Genetic association of Fc receptor-like 3 polymorphisms with autoimmune pancreatitis in Japanese patients.
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Asian People↗
Biomedical subjects
Y Katsuyama
Publications and source records attributed to Y Katsuyama.
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↗
Conversion from tacrolimus to cyclosporine microemulsion therapy in liver transplant recipients.
The calcineurin inhibitors cyclosporine and tacrolimus have distinct advantages and drawbacks. Therefore it is important to tailor their use to the patient's tolerance. In some patients, the need to ameliorate the adverse effects of tacrolimus may necessitate a switch to cyclosporine-based therapy. Rescue therapy with a cyclosporine microemulsion (Neoral)-based regimen for transplant patients intolerant of tacrolimus has been evaluated to assess the best method of switching and determine the initial and maintenance doses of Neoral in children and adults. Our aims were to evaluate not only these facets, but also the pharmacokinetics of Neoral in stable patients, including target 2-hour postdose blood concentrations (C2) of cyclosporine in liver transplant recipients. Eighteen liver transplant patients switched from tacrolimus to Neoral underwent a program of cyclosporine blood level monitoring. The conversions were conducted safely; the incidence of acute rejection episodes was low (11.1%). Statistical analysis showed that the C2 correlated with the area under the time-blood concentration curve of cyclosporine for 0 to 4 hours after dosing (R=0.970). We determined the maintenance doses of Neoral for pediatric and adult patients as well as the feasibility of C2 quantitated monitoring in liver transplantation.
Administration, Oral↗
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↗
Sequencing-based typing of HLA-B*51 alleles and the significant association of HLA-B*5101 and -B*5108 with Behçet's disease in Greek patients.
Behçet's disease (BD) is widely known to be strongly associated with human leukocyte antigen (HLA) B51 in many different ethnic groups.Recently, HLA-B51 allele typing of Greek BD patients was performed to study the distribution of B*5101-B*5107 alleles in this Greek population, the B51 antigen strongly associated with BD was found to be predominantly encoded by allele B*5101. As it is now known that the B51 antigen can be encoded by 21 alleles, B*5101-B*5121, we performed HLA-B*51 allele genotyping among 58 Greek patients with BD. After serological HLA typing, typing of HLA-B*51 alleles was performed using the polymerase chain reaction-sequencing-based typing (PCR-SBT) method. The frequency of the B51 antigen was found to be significantly higher in the patient group as compared with the control group (75.9% of patients vs 22.0% of controls. In the genotyping of B51 alleles, 34 out of 44 B51-positive patients possessed B*5101, 13 out of the 44 carried B*5108. In contrast, all of the 9 B51-positive normal controls carried B*5101. This study revealed a strong association between Greeks with BD, both B*5101, B*5108, provided important insights into the molecular mechanism underlying the association between HLA status, this disease.
Alleles↗
Susceptibility locus for non-obstructive azoospermia is localized within the HLA-DR/DQ subregion: primary role of DQB1*0604.
Non-obstructive azoospermia is a male infertility characterized by no or little sperm in semen as a result of a congenital dysfunction in spermatogenesis. Previous studies have reported a higher prevalence of particular human leukocyte antigen (HLA) antigens in non-obstructive azoospermia. As the expression of the RING3 gene located in the HLA class II region was predominant in the testis, mainly around spermatids and pachytene spermatocytes, it is tempting to speculate that RING3 is one of the strong candidate genes responsible for the pathogenesis of the disease. In this study, the genetic polymorphism in the RING3 gene was investigated by the direct sequencing technique. As a result, a total of 14 single nucleotide polymorphisms were identified. Among them, six were localized in the coding region but none of them was accompanied by an amino-acid substitution. No significant difference in the allelic distribution at these 14 polymorphic sites was observed between the patients and healthy controls, suggesting that the susceptible gene for non-obstructive azoospermia is not the RING3 gene. Then, in order to map the susceptibility locus for non-obstructive azoospermia precisely within the HLA region, 11 polymorphic microsatellite markers distributed from the SACM2L gene just outside the HLA class II region (187 kb telomeric of the DPB1 gene) to the OTF3 gene in the HLA class I region were subjected to association analysis in the patients. Statistical analysis of distribution in the allelic frequency at each microsatellite locus demonstrated that the pathogenic gene for non-obstructive azoospermia is located within the HLA-DR/DQ subregion. In fact, DRB1*1302 and DQB1*0604 were found to be strongly associated with non-obstructive azoospermia by polymerase chain reaction-based DNA typing. Further, haplotype analysis suggested that the DQB1*0604 allele may play a decisive role in the pathogenesis of non-obstructive azoospermia.
