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A B Begovich

Publications and source records attributed to A B Begovich.

At least 19 recordsLinked to original sources
PubMed2006

The 620W allele is the PTPN22 genetic variant conferring susceptibility to RA in a Dutch population.

OBJECTIVES: A missense SNP, C1858T, in PTPN22 has been identified as a genetic risk factor for rheumatoid arthritis (RA). Subsequent work has suggested that other variants in this gene, in particular a haplotype marked by the minor allele of rs3789604, are associated with RA in white North Americans independent of C1858T. We tested this hypothesis in an independent white Dutch study. METHODS: A total of 667 RA patients and 286 controls were genotyped for 13 PTPN22 single nucleotide polymorphisms (SNPs) by allele-specific kinetic polymerase chain reaction. rs3789604 was genotyped in an additional 410 RA and 270 UA patients participating in the Leiden early arthritis inception cohort. We conducted single-marker and haplotype association tests. RESULTS: The sole haplotype strongly associated with RA in our Dutch population carries the PTPN22 1858T allele. A second haplotype identical at all other SNPs tested except 1858 was not associated with disease. No significant association of the haplotype tagged by the 3' PTPN22 SNP, rs3789604, with RA susceptibility (P = 0.134) was observed in our sample set. CONCLUSION: We conclude that C1858T is the sole PTPN22 variant predisposing to RA in our white Dutch sample set.

Adult↗
PubMed2005

The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status.

We have recently described the association between rheumatoid arthritis and a coding single-nucleotide polymorphism in the intracellular protein tyrosine phosphatase, PTPN22. The disease-associated polymorphism, 1858 C/T (rs2476601), encodes an amino-acid change (R620W) in one of four SH3 domain binding sites in the PTPN22 molecule. We have now extended our initial studies to address three questions: (1) Is the association with rheumatoid arthritis limited to rheumatoid factor (RF) positive disease? (2) Does homozygosity for PTPN22 R620W substantially increase disease susceptibility? (3) Is there an interaction between PTPN22 and the rheumatoid arthritis (RA)-associated HLA-DRB1 shared epitope alleles? A total of 1413 Caucasian rheumatoid arthritis patients and 1401 Caucasian controls were genotyped. The results support the view that PTPN22 was strongly and preferentially associated with RF positive disease (OR=1.75, 95% CI 1.46-2.10, P=1.3 x 10(-9)). The PTPN22 risk allele was not significantly associated with RF negative disease (OR=1.19, 95% CI 0.92-1.53, P=0.18), although a very weak association cannot be completely excluded. There was a strong dose effect on disease risk; two copies of the PTPN22 R620W allele more than doubles the risk for RF positive RA (OR=4.57, 95% CI 2.35-8.89). There was no evidence of a genetic association between PTPN22 and HLA susceptibility alleles.

Alleles↗
PubMed2005

Finnish case-control and family studies support PTPN22 R620W polymorphism as a risk factor in rheumatoid arthritis, but suggest only minimal or no effect in juvenile idiopathic arthritis.

Several studies have identified the PTPN22 allelic variant 1858 C/T that encodes the R620W amino-acid change as a putative susceptibility factor in autoimmune diseases. The current study was undertaken to examine a large cohort of Finnish rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) subjects using both population control and, importantly, family-based association methods. The latter is particularly important when, as is the case for the 1858 C/T polymorphism, the frequency of the variant allele (T) differs in both major ancestral populations and in subpopulations. The analysis of rheumatoid factor-positive 1030 RA probands from Finland provides strong support for association of this variant in both population studies (allele specific odds ratio (OR)=1.47, 95% confidence interval (CI)=1.27-1.70, P=3 x 10(-7)) and in family studies (P<10(-6)). In contrast, no allelic association was seen with JIA (230 probands) and only weak evidence for a genotypic effect of 1858T homozygotes was observed in this population.

Alleles↗
PubMed2003

HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course.

