alleles were not found more commonly in persons who developed arthritis after Lyme disease vaccination, and immune responses to OspA were not significantly more common in arthritis cases. These results suggest that Lyme disease vaccine is not a major factor in the development of arthritis in these cases. [source]

Transfer of the shared epitope through microchimerism in women with rheumatoid arthritis

J. M. Rak
Objective Rheumatoid arthritis (RA) is an autoimmune disease that affects mostly women and is associated with HLA,DRB1 genes having in common a shared epitope sequence. In parallel, cells and/or DNA originating from pregnancy (microchimerism) persist for decades and could contribute to autoimmunity. The aim of this study was to examine whether microchimerism may be a source of the shared epitope among women with RA. Methods Women with RA and healthy women who lacked RA-associated genes such as HLA,DRB1*01 (n = 33 and n = 46, respectively) and/or HLA,DRB1*04 (n = 48 and n = 64, respectively), were tested for DRB1*01 or DRB1*04 microchimerism by HLA-specific quantitative polymerase chain reaction assays. As controls, alleles not associated with RA (DQB1*02 and DRB1*15/16) were also analyzed. Results Compared with healthy women, women (42% with RA had a higher frequency and higher levels of DRB1*04 microchimerism versus 8%; P = 0.00002) as well as DRB1*01 microchimerism (30% versus 4%; P = 0.0015). Moreover, no difference in microchimerism was observed for alleles not associated with RA. Conclusion Women with RA had microchimerism with RA-associated HLA alleles, but not with non,RA-associated HLA alleles, more often and at higher levels compared with healthy women. These observations are the first to indicate that microchimerism can contribute to the risk of an autoimmune disease by providing HLA susceptibility alleles. [source]

HLA,DRB4 as a genetic risk factor for Churg-Strauss syndrome

Augusto Vaglio
Objective To explore the association between HLA alleles and Churg-Strauss syndrome (CSS), and to investigate the potential influence of HLA alleles on the clinical spectrum of the disease. Methods Low-resolution genotyping of HLA,A, HLA,B, and HLA,DR loci and genotyping of TNFA ,238A/G and TNFA ,308A/G single-nucleotide polymorphisms were performed in 48 consecutive CSS patients and 350 healthy controls. Results The frequency of the HLA,DRB1*07 allele was higher in the CSS patients than in controls (27.1% versus 13.3%; ,2 = 12.64, P = 0.0003, corrected P [Pcorr] = 0.0042, odds ratio [OR] 2.42, 95% confidence interval [95% CI] 1.47,3.99). The HLA,DRB4 gene, present in subjects carrying either HLA,DRB1*04, HLA,DRB1*07, or HLA,DRB1*09 alleles, was also far more frequent in patients than in controls (38.5% versus 20.1%; ,2 = 16.46, P = 0.000058, Pcorr = 0.000232, OR 2.49, 95% CI 1.58,3.09). Conversely, the frequency of the HLA,DRB3 gene was lower in patients than in controls (35.4% versus 50.4%; ,2 = 7.62, P = 0.0057, Pcorr = 0.0228, OR 0.54, 95% CI 0.35,0.84). CSS has 2 major clinical subsets, antineutrophil cytoplasmic antibody (ANCA),positive, with features of small-vessel vasculitis, and ANCA-negative, in which organ damage is mainly mediated by tissue eosinophilic infiltration; analysis of HLA,DRB4 in patients categorized by different numbers of vasculitic manifestations (purpura, alveolar hemorrhage, mononeuritis multiplex, rapidly progressive glomerulonephritis, and constitutional symptoms) showed that its frequency strongly correlated with the number of vasculitis symptoms (P for trend = 0.001). Conclusion These findings indicate that HLA,DRB4 is a genetic risk factor for the development of CSS and increases the likelihood of development of vasculitic manifestations of the disease. [source]

HLA polymorphisms in African Americans with idiopathic inflammatory myopathy: Allelic profiles distinguish patients with different clinical phenotypes and myositis autoantibodies

Terrance P. O'Hanlon
Objective To investigate possible associations of HLA polymorphisms with idiopathic inflammatory myopathy (IIM) in African Americans, and to compare this with HLA associations in European American IIM patients with IIM. Methods Molecular genetic analyses of HLA,A, B, Cw, DRB1, and DQA1 polymorphisms were performed in a large population of African American patients with IIM (n = 262) in whom the major clinical and autoantibody subgroups were represented. These data were compared with similar information previously obtained from European American patients with IIM (n = 571). Results In contrast to European American patients with IIM, African American patients with IIM, in particular those with polymyositis, had no strong disease associations with HLA alleles of the 8.1 ancestral haplotype; however, African Americans with dermatomyositis or with anti,Jo-1 autoantibodies shared the risk factor HLA,DRB1*0301 with European Americans. We detected novel HLA risk factors in African American patients with myositis overlap (DRB1*08) and in African American patients producing anti,signal recognition particle (DQA1*0102) and anti,Mi-2 autoantibodies (DRB1*0302). DRB1*0302 and the European American,, anti,Mi-2,associated risk factor DRB1*0701 were found to share a 4,amino-acid sequence motif, which was predicted by comparative homology analyses to have identical 3-dimensional orientations within the peptide-binding groove. Conclusion These data demonstrate that North American IIM patients from different ethnic groups have both shared and distinct immunogenetic susceptibility factors, depending on the clinical phenotype. These findings, obtained from the largest cohort of North American minority patients with IIM studied to date, add additional support to the hypothesis that the myositis syndromes comprise multiple, distinct disease entities, perhaps arising from divergent pathogenic mechanisms and/or different gene,environment interactions. [source]

