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Biomedical subjects

J K Kulski

Publications and source records attributed to J K Kulski.

At least 19 recordsLinked to original sources
PubMed2006

Novel cynomolgus macaque MHC-DPB1 polymorphisms in three South-East Asian populations.

Cynomolgus macaques (Macaca fascicularis, Mafa), alias the crab-eating monkeys or long-tailed macaques, live across a vast range of South-East Asia. These non-human primates have emerged as important animal models in infectious and chronic diseases and transplantation studies, necessitating a more extensive characterization of their major histocompatibility complex polymorphic regions. The current information on the polymorphic variation or diversity of the Mafa-DPB1 locus is largely limited in comparison with the more commonly studied rhesus macaque DPB1 locus. In this article, to better elucidate the degree and types of polymorphisms and genetic differences of Mafa-DPB1 locus among three South-East Asian populations and to investigate how the allele differences between macaques and humans might affect their respective immune responses, we identified 40 alleles within exon 2 of the Mafa-DPB1 locus by DNA sequencing using 217 individuals. We also performed evolutionary and population analyses using these sequences to reveal some population-specific alleles and trans-species allelic conservation between the cynomolgus macaques and the rhesus macaques. Of the 40 new alleles, eight belong to a newly identified lineage group not previously found in the rhesus macaque species. This allele information will be useful for medical researchers using the cynomolgus macaques in disease and immunological studies.

Alleles↗
PubMed2006

Four-digit allele genotyping of the HLA-A and HLA-B genes in Japanese patients with Behcet's disease by a PCR-SSOP-Luminex method.

The present study represents the first four-digit allele genotyping of HLA-A and -B in Japanese Behcet's disease (BD) patients and controls using a new genotyping method (named the PCR-SSOP-Luminex method) to determine the association of certain HLA-A or -B alleles with BD. Peripheral blood lymphocytes were collected from 180 Japanese BD patients and 170 healthy controls. The genotype frequency of HLA-B*5101 was significantly increased in the patients (61.7%) as compared with the controls (15.9%) (Pc = 1 x 10(-16), OR = 8.5). When we recalculated the phenotype frequencies after excluding the HLA-B*51-positive patients and controls to account for the effects of the linkage disequilibrium and the abundance of the HLA-B*51 allele, the frequencies of HLA-A*2602 and HLA-B*3901 had a weak association in the patient group without HLA-B*51 as compared with the control group without HLA-B*51 (A*2602; Pc = 0.130, OR = 4.3, B*3901; Pc = 0.099, OR = 3.5). This study confirmed on the basis of using a new and more accurate genotyping method that Japanese BD patients have a strong primary association with HLA-B*5101. The significant increase of HLA-A*2602 and B*3901 in the patient group without HLA-B*51 suggests that these two alleles might also have some secondary influence on the onset of BD.

Alleles↗
PubMed2006

The association between non-melanoma skin cancer and a young dimorphic Alu element within the major histocompatibility complex class I genomic region.

A non-melanoma skin cancer (NMSC) susceptibility locus within the major histocompatibility complex (MHC) class I region was previously identified telomeric of the HLA-C gene using high-density microsatellite markers. Here, we have extended the previous microsatellite study by using the same DNA samples obtained from 154 NMSC patients and 213 normal controls from the town of Busselton in Western Australia and examined the relationship between five polymorphic Alu insertions (POALINs) within the MHC class I region and their association with NMSC. The genotype distribution of the AluyTF insertion that is located within the NMSC susceptibility region telomeric of the HLA-C gene was significantly increased according to the Fisher's exact test in the NMSC patients, and it was not in Hardy-Weinberg equilibrium in the control group. There was no difference between the cancer patients and controls for the genotypes of the AluyMICB locus within intron 1 of the MICB gene and the other three POALINs (AluyHJ, AluyHG and AluyHF) that are located within the genomic region of the HLA-A, -G and -F gene cluster. The test for significant linkage disequilibrium for 10 pairs of POALIN loci and estimations of two locus POALIN haplotype frequencies also revealed AluyTF differences between the cases and controls. In conclusion, the MHC class I POALIN, AluyTF, that is located within the NMSC susceptibility locus and near the HLA-C gene was strongly associated with NMSC. This finding, using five different polymorphic Alu insertion markers, supports the previous microsatellite association study that one or more genes located in close proximity to the AluyTF insertion has a potential role in NMSC.