Models of disease susceptibility in multiple sclerosis (MS) often assume a dominant action for the HLA-DRB1*1501 allele and its associated haplotype (DRB1*1501-DQB1*0602 or DR2). A robust and phenotypically well-characterized MS data set was used to explore this model in more detail. A dose effect of HLA-DR2 haplotypes on MS susceptibility was revealed. This observation suggests that, in addition to the role of HLA-DR2 in MS, two copies of a susceptibility haplotype further increase disease risk. Second, we report that DR2 haplotypes modify disease expression. There is a paucity of benign MS and an increase of severe MS in individuals homozygous for DR2. Concepts of the molecular mechanisms that underlie linkage and association of the human leukocyte antigen (HLA) region to MS need to be revised to accommodate these data.

Disease Progression↗
PubMed2002

Two new HLA-B alleles, B*4422 and B*4704, identified in a study of families with autoimmunity.

HLA-B typing of approximately 1 262 individuals from a study of 372 simplex families with multiple sclerosis has led to the identification of two new alleles (HLA-B*4422 and HLA-B*4704). Sequencing confirmed that both of these new alleles represent novel combinations of previously described sequence motifs, reinforcing the notion that recombination and/or gene conversion-like events play an important role in generating HLA allelic diversity. The identification of these new alleles brings the total number of HLA-B alleles to 465.

Alleles↗
PubMed2001

Effect of HLA class II gene disparity on clinical outcome in unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia: the US National Marrow Donor Program Experience.

The clinical importance of HLA class II gene disparity in unrelated stem cell transplantation is not entirely known. The impact was evaluated of matching donors and recipients for HLA-DR, HLA-DQ, and HLA-DP genes on clinical outcome after stem cell transplantation for chronic myeloid leukemia (CML) performed between 1988 and 1997. HLA-DRB1, -DQA1, -DQB1, -DPA1, and -DPB1 alleles were identified in 831 transplant pairs using a combination of sequence-specific oligonucleotide probes, sequence-specific priming, and sequencing methods. Among the 831 pairs, 696 (84%) were HLA-A and -B serologically matched; of these, 565 (81%) were also matched for HLA-DRB1. HLA-DRB1 matching correlated with significantly improved survival (relative risk [RR], 1.29 [95% confidence interval (CI), 1.02-1.64; P =.04]) independently of HLA-DQA1 or HLA-DQB1 (RR, 1.01 [95% CI, 0.81-1.26; P =.94]) and HLA-DPA1 or HLA-DPB1 (RR, 1.11 [95% CI, 0.84-1.48; P =.46]). Single-locus HLA-DQ or HLA-DP disparity was not associated with significantly poorer survival. For patients who underwent transplantation in the first chronic phase (CP) from HLA-A, B matched donors, the presence of DRB1 allele mismatching was independently associated with increased incidence of grades III-IV acute graft-versus-host disease (GVHD). No significant associations of class II allele mismatching with risk for delayed engraftment or chronic GVHD disease were detected. This study clearly demonstrates the importance of precise matching of HLA-DRB1 alleles for successful transplantation. Furthermore, a good-risk population of patients whose transplantations were performed in the first CP of disease from HLA-A, B, DRB1 matched unrelated donors can be shown to have superior survival.

Alleles↗
PubMed2001

Genetic variability and linkage disequilibrium within the HLA-DP region: analysis of 15 different populations.

In order to understand the forces governing the evolution of the genetic diversity in the HLA-DP molecule, polymerase chain reaction (PCR)-based methods were used to characterize genetic variation at the DPA1 and DPB1 loci encoding this heterodimer on 2,807 chromosomes from 15 different populations including individuals of African, Asian, Amerindian, Indian and European origin. These ethnically diverse samples represent a variety of population substructures and include small, isolated populations as well as larger, presumably admixed populations. Ten DPA1 and 39 DPB1 alleles were identified and observed on 87 distinct DP haplotypes, 34 of which were found to be in significant positive linkage disequilibrium in at least one population. Some haplotypes were found in all ethnic groups while others were confined to a single ethnic group or population. Strong positive global linkage disequilibrium (Wn) between DPA1 and DPB1 was present in all 15 populations. The African populations displayed the lowest values of Wn whereas the Amerindian populations displayed near absolute disequilibrium. Analysis of the distribution of haplotypes using the normalized deviate of the Ewens-Watterson homozygosity statistic, F, suggests that DP haplotypes encoding the functional heterodimer are subject to much lower degrees of balancing selection than other loci within the HLA region. Finally, neighbor joining tree analyses demonstrate the power of haplotype diversity for inferring the relationships between the different populations.