Alleles↗
Analysis of microsatellite polymorphism around the HLA-B locus in Iranian patients with Behçet's disease.
We have previously suggested that in a Japanese population the susceptible locus for Behçet's disease (BD) is HLA-B51 itself. To confirm this finding in another population, we performed HLA class I typing using the PCR-SSP method and analyzed eight polymorphic markers distributed within 1100 kb around the HLA-B gene using automated sequencer and subsequent automated fragment detection by fluorescent-based technology with the DNA samples of 84 Iranian patients with BD and 87 healthy ethnically matched controls. As a result, three microsatellite alleles (MICA-A6, MIB-348, C1-4-1-217) and HLA-B51 were found to be strongly associated with BD. Of these alleles HLA-B51 is the most strongly associated allele. There were no alleles that were increased in allele frequency at any microsatellite loci centromeric of MICA or telomeric of HLA-B51. Therefore, HLA-B51 was confirmed to be by far the most strongly associated gene with BD in an Iranian population.
Behcet Syndrome↗
Allelic structure and distribution of two STR loci, D8S580 and D22S442, in the Japanese population.
The allelic frequency and structural characteristics of two STR loci D8S580 and D22S442 were investigated using blood samples from 143 unrelated healthy Japanese individuals. Thirty-eight alleles in D8S580 locus and 13 alleles in D22S442 locus were identified. The discrimination power, heterozygosity, and the polymorphic information content of those loci displayed high values (0.98, 0.88, and 0.87 in D8S580 and 0.97, 0.86 and 0.85 in D22S442), and their frequency distributions met Hardy-Weinberg equilibrium expectations. The allelic pattern of D8S580 was complex and differentiated into three groups (group I: alleles 184-194bp; group II: alleles 203-223, 235, 239, 243, 252 and 255bp; group III: alleles 227-286bp). Most of their alleles contained five categories of repeat units (A: aaaag; B: aaag; C: aagg; D: caag; E: agaa). On the other hand, D22S442 contained only two types of repeat units (A: agga; B: aggg). The present study, hence, proves that both D8S580 and D22S442 are highly polymorphic and represent stable genetic markers applicable to forensic investigations.
Alleles↗
A second susceptibility gene for developing rheumatoid arthritis in the human MHC is localized within a 70-kb interval telomeric of the TNF genes in the HLA class III region.
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease with a multifactorial genetic basis. However, pathogenic genes for RA other than the human leukocyte antigen (HLA)-DRB1 gene have yet to be identified. Here, we investigated whether there is a second susceptibility locus for RA within the human major histocompatibility complex using 18 microsatellite markers distributed from the centromeric (HSET) to the telomeric end (P5-15) of the 3.6-Mb HLA region. Statistical studies of associated alleles on each microsatellite locus showed that one pathogenic gene for RA in the HLA region is localized in the DRB1 gene, as expected. Further, a second susceptibility gene of RA was suggested to be present in the HLA class III region, narrowed to 70 kb, that is just telomeric of the TNF gene cluster (TNFA and LTA) and that is located between the microsatellites TNFa and C1-2-A. In this critical segment, four expressed genes have been thus far identified, NFKBIL1 (IkappaBL), ATP6G, BAT1, and MICB, all of which are candidate genes for determining susceptibility to RA. These results exclude the possibility of involvement of the TNFA genes (TNF-alpha) in the development of RA, which was suggested previously to be a strong candidate for RA in the class III region.