Aged↗
PubMed2005

Polymorphic Alu insertions and their associations with MHC class I alleles and haplotypes in the northeastern Thais.

Polymorphic Alu insertions (POALINs) are known to contribute to the strong polymorphic nature of the Major Histocompatibility Complex (MHC). Previous population studies on MHC POALINs were limited to only Australian Caucasians and Japanese. Here, we report on the individual insertion frequency of the five POALINs within the MHC class I region, their HLA-A and -B associations, and the three and four locus alpha block POALIN haplotype frequencies in the Northeastern (NE) Thai population. Of the five POALINs, the lowest frequency was 0.018 for AluyHF and the highest frequency was 0.292 for AluyHJ and AluyHG. The strongest positive associations between the POALINs and HLA class I alleles was between AluyMICB and HLA-B*57, AluyHJ and HLA-A*24 and HLA-A*01, and AluyHG and HLA-A*02, supporting previous findings in Caucasians and Japanese. Single POALIN haplotypes were found more frequently than multiple POALIN haplotypes. However, of the seven different POALIN haplotypes within the MHC alpha block, there were only two significant differences between the NE Thais, Caucasians and Japanese. This study confirms that the MHC POALINs are in linkage disequilibrium with HLA-A and -B alleles and that there are significant frequency differences for some of the POALINs when compared between NE Thai, Caucasians and Japanese.

Alu Elements↗
PubMed2005

The haplotype block, NFKBIL1-ATP6V1G2-BAT1-MICB-MICA, within the class III-class I boundary region of the human major histocompatibility complex may control susceptibility to hepatitis C virus-associated dilated cardiomyopathy.

Cardiomyopathy is a heart muscle disease with impaired stretch response that can result in severe heart failure and sudden death. A small proportion of hepatitis C virus (HCV)-infected patients may be predisposed to develop dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). The molecular mechanisms involved in the predisposition remain unknown due in part to the lack of information on their genetic background. Because the human leukocyte antigen (HLA) region has a pivotal role in controlling the susceptibility to HCV-induced liver disease, we hypothesized that particular HLA alleles and/or non-HLA gene alleles within the human major histocompatibility complex (MHC) genomic region might control the predisposition to HCV-associated DCM (HCV-DCM) and/or HCV-associated HCM (HCV-HCM). Here, we present mapping results of the MHC-related susceptibility gene locus for HCV-associated cardiomyopathy by analyzing microsatellite and single nucleotide polymorphism markers. To delineate the susceptibility locus, we genotyped 44 polymorphic markers scattered across the entire MHC region in a total of 59 patients (21 HCV-DCM and 38 HCV-HCM) and 120 controls. We mapped HCV-DCM susceptibility to a non-HLA gene locus spanning from NFKBIL1 to MICA gene loci within the MHC class III-class I boundary region. Our results showed that HCV-DCM was more strongly associated with alleles of the non-HLA genes rather than the HLA genes themselves. In addition, no significant association was found between the MHC markers and HCV-HCM. This marked difference in the MHC-related disease susceptibility for HCV- associated cardiomyopathy strongly suggests that the development of HCV- DCM and HCV-HCM is under the control of different pathogenic mechanisms.

Adaptor Proteins, Signal Transducing↗
PubMed2005

ERVK9, transposons and the evolution of MHC class I duplicons within the alpha-block of the human and chimpanzee.

The genomic sequences within the alpha-block (approximately 288-310 kb) of the human and chimpanzee MHC class I region contains ten MHC class I genes and three MIC gene fragments grouped together within alternating duplicated genomic segments or duplicons. In this study, the chimpanzee and human genomic sequences were analyzed in order to determine whether the remnants of the ERVK9 and other retrotransposon sequences are useful genomic markers for reconstructing the evolutionary history of the duplicated MHC gene families within the alpha-block. A variety of genes, pseudogenes, autologous DNA transposons and retrotransposons such as Alu and ERVK9 were used to categorize the ten duplicons into four distinct structural groups. The phylogenetic relationship of the ten duplicons was examined by using the neighbour joining method to analyze transposon sequence topologies of selected Alu members, LTR16B and Charlie9. On the basis of these structural groups and the phylogeny of the duplicated transposon sequences, a duplication model was reconstructed involving four multipartite tandem duplication steps to explain the organization and evolution of the ten duplicons within the alpha-block of the chimpanzee and human. The phylogenetic analysis and inferred duplication history suggests that the Patr/HLA-F was the first MHC class I gene to have been fixed and not required as a precursor for further duplication within the alpha-block of the ancestral species.