Alleles↗
PubMed2001

Three new DP alleles identified in a study of 800 unrelated bone marrow donor-recipient pairs.

HLA-DP genotyping of 800 unrelated donor-recipient pairs in phase 5 of a retrospective analysis of unrelated bone marrow transplantation, sponsored by the National Marrow Donor Program (NMDP), has identified two new DPB1 alleles (DPB1*8701 and DBP1*8801) and one new DPA1 (DPA1*0108) allele. Sequencing confirmed that all three of these new alleles represent novel combinations of previously described sequence motifs, reinforcing the notion that "gene conversion-like" events play an important role in generating HLA allelic diversity. The identification of these new alleles brings the total number of DPA1 alleles to 20 and the total number of DPB1 alleles to 94.

Alleles↗
PubMed2000

Evolution of Pacific/Asian populations inferred from HLA class II allele frequency distributions.

The allele frequency distributions for the HLA class II loci, DRB1, DQB1 and DPB1, in eight Pacific/Asian populations: Hawaiian, Samoan, Malay, Papua New Guinea (PNG) Highlands, and two Indonesian and PNG Lowland groups, were determined using high-resolution polymerase chain reaction/sequence-specific oligonucleotide probe (PCR/SSOP) typing methods. The allele frequency distributions for the HLA-DRB1 locus were determined for a third Indonesian population as well as for an additional Filipino population. DRB1 alleles in the DR2 serogroup (or allelic lineage) are very common in this region; in some populations, more than 50% of the alleles belong to this serogroup. The DRB1*1502 allele is frequent in nine of the ten populations studied, reaching a frequency of 0.48 in one Indonesian population and among Filipinos. Extensive DR-DQ haplotype diversity was detected in these populations. Seven different DR2-DQB1 haplotypes were observed in the Indonesian and PNG Lowland populations, eight in the PNG Highlands and ten in Malays and Filipinos. The DRB1*0410 allele, commonly observed in Australia, is observed in the PNG Highlands at a low frequency (f=0.03) and is absent in the other populations. Two additional DRB1 alleles commonly observed in Australia, DRB1*0405 and *1407, are also observed in the PNG Highlands at high frequencies (f=0.132 and 0.126), while they are rare in the PNG Lowlands (f=0.039 and 0.013). These alleles are generally rare or absent in the other populations. The DPB1*0501 allele, common in Chinese and Japanese populations, is most frequent in the Samoan, Hawaiian, Indonesian, and Malay populations, and the *0401 allele is the most frequent DPB1 allele in the PNG Lowlands. Both of these alleles have the same very high frequency (f=0.34) in the PNG Highlands. Analyses of homozygosity (the Ewens-Watterson F statistic) in these and other populations indicate that, while most allele frequency distributions are consistent with balancing selection, values of F for the Indonesian and Javan populations may reflect positive directional selection. Phylogenetic trees constructed using the allele frequencies at the DRB1 locus of the populations reported here, as well as those for additional Pacific, Asian, and Australian populations, indicate that the PNG Highland population is more closely related to Australian populations than to PNG Lowland populations, while the PNG Lowlands are more closely related to other Melanesian populations.

Alleles↗
PubMed2000

The extent of HLA class II allele level disparity in unrelated bone marrow transplantation: analysis of 1259 National Marrow Donor Program donor-recipient pairs.