Alleles↗
Characterization of the amyR gene encoding a transcriptional activator for the amylase genes in Aspergillus nidulans.
The Aspergillus nidulans amyR gene and its cDNA were cloned and sequenced. The genomic gene comprised 2,092 bp, interrupted by two short introns, and encoded a cys-6 zinc transcriptional activator (AMYR) of 662 amino acid residues with a calculated molecular mass of 72,862 Da. Disruption of the amyR gene caused defects in the utilization of maltose and starch and abolished expression of the taaG2 gene encoding A. oryzae Taka-amylase A, which is inducibly and abundantly expressed in the wild-type A. nidulans. Expression of the amyR gene was under the control of the carbon catabolite repressor, CREA. The growth defect of the malA1 mutant on maltose was complemented by the amyR gene; and the amyR gene derived from the mutant possessed a single mutation, from A to T, at position 1,483, resulting in a substitution of His478 to Leu. These results indicate that the amyR gene is identical to the genetically defined malA gene. AMYR possessed five domains (Zn and MH1-MH4) homologous to Mal63p, a transcriptional activator for the genes involved in maltose utilization in Saccharomyces cerevisiae. The His478 to Leu substitution lay within the MH3 domain, corresponding to the negative regulatory domain of Mal63p which relieves the inhibitory effect on the activation function in response to maltose.
Amino Acid Sequence↗
Microsatellite mapping of a susceptible locus within the HLA region for Behçet's disease using Jordanian patients.
Behçet's disease (BD) has been established to be associated with HLA-B51. However, it has not been revealed whether the HLA-B51 gene itself or another gene located near the HLA-B gene is directly involved in the pathogenesis of BD. Previously, using Japanese BD patients, our group has narrowed down a BD-causative gene to 46 kb between the MICA and HLA-B genes by means of fine mapping analysis with eight microsatellite markers distributed within a 1100 kb segment around the HLA-B gene. To know whether this mapping result is generally observed in BD of another population we have investigated repeat polymorphisms of the same microsatellite markers in Jordanian BD patients. Furthermore, we have evaluated these data by Mantel-Haenzel stratified analysis to find out a primarily associated locus for BD. As a result, HLA-B51 was found to be the most strongly and primarily associated marker. This result suggests that the pathogenic gene of BD is HLA-B51 itself, but unlikely to be other genes located in the vicinity of HLA-B.
Adolescent↗
A close relationship of triplet repeat polymorphism in MHC class I chain-related gene A (MICA) to the disease susceptibility and behavior in ulcerative colitis.
Major histocompatibility complex (MHC) class I chain-related gene A (MICA) has been found near the HLA-B gene. The MICA molecule is exclusively expressed on gastrointestinal epithelium and recognized by intestinal epithelial gamma delta T cells, where it exhibits a triplet repeat polymorphism in the transmembrane region. We investigated the possible correlation between MICA genetic polymorphism and ulcerative colitis (UC). Eighty-three patients with UC and 132 unrelated controls were included in this study. All subjects were Japanese. A triplet repeat polymorphism in the transmembrane region of the MICA was determined by direct sequencing procedures after amplification by a polymerase chain reaction. A significantly higher allele and phenotype frequencies of MICA A6 allele were observed in patients with UC than controls (allele frequency: P(c)=0.000011, phenotype frequency: P(c)=0.0049 odds ratio=2.62). A6 homozygous patients with UC showed significantly earlier onset of UC than patients without the A6 allele ((P)c=0.0042). Phenotypes of MICA A6 allele in Japanese are closely related to the disease susceptibility and behavior in UC. Examinations of MICA polymorphism in other ethnic groups may provide important information about the locus of primary responsible gene for UC.
Adolescent↗
HLA class I genotyping including HLA-B*51 allele typing in the Iranian patients with Behçet's disease.