Animals↗
PubMed2005

Polymorphic Alu insertions within the Major Histocompatibility Complex class I genomic region: a brief review.

Most polymorphic Alu insertions (POALINs) belong to a subgroup of the Alu multicopy retrotransposon family of short interspersed nucleotide elements (SINEs) that are categorized as AluYb8 and AluYa5. The number of AluYb8/AluYa5 members (approximately 4,492 copies) is significantly less than the approximately one million fixed Alu copies per human genome. We have studied the presence of POALINs within the Major Histocompatibility Complex (MHC) class I region on the short arm of chromosome 6 (6p21.3) because this region has a high gene density, many genes with immune system functions, large sequence variations and diversity, duplications and redundancy, and a strong association with more than 100 different diseases. Since little is known about POALINs within the MHC genomic region, we undertook to identify some of the members of the AluYb8/AluYa5 subfamily and to study their frequency of distribution and genetic characteristics in different populations. As a result of our comparative genomic analyses, we identified the insertion sites for five POALINs distributed within the MHC class I region. This brief review outlines the locations of the insertions and sequence features of the five MHC POALINs, their single site and haplotype frequencies in different geographic populations, and their association with different HLA class I genes and disease. We show that the MHC POALINs have a potential value as lineage and linkage markers for the study of human population genetics, disease associations, genomic diversity and evolution.

Chromosome Mapping↗
PubMed2004

Association of polymorphic MHC microsatellites with GVHD, survival, and leukemia relapse in unrelated hematopoietic stem cell transplant donor/recipient pairs matched at five HLA loci.

In order to determine whether matching/mismatching for microsatellite polymorphism provides useful information on acute graft-vs-host disease (GVHD), survival, and leukemia relapse in hematopoietic stem cell (HSC) transplantation, we genotyped for polymorphisms at 13 microsatellite loci within the major histocompatibility complex (MHC) of 100 unrelated HSC transplant donor-recipient pairs who were matched at five classical human leukocyte antigen (HLA) loci. A high percentage of allele matching was obtained for five microsatellite loci, DQCARII (96%), MICA (93%), MIB (89%), C1-3-1 (93%), and D6S510 (97%), that are localized within 100 kb of the HLA-DR, HLA-DQ, HLA-B, HLA-C, or HLA-A locus. In contrast, the other eight microsatellites are located farther away from the HLA classical loci and have much lower percentages of allele matching [e.g. tumor necrosis factor a (TNFa) (73%), TNFd (74%), D6S273 (64%), C3-2-11 (46%), C5-3-1 (50%), C5-4-5 (63%), C5-2-7 (68%), and D6S265 (81%)]. Therefore, there were at least eight microsatellite markers with relatively high percentages of mismatches in the donor/recipient pairs with acute or chronic GVHD, poor graft survival, and leukemia relapse. However, there were no statistically significant associations between mismatched donor-recipient pairs at the 13 microsatellite loci and acute or chronic GVHD, graft survival, and leukemia relapse. Nevertheless, allele matching at the microsatellite TNFd locus near the TNFa gene was found by the Fisher's exact double-sided test to be significantly associated with decreased survival in the grade III/IV acute GVHD group. Overall, these results suggest that the matching of microsatellite polymorphisms within the HLA region, especially the ones farthest from the classical HLA loci, was not useful indicator for the outcome of HSC transplantation from unrelated donors. In this regard, the future determination of the genome-wide microsatellite genotypes in HLA-matched donor-recipient pairs, outside the MHC, may be a better possibility for identifying minor histocompatibility genes in linkage disequilibria with microsatellites as potential predictive markers for the occurrence of acute GVHD and survival rate in HSC transplantation.

Adolescent↗
PubMed2004

An update of the HLA genomic region, locus information and disease associations: 2004.