The influence of patient characteristics, disease variables, and HLA alleles on the development of radiographically evident sacroiliitis in juvenile idiopathic arthritis

Berit Flatř
Objective To assess the frequency of sacroiliitis and the radiographic and clinical outcome in juvenile idiopathic arthritis (JIA) and determine patient characteristics, early disease variables, and genetic markers that predict development of sacroiliitis. Methods We performed a retrospective cohort study of 314 (79%) of the 400 JIA patients first admitted to the hospital between 1980 and 1985. The participants were examined after a median disease duration of 14.9 years (range 11.7,25.1). Radiographs of the sacroiliac joints, hips, ankles, and tarsi were obtained and studied in a blinded manner by 2 radiologists. The presence of HLA,DRB1 and DPB1 alleles was determined by genotyping and that of HLA,B27 by serologic testing. Variables relating to the onset and course of the disease were obtained by chart reviews. Results Twenty (6%) of the JIA patients developed radiographic sacroiliitis according to the New York criteria. In 9 patients (45%), sacroiliitis had not been demonstrated before the followup examination. At followup, spinal flexion (lateral and anterior) was reduced in 70,75% of patients with sacroiliitis and in 30,35% of those without sacroiliitis. Compared with the JIA patients without sacroiliitis, those with sacroiliitis more frequently had inflammatory back pain, enthesitis, radiographic changes in the hips and calcanei, erosions of any peripheral joint, and uveitis. Predictors of sacroiliitis were HLA,B27, absence of DPB1*02, hip joint involvement within the first 6 months, and disease onset after age 8 years. The following factors were more common among patients in whom sacroiliitis developed than in other JIA patients: DRB1*04, male sex, family history of ankylosing spondylitis, psoriasis, inflammatory back pain, and enthesitis within the first 6 months. Conclusion In the current study, radiographically evident sacroiliitis had developed in 6% of JIA patients after a median disease duration of 14.9 years. HLA,B27, absence of DPB1*02, late onset of disease, and early hip involvement were predictors of sacroiliitis. [source]

Multiple sclerosis in a family on the Faroe Islands

S. Binzer
Background,,, John Kurtzke has proposed that multiple sclerosis (MS) on the Faroe Islands occurred as a result of the spread of a transmittable agent brought to the country during World War II. Aim,,, Kurtzke's theory has been opposed earlier and in this study, we present a family from the Faroe Islands containing a total of 14 family members with MS which show further inconsistencies with the theory. The present study is to our knowledge, the first description of familial incidences of MS on the Faroe Islands. Methods,,, Medical histories were gathered from 12 family members and 6 of the 8 living MS cases were human leukocyte antigen (HLA)-typed. Results,,, Seven family members had primary progressive MS (PPMS), while five had relapsing remitting MS. The HLA-DR15 allele was carried by the three cases with the most aggressive form of MS and they shared a common haplotypes. The HLA types carried by the remaining cases varied. Conclusion,,, This research questions Kurtzke's theory as three of the cases do not conform to the epidemic cohorts described. Furthermore, there appears to be a higher than usual prevalence of PPMS. The high degree of heterogeneity of the HLA types carried indicates that HLA alleles do not independently explain the risk of developing MS. [source]

Testicular carcinoma and HLA Class II genes

CANCER, Issue 9 2002
Dirk J. A. Sonneveld M.D., Ph.D.
Abstract BACKGROUND The association with histocompatibility antigens (HLA), in particular Class II genes (DQB1, DRB1), has recently been suggested to be one of the genetic factors involved in testicular germ cell tumor (TGCT) development. The current study, which uses genotyping of microsatellite markers, was designed to replicate previous associations. METHODS In 151 patients, along with controls comprising parents or spouses, the HLA region (particularly Class II) on chromosome 6p21 was genotyped for a set of 15 closely linked microsatellite markers. RESULTS In both patients and controls, strong linkage disequilibrium was observed in the genotyped region, indicating that similar haplotypes are likely to be identical by descent. However, association analysis and the transmission disequilibrium test did not show significant results. Haplotype sharing statistics, a haplotype method that derives extra information from phase and single marker tests, did not show differences in haplotype sharing between patients and controls. CONCLUSION The current genotyping study did not confirm the previously reported association between HLA Class II genes and TGCT. As the HLA alleles for which associations were reported are also prevalent in the Dutch populations, these associations are likely to be nonexistent or much weaker than previously reported. Cancer 2002;95:1857,63. © 2002 American Cancer Society. DOI 10.1002/cncr.10903 [source]