It is well known that Behçet's disease (BD) is strongly associated with human leukocyte antigen (HLA) B51 in many ethnic groups. However, there has been no published report as yet with respect to this association among the Iranian people. Furthermore, since it is now known that the B51 antigen can be encoded by 21 alleles, B*5101-B*5121, we performed HLA-B*51 allele typing as well as HLA class I genotyping of 48 Iranian patients with this disease. As a result, the frequency of the B*51 allele was significantly higher (62.1%) in the patient group as compared with the ethnically matched control group (31.8%) (Pc=0.067, R.R.=3.51). In the genotyping of B*51 alleles, 33 out of the 36 B*51-positive patients possessed B*5101 and the remaining 3 carried B*5108. This study revealed that Iranian patients with BD also had a strong association with HLA-B51. In addition, this significantly high incidence of HLA-B*51 was found to be caused by an increase in both the HLA-B*5101 and HLA-B*5108 alleles. However, there was no significant difference in the HLA-B*51 allelic distribution between the patient and control groups.
Alleles↗
Stratification analysis of MICA triplet repeat polymorphisms and HLA antigens associated with ulcerative colitis in Japanese.
We previously reported a conserved haplotype of HLA B52-DR2 and a significantly high frequency of the major histocompatibility complex (MHC) class I chain-related gene A (MICA) transmembrane-short tandem repeat (TM-STR) 6 allele in Japanese patients with ulcerative colitis (UC). To examine the predominance of the MICA TM-STR 6 allele as a marker of the susceptibility to UC within the susceptible haplotype, the association of each allele with UC was estimated following stratification of the patients to control for any possible confounding effects of other alleles positively associated with UC. Sixty-four patients with UC and 236 unrelated healthy controls were included in this study. All subjects were Japanese. HLA-A, -B, -C, and -DR antigens were determined serologically. A triplet repeat polymorphism of the MICA was determined by direct sequencing. To control for the effect of linkage disequilibrium, Mantel-Haenszel weighed odds ratios were calculated. Significantly higher phenotype frequencies of B52, MICA TM-STR 6, and DR2 were observed in patients with UC. Linkage disequilibria among alleles associated with UC revealed that a B52 - MICA TM-STR 6 - DR2 haplotype was conserved in patients with UC, as in controls. When the association of HLA-B52 was estimated after patient stratification for the possible confounding effect of MICA TM-STR 6 or DR2, a strong significant association of B52 with UC was still observed. In contrast, no association with UC was observed for MICA TM-STR 6 or DR2, after stratification of the possible confounding effect of HLA-B52. These results imply that the significant increase in MICA TM-STR 6 in Japanese patients with UC is attributable to linkage disequilibrium with HLA-B52.
Colitis, Ulcerative↗
HLA-B*51 allele analysis by the PCR-SBT method and a strong association of HLA-B*5101 with Japanese patients with Behçet's disease.
Behçet's disease (BD) is known to be associated with human leukocyte antigen (HLA) B51 in many different ethnic groups. An increased incidence of HLA-B51 in the patient group has also been reported in a Japanese population. Recently, the B51 antigen has been identified to comprise 21 alleles, B*5101-B*5121. Further, not only HLA-B*5101 but also HLA-B*5108 were found to be relatively increased in the patient groups among Italian and Saudi Arabian populations. Therefore, we performed HLA-B*51 allele genotyping by the polymerase chain reaction-sequencing based typing (PCR-SBT) method in order to investigate whether there is any correlation of one particular B51-associated allele with Japanese BD. Ninety-six Japanese patients with BD and 132 healthy Japanese volunteers were enrolled in this study. As a result, the phenotype frequency of the B51 antigen was confirmed to be remarkably increased in the patient group as compared to the ethnically matched control group (59.4% in patients vs. 13.6% in controls; Pc=0.0000000000098, R.R.=9.3). In the B*51 allele genotyping, 56 out of 57 B51-positive patients were defined as B*5101 and the remaining one was B*5102. In contrast, all of 18 B51-positive normal controls were B*5101. None of the Japanese patients and healthy controls carried the HLA-B*5108 allele. This study revealed that B*51 allelic distribution in Japanese was different from those in Italian and Saudi Arabian populations, and that the significantly high incidence of the HLA-B51 antigen in the Japanese BD patient group was mostly caused by the significant increase of the HLA-B*5101 allele.