The human major histocompatibility (MHC) genomic region at chromosomal position 6p21 encodes the six classical transplantation HLA genes and many other genes that have important roles in the regulation of the immune system as well as in some fundamental cellular processes. This small segment of the human genome has been associated with more than 100 diseases, including common diseases--such as diabetes, rheumatoid arthritis, psoriasis, asthma and various autoimmune disorders. The MHC 3.6 Mb genomic sequence was first reported in 1999 with the annotation of 224 gene loci. The locus and allelic information of the MHC continue to be updated by identifying newly mapped expressed genes and pseudogenes based on comparative genomics, SNP analysis and cDNA projects. Since 1999, new innovations in bioinformatics and gene-specific functional databases and studies on the MHC genes have resulted in numerous changes to gene names and better ways to update and link the MHC gene symbols, names and sequences together with function, variation and disease associations. In this study, we present a brief overview of the MHC genomic structure and the recent information that we have gathered on the MHC gene loci via LocusLink at the National Centre for Biological Information (http://www.ncbi.nih.gov/.) and the MHC genes' association with various diseases taken from publications and records in public databases, such as the Online Mendelian Inheritance in Man and the Genetic Association Database.

Computational Biology↗
PubMed2004

Identification of two new C4 alleles by DNA sequencing and evidence for a historical recombination of serologically defined C4A and C4B alleles.

Nucleotide polymorphisms of the C4 genes were investigated by direct sequencing of seven different homozygous typing cells from the 10IHW panels. Two novel sequences were identified within the C4d region of the C4 genes. Our sequencing analyses extend previous findings suggesting that a recombination hot spot is likely to have occurred between codon positions 1157 and 1186 within the C4d region. The classification of electrophoretically defined C4A and C4B alleles can be further subtyped by sequencing. Because the central major histocompatibility complex region that carries various copies of the C4 gene has been associated with a range of disorders; further analysis at the sequence level within the C4 locus may provide informative genetic markers for the investigation of disease-associated polymorphisms.

Alleles↗
PubMed2003

Localization of a non-melanoma skin cancer susceptibility region within the major histocompatibility complex by association analysis using microsatellite markers.

The major histocompatibility complex (MHC) is known to have a role in the development of non-melanoma skin cancer (NMSC), although the genes and mechanisms involved have yet to be determined. To identify the susceptibility locus for NMSC within the MHC, we used a collection of well-defined polymorphic microsatellite markers from the Human leucocyte antigen (HLA) region for an association analysis of 150 cases with NMSC and 200 healthy controls selected from the Busselton population in Western Australia. High-resolution mapping was undertaken using a total of 40 highly polymorphic markers located at regular intervals across the HLA region (3.6Mb). Polymerase chain reaction (PCR) analysis was initially performed on pooled DNA markers to detect those markers that showed different allele profiles. Statistically significant differences in allelic frequencies (differentiating alleles) were found between cases and controls at three polymorphic microsatellite loci within a 470-kb genomic susceptibility region ranging between 6 kb centromeric of the HLA-B gene and intron 5 of the DDR gene. Interestingly, this genome region corresponded completely with the psoriasis-susceptibility locus. The three differentiating alleles and another four markers outside the susceptibility region were then PCR tested by individual genotyping of cases and controls. The newly identified susceptibility locus for NMSC within the MHC was found to be significantly different between the cases and controls by comparisons of allele frequencies at the three differentiating loci estimated from DNA pools and then confirmed by individual genotyping. This is the first study using high density microsatellite markers to localize a NMSC susceptibility region within the human genome.

Australia↗
PubMed2003

Association of MHC dimorphic Alu insertions with HLA class I and MIC genes in Japanese HLA-B48 haplotypes.