Association of HLA DQ4-DR8 haplotype with papillary thyroid carcinomas

Teresa Porto
Summary Objective, The association of the human leucocyte antigen (HLA) system with thyroid carcinomas is not clear. We sought to relate HLA alleles to susceptibility to papillary thyroid carcinoma (PTC) and also to clinical and pathological characteristics of PTC patients. Design and patients, The distribution of HLA in 181 unrelated Caucasian patients with PTC was compared to the HLA distribution in 315 normal controls, 31 patients with follicular carcinoma (FTC), 29 patients with lymphocytic thyroiditis (LT) and 50 patients with multinodular goitre (MNG), using a microlymphocytotoxicity assay. Results, Compared to normal controls, patients with PTC showed a significantly increased frequency of HLA-DQ4 [12·8%vs. 3·5%, P = 0·0005, Pcorrected (Pc) = 0·0032, odds ratio (OR) = 4·058, 95% confidence interval (95% CI) = 1·820,9·045] and HLA-DR8 (10·9%vs. 4·3%, P = 0·013, Pc > 0·05, OR = 2·752, 95% CI = 1·275,5·940). DQ4 and DR8 were also significantly increased in patients with MNG (DQ4, 16·3%; DR8, 16·3%) compared to controls (DQ4, P = 0·0019, Pc = 0·011, OR = 5·420, 95% CI = 1·978,14·852; DR8, P = 0·0044, Pc = 0·062). Linkage disequilibrium (LD) for these two alleles was present in controls (D = 0·0130, P = 9·7e-57) and in MNG patients (D = 0·0730, P = 4·6e-19) but not in PTC patients (D = 0·038, P > 0·05). In the subgroup of PTC subjects with concomitant nonthyroidal neoplasias (n = 27), there was a significant (P < 0·05) increase in the frequency of B57 (18·5%), DR11 (56·5%) and DQ3 (81·8%) compared to PTC patients without coexistent neoplasias (2·0%, 21% and 47%, respectively). No significant differences of HLA allele distribution was found in relation to PTC histology, age at diagnosis (> 45 or , 45 years), gender or tumour,node,metastasis (TNM) staging. In patients with FTC, the frequency of DR17 (FTC = 51·6%; controls = 22·5%; P = 0·0009; Pc = 0·0138) was significantly increased compared to controls. Patients with LT showed a higher frequency of the DR11 allele (48·3%) than controls (DR11 = 21·3%; P = 0·0028, Pc = 0·039, OR = 3·445, 95% CI = 1·568,7·567). Conclusions, We have typed the largest series of patients with thyroid carcinomas reported to date, and found that DR8 and DQ4 are independent susceptibility markers for PTC. [source]

The influence of human leucocyte antigen (HLA) genes on autoimmune thyroid disease (AITD): results of studies in HLA-DR3 positive AITD families

Yoshiyuki Ban
Summary objective Population-based, case,control studies have consistently shown association of Graves' disease (GD) with human leucocyte antigen (HLA)-DR3 in Caucasian populations. HLA association studies in Hashimoto's thyroiditis (HT) have also suggested an association with DR3, as well as with other HLA alleles. In contrast, HLA linkage studies in autoimmune thyroid disease (AITD) have been largely negative. The aim of the present study was to investigate the role of HLA in AITD and to explain the observed associations, but lack of linkage, by examining only AITD families with the associated allele, DR3. patients We studied 99 probands (60 with GD and 39 with HT) from 99 multiplex, multigenerational Caucasian AITD families, and 135 age- and sex-matched Caucasian controls in association studies. In addition, a dataset of 34 Caucasian AITD families (out of the 99 families) with HLA-DR3 positive probands were analysed in linkage studies. design HLA typing was performed using the technique of group-specific polymerase chain reaction-amplification with restriction enzyme digestion. Whole genome screening was performed using the ABI microsatellite panels. For fine mapping of the HLA region, we used the following markers: D6S276, D6S464, D6S439, D6S273, tumour necrosis factor , and D6S1610. LOD scores were calculated using the LIPED and GeneHunter programs. results Case,control association analyses using the probands from our 99 Caucasian families showed an association of GD with DRB1*03 [P = 0·00032, relative risk (RR) = 3·4]. Linkage analysis for the HLA region in the 34 DR3 positive AITD families showed negative LOD scores throughout the region. The two-point LOD score at marker D6S273 (the closest to HLA-DRB1) was ,3·0, and the multipoint LOD score was ,7·6, demonstrating strong evidence against linkage to the HLA region in the subset of DR3 positive families. Whole genome screening in the subset of 34 DR3 positive families revealed one locus showing evidence for linkage to AITD: D3S1580 on chromosome 3q27 with a maximum two-point LOD score of 2·1. conclusions The HLA locus did not cosegregate with disease in DR3 positive families, suggesting that HLA genes are not major genes for AITD expression even within DR3 positive families; Hence, although HLA-DR3 was associated with GD in the probands, it was most likely a modulating gene and not causative; and, as the DR3 positive families showed evidence for linkage with D3S1580, it may imply that the DR3 gene modulated the effect of a susceptibility gene within the D3S1580 locus. [source]