A comprehensive analysis of the HLA-D region loci, DRB1, DRB3, DRB5, DQA1, DQB1, DPA1 and DPB1, was performed to determine allelic diversity and underlying HLA disparity in 1259 bone marrow recipients and their unrelated donors transplanted through the National Marrow Donor Program. Although 43.0% of DRB1 alleles known to exist at the beginning of the study were found in this predominantly Caucasian transplant population, a few alleles predominated at each locus. In recipients, 67.1% of DRB1 alleles identified were one or two of six common DRB1 alleles. Only 118 (9.4%) donor-recipient pairs were matched for all alleles of DRB1, DQA1, DQB1, DPA1 and DPB1. While 79.4% of the pairs were matched for DRB1, only 13.2% were matched for DPB1 alleles. Almost 66% of pairs differed by more than one allele mismatch and 59.0% differed at more than one HLA-D locus. DQB1 was matched in 85.9% of DRB1-matched pairs. In contrast, only 13.9% of the pairs matched for DRB1, DQA1 and DQB1 were also matched for DPA1 and DPB1. This database, highlighting the underlying HLA disparity within the pairs, forms the foundation of an ongoing study to establish the relationship between HLA matching and successful outcome in unrelated allogeneic stem cell transplant.

Alleles↗
PubMed1999

T cell receptor BV gene rearrangements in the spinal cords and cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal disorder whose etiology and pathogenesis remain unknown. Recent studies, however, have demonstrated the presence of inflammatory infiltrates within ALS spinal cord and suggested the possibility of an immune-mediated process in motor neuron degeneration. We have analyzed the diversity of T-cells in the spinal cord in ALS. Reverse transcriptase polymerase chain reaction (RT-PCR) with variable (V) region sequence specific oligonucleotide primers was used to amplify T-cell receptor (TCR)BV transcripts from spinal cords obtained at autopsy from patients with ALS, patients who died without inflammatory disease of the central nervous system, brains from patients with ALS, and brains from patients who died with inflammatory CNS disease. Sequencing was then performed on the amplified transcripts. An overall increase in the level of TCRBV 2 transcripts was detected in ALS specimens when compared to controls. This result was independent of the HLA genotype of the individual. Furthermore, enrichment of TCRBV2-positive T cells could be demonstrated in cerebrospinal fluid derived from patients with ALS, using PCR analysis and a T cell stimulation assay with toxic shock syndrome toxin-1 (TSST-1), a Vbeta2-specific superantigen. Our results suggest that an immunological process involving the specific expansion of Vbeta2 TCR-positive T-cells may be important in the pathogenesis of ALS.

Adult↗
PubMed1999

Four new DP alleles identified in a study of 500 unrelated bone marrow donor-recipient pairs.

HLA-DP genotyping of 500 donor recipient pairs in a retrospective analysis sponsored by the National Marrow Donor Program (NMDP) identified four new DP alleles, two DPB1 and two DPA1. DNA sequencing confirmed that DPB1*8001 and *8101, each found in a single individual, are novel combinations of previously described sequence motifs in the six variable regions of DPB1. DPA1*02014, found in two individuals, is identical to DPA1*02011 except for a novel silent substitution, a G to A transition at the third position of codon 14. DPA1*01032, found in one individual, is identical to DPB1*01031 except for a silent G to A transition at the third position of codon 20. The identification of these novel alleles brings the total number of reported DPB1 alleles to 85 and DPA1 alleles to 15.

Alleles↗
PubMed1998

Three new DP alleles identified in sub-Saharan Africa: DPB1*7401, DPA1*02013, and DPA1*0302.

HLA-DP genotyping of over 400 individuals from sub-Saharan Africa identified three new DP alleles: DPB1*7401, DPA1*02013, and DPA1*0302. DNA sequencing confirmed that DPB1*7401, found in one individual, is a novel combination of previously described sequence motifs in the six variable regions of DPB1. DPA1*02013, found in one individual, is identical to DPA1*02012 except for two silent substitutions, a T to C transition in codon 37, and an A to G transition in codon 38. DPA1*0302, identified in seven individuals, is identical to DPA1*0301 except for a C to T transition at the second position of codon 66. The identification of these novel alleles brings the total number of reported DPB1 alleles to 77 and DPA1 alleles to 11.