A large proportion of Japanese with the HLA-B48 allele have a MICA gene deletion associated with a MICB null allele within the class I region of the Major Histocompatibility Complex (MHC). Here, we report for the first time a novel positive association between the presence of a polymorphic Alu insertion, AluyMICB, within the first intron of the MICB gene and the MICAdel/MICBnull/HLA-B48 haplotype for five of six well-characterized Japanese cell-lines. The AluyMICB insertion was found to be present at a frequency of 0.242 in 86 Japanese tissue donors and in four of the five individuals with the HLA-B48 allele. The AluyMICB insertion was also associated with at least three different MICB alleles, *0102, *0107N and *0105, and three different HLA-B alleles, B13, B48 and B57, respectively, in the seven Workshop cell-lines (the 4th Asia-Oceania Histocompatibility Workshop, and the 10th International Histocompatibility Workshop) and the six Japanese cell-lines that were selected for this study. Based on the analysis of associations between different polymorphic markers within the beta block, the MICB*0102 allele was inferred to be the ancestral form of the MICB*0105 and MICB*0107N alleles. The AluyMICB polymorphism can now be used to further investigate its relationship with other MICB alleles and consequently their origins. In addition, we have examined the absence and presence of three other polymorphic Alu markers distributed within the alpha block of the class I region of the HLA-B48/AluyMICB haplotype. We conclude that the extended HLA-B haplotypes are best defined by considering multiple genomic sites including the four polymorphic Alu insertions described in this study.

Alu Elements↗
PubMed2002

Corneodesmosin DNA polymorphisms in MHC haplotypes and Japanese patients with psoriasis.

In order to examine the relationship between corneodesmosin (CDSN) and psoriasis we have determined the presence of CDSN polymorphisms by DNA sequencing in (a) nine B-LCL cell lines of major histocompatibility complex ancestral haplotypes known to be associated with psoriasis vulgaris including 13.1AH, 46.1AH, 46.2 and 57.1AH, and in (b) a group of 267 unrelated individuals comprising Japanese psoriasis patients (n = 101) and Japanese subjects without the disease (n = 166). Three novel CDSN gene sequences were identified. In addition, we have classified the 18 alleles into seven main groups based on phylogeny of non-synonymous substitutions. However, we have found no statistically significant differences between the patients and the unaffected individuals in any of these groups. These findings indicate that CDSN is not a major psoriasis susceptibility gene.

Alleles↗
PubMed2001

The association between HLA-A alleles and an Alu dimorphism near HLA-G.

The AluYb8 sequences are a subfamily of short interspersed Alu retroelements that have been amplified within the human genome during recent evolutionary time and are useful polymorphic markers for studies on the origin of human populations. We have identified a new member of the Yb8 subfamily, AluyHG, located between the HLA-H and -G genes and 88-kb telomeric of the highly polymorphic HLA-A gene within the alpha block of the major histocompatibility complex (MHC). The AluyHG element was characterised with a view to examining the association between AluyHG and HLA-A polymorphism and reconstructing the history of the MHC alpha block. A specific primer pair was designed for a simple PCR assay to detect the absence or presence (dimorphism) of the AluyHG element within the DNA samples prepared from a panel of 46 homozygous cell-lines containing complete or recombinant ancestral haplotypes (AH) of diverse ethnic origin and 92 Caucasoid and Asian subjects on which HLA-A typing was available. The AluyHG insertion was most strongly associated with HLA-A2 and, to a lesser degree with HLA-A1, -A3, -A11, and A-19. The gene frequency of the AluyHG insertion for 146 Caucasians and 94 Chinese-Han was 0.30 and 0.32 and there was no significant difference between the observed and expected frequencies. The results of the association studies and the phylogenetic analysis of HLA-A alleles suggest that the AluyHG sequence was integrated within the progenitor of HLA-A2, but has been transferred by recombination to other human ancestral populations. In this regard, the dimorphic AluyHG element is an important diagnostic marker for HLA association studies and could help in elucidating the evolution and functions of the MHC alpha block and polymorphism within and between ancestral haplotypes.

Alleles↗
PubMed2001

Genomic and phylogenetic analysis of the human CD1 and HLA class I multicopy genes.