Alleles↗
Neuronal form in the central nervous system of the tadpole larva of the ascidian Ciona intestinalis.
The dorsal tubular central nervous system (CNS) of the ascidian tadpole larva is a diagnostic feature by which the chordate affinities of this group, as a whole, are recognized. We have used two methods to identify larval neurons of Ciona intestinalis. The first is serial electron microscopy (EM), as part of a dedicated study of the visceral ganglion (1), and the second is the transient transfection of neural plate progeny with green fluorescent protein (GFP) (2), to visualize the soma and its neurites of individual neurons in whole-mounted larvae of C. intestinalis. Our observations reveal that ascidian larval neurons are simple inform, with a single axonal neurite arising from a soma that is either monopolar or has only very few, relatively simple neurites arising from it, as part of a presumed dendritic arbor. Somata in the visceral ganglion giving rise to axons descending in the caudal nerve cord are presumed to be those of motor neurons.
Animals↗
The structure, frequency, and forensic application of the STR locus D16S543 in the Japanese population.
D16S543 is a complex STR locus consisting of five types of repeat units. The frequency distribution and genetic characteristics of this locus in Japanese were investigated using blood samples from 124 unrelated Japanese and 15 families. Alleles were detected using denatured polyacrylamide gels followed by automated analysis on an ABI 373 sequencer using Genescan software 672. Twenty-one alleles were identified, ranging in size from 281 to 489 bp. An allelic ladder containing the 21 alleles was constructed and used as a typing standard. The repeat unit arrays allowed the 21 alleles to be classified into three distinct groups, including alleles 1 to 7 in group I, alleles 8 to 14 in group II, and alleles 15 to 22 in group III. The alleles in group II were characterized by the insertion of one repeat unit of CAGG, one of AAAG, and three of AAGG, while the group III alleles differed from those of groups I and II by the insertion of a total of 32 repeat units ranging in 5 types. Within each group, the alleles differed from each other only in one 5' side tetranucleotide AAGG. The power of discrimination (Pd) and the estimated heterozygosity were calculated to be 0.989 and 0.934, respectively. Typing of this locus was successfully applied in four old forensic materials. The study presented herein demonstrates that D16S543 is a highly polymorphic and applicable locus in Japanese.
Alleles↗
Primary structure, developmental expression and functional properties of an inward rectifier K+ channel of the tunicate.
A cDNA encoding for a tunicate inward rectifier K+ channel (TuIRK) was isolated. TuIRK exhibited the highest similarity (approximately 50%) with mammalian Kir2 (IRK) subfamily. Maternal RNA of TuIRK was detected by RT-PCR in unfertilized eggs. By in situ hybridization, the transcript was observed at the 32-cell stage, restricted at the 64-cell stage in anterior epidermal cells of a4-2 blastomere lineage, and disappeared at the late gastrula stage. Therefore, TuIRK was identified to be the inward rectifier whose expression was previously reported to change dramatically upon the neural/epidermal cell fate selection. In Xenopus oocytes, TuIRK expressed a strongly inward rectifying K+ current. The basic electrophysiological properties of TuIRK were similar to those of the mouse IRK1 (mIRK1), except that the sensitivity to the block by extracellular Mg2+ was much lower than that of mIRK1. To identify the structural determinant, we made mutants of the pore region, and then of the extracellular loop (N226 of TuIRK, and E125 of mIRK1). In E125N mutant of mIRK1, the sensitivity to the Mg2+ block was decreased significantly, whereas N226E of TuIRK1 did not acquire the sensitivity. These results demonstrate the contribution of this site to the Mg2+ block and the presence of additional determinant(s).
Amino Acid Sequence↗