Africa South of the Sahara↗
PubMed1997

Chromosome 19 single-locus and multilocus haplotype associations with multiple sclerosis. Evidence of a new susceptibility locus in Caucasian and Chinese patients.

CONTEXT: Susceptibility to multiple sclerosis (MS) involves a genetically complex autoimmune component. However, except for genes in the HLA system, specific susceptibility loci are unknown or unconfirmed. OBJECTIVE: To investigate several loci spanning 3 candidate regions for a role in multiple sclerosis (MS) susceptibility in 2 ethnic groups using both single-locus and haplotype analyses. The 3 regions include HLA on chromosome 6p21.3, APOE on chromosome 19ql 3.2, and MBP(myelin basic protein) on chromosome 18q23. DESIGN: Case-control association testing. SUBJECTS: A total of 120 Caucasian patients with MS and 107 unrelated control individuals from California, and 32 patients and 32 unrelated control individuals from Beijing, China. All patients with MS were diagnosed as having clinically definite disease according to published criteria. MAIN OUTCOME MEASURES: Chi2 Testing of loci and individual alleles and haplotypes. Haplotype frequencies were estimated with standard maximum likelihood methods. RESULTS: The HLA effect is due to the class II DR2 haplotype, DRB1*1501-DQA1*0102-DRB1*0602; contributions to MS susceptibility from additional DRB1-DQB1 alleles or other HLA region loci were not observed. Variation within the MBP locus on chromosome 18q23 showed no effect in MS. The distribution of haplotypes from 5 loci within the chromosome 19q13.2 region, including D19S178, D19S574, APOE, APOC2, and D19S219, differed between patient and control samples. D19S574 showed a significant effect (P=.015) in Caucasian patients with MS due to the increased frequency of a single allele (P=.002). The APOE variation, prominent in other neurological diseases, showed no influence on MS susceptibility, despite its location within the chromosome 19q13.2 region. Interaction effects between DR2 and chromosome 19q13.2 or MBP in MS susceptibility were not apparent. CONCLUSIONS: The significant chromosome 19q13.2 single-locus and multilocus haplotype associations with MS in Caucasian and Chinese patient samples indicate an effect from a nearby disease susceptibility locus. These initial observations are an encouraging step toward the description of non-HLA genetic susceptibility to MS.

Alleles↗
PubMed1997

Genetic variability and linkage disequilibrium within the DP region in the CEPH families.

A PCR-based SSO-assay has been developed to characterize the allelic polymorphism at the HLA-DPA1 locus. To validate the performance of this assay, 77 samples were typed side by side in a blinded fashion by the SSO assay and sequencing-based typing (SBT); 100% concordance was seen between the two methods. To address questions of genetic variability and linkage disequilibrium within the class II region, 478 members of the 37 original Caucasian Centre d'Etude du Polymorphisme Humain (CEPH) families were typed for DPA1 using the SSO assay providing information on 247 independent chromosomes. Six of the eight known DPA1 alleles were detected in this population; DPA1*0103 was the most frequent allele. Analysis of the distribution of allele and haplotype frequencies using the homozygosity statistic suggests that balancing selection does not appear to be acting on the DPA1 locus nor on the functional DP heterodimer in this population. Family data permits the unambiguous assignment of haplotypes. Of the 247 independent chromosomes analyzed, 24 distinct DPA1-DPB1 haplotypes were identified with DPA1*0103-DPB1*0401 being the most common. Twelve of the 18 DPB1 alleles identified in this population have an exclusive association with one DPA1 allele. Of the remaining six DPB1 alleles, four are present at a frequency of >3% and show preferential association with just one DPA1 allele. Calculation of the normalized disequilibrium parameter (D') shows 13 DP haplotypes to be in significant positive disequilibrium. These data suggest there is strong linkage disequilibrium between the DPA1 and DPB1 loci in this Caucasoid population and provide a basis with which to study linkage disequilibrium in other ethnic groups as well as analyze the evolutionary forces which govern allelic and haplotypic variation.

Alleles↗