The human CD1 proteins belong to a lipid-glycolipid antigen-presenting gene family and are related in structure and function to the MHC class I molecules. Previous mapping and DNA hybridization studies have shown that five linked genes located within a cluster on human chromosome 1q22-23 encode the CD1 protein family. We have analyzed the complete genomic sequence of the human CD1 gene cluster and found that the five active genes are distributed over 175,600 nucleotides and separated by four expanded intervening genomic regions (IGRs) ranging in length between 20 and 68 kb. The IGRs are composed mostly of retroelements including five full-length L1 PA sequences and various pseudogenes. Some L1 sequences have acted as receptors for other subtypes or families of retroelements. Alu molecular clocks that have evolved during primate history are found distributed within the HLA class I duplicated segments (duplicons) but not within the duplicons of CD1. Phylogeny of the alpha3 domain of the class I-like superfamily of proteins shows that the CD1 cluster is well separated from HLA class I by a number of superfamily members including MIC (PERB11), HFE, Zn-alpha2-GP, FcRn, and MR1. Phylogenetically, the human CD1 sequences are interspersed by CD1 sequences from other mammalian species, whereas the human HLA class I sequences cluster together and are separated from the other mammalian sequences. Genomic and phylogenetic analyses support the view that the human CD1 gene copies were duplicated prior to the evolution of primates and the bulk of the HLA class I genes found in humans. In contrast to the HLA class I genomic structure, the human CD1 duplicons are smaller in size, they lack Alu clocks, and they are interrupted by IGRs at least 4 to 14 times longer than the CD1 genes themselves. The IGRs seem to have been created as "buffer zones" to protect the CD1 genes from disruption by transposable elements.

Antigens, CD1↗
PubMed2001

New polymorphic microsatellite markers in the human MHC class III region.

The human major histocompatibility complex (MHC) class III region spanning approximately 760 kb is characterized by a remarkably high gene density with 59 expressed genes (one gene every 12.9 kb). Recently, susceptibility loci to numerous diseases, such as Graves disease, Crohn disease, and SLE have been suggested to be localized to this region, as assessed by associations mainly with genetic polymorphisms of TNF and TNF-linked microsatellite loci. However, it has been difficult to precisely localize these susceptibility loci to a single gene due to a paucity to date of polymorphic markers in the HLA class III region. To facilitate disease mapping within this region, we have analyzed 2 approximately 5 bases short tandem repeats (microsatellites) in this region. A total of 297 microsatellites were identified from the genomic sequence, consisting of 69 di-, 62 tri-, 107 tetra-, and 59 penta-nucleotide repeats. It was noted that among them as many as 17 microsatellites were located within the coding sequence of expressed genes (NOTCH4, PBX2, RAGE, G16, LPAAT, PPT2, TNXB, P450-CYP21B, G9a, HSP70-2, HSP70-1, HSP-hom, MuTSH5 and BAT2). Eight microsatellite repeats were collected as polymorphic markers due to their high number of alleles (11.9 on average) as well as their high polymorphic content value (PIC) (0.63). By combining the 38 and the 22 polymorphic microsatellites we have previously collected in the HLA class I and class II regions, respectively, we have now established a total of 68 novel genetic markers which are uniformly interspersed with a high density of one every 63.3 kb throughout the HLA region. This collection of polymorphic microsatellites will enable us to search for the location of any disease susceptible loci within the HLA region by association analysis.

Chromosome Mapping↗
PubMed2001

The absence of disease-specific polymorphisms within the HLA-B51 gene that is the susceptible locus for Behçet's disease.

Behçet's disease is known to be associated with HLA-B51 in many different populations. Genetic evidence supports that the susceptible gene for Behçet's disease is the HLA-B51 allele at the HLA-B locus. This study was aimed to determine the HLA-B51 nucleotide sequence variation in three Behçet's disease patients and three healthy controls in order to elucidate if any disease specific mutations or polymorphisms may exist in the HLA-B51 gene of patients. Long-range polymerase chain reaction (PCR) was first carried out to give a PCR-amplified product of 9.5 kb which was then used as a template for nested PCR to give a final amplified product of 4.2 kb. This final product containing the 1.3-kb promoter/enhancer region and the entire HLA-B gene except for a 363-bp 3' terminal end segment encoding the 3' untranslated region was subcloned by the BP cloning technique and sequenced. The sequencing results showed that all the patients possessed the HLA-B*51011 allele, and there were no differences in the exonic nucleotide sequences between the three Behçet's disease patients and the three healthy controls. The HLA-B*51011 intronic and promoter/enhancer nucleotide sequences from the three patients had 22 single nucleotide polymorphisms (SNPs), a single insertion of 6 bp and a single deletion of 2 bp. On the other hand, the three healthy controls had 24 SNPs in their intronic and promoter/enhancer regions. However, none of these polymorphisms in the patients were specific for the disease. Therefore, these results clearly demonstrate that the HLA-B exonic sequence that encodes the HLA-B51 allele is the real pathogenic factor in Behçet's disease.

5' Flanking Region↗