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Biomedical subjects

M J Giphart

Publications and source records attributed to M J Giphart.

At least 19 recordsLinked to original sources
PubMed1998

D6STNFa microsatellite locus correlates with CTLp frequency in unrelated bone marrow donor-recipient pairs.

The use of unrelated donors for bone marrow transplantation is associated with an increased morbidity and mortality when compared with HLA identical siblings, primarily due to an increased rate of graft-versus-host-disease. HLA matching for donors and recipients is the most important factor influencing the outcome of BMT. However, unrelated donor selection generally relies on matching only for HLA antigens without considering potential incompatibility for other MHC loci. Cellular assays have been developed to predict incompatibility that cannot be detected by current typing methods. The CTLp frequencies correlate with the degree of incompatibility of patient/donor and the clinical grade of GVHD. Since the CTLp assay is expensive and time consuming, an alternative is wanted. We studied the means of matching for microsatellites in determining MHC identity and possible correlation with CTLp frequencies. Therefore, 26 recipient/donor pairs were analysed for eleven microsatellite loci within and around the MHC region. Our study provides evidence that the D6STNFa locus correlates with CTLp frequency. The D6STNFa locus provides an additional marker that may help to improve the matching of unrelated donors and bone marrow recipients.

Bone Marrow Transplantation↗
PubMed1998

Genetic structure of IDDM1: two separate regions in the major histocompatibility complex contribute to susceptibility or protection. Belgian Diabetes Registry.

We analyzed 11 markers in the IDDM1 region in 120 IDDM patients and 83 healthy control subjects who were fully matched for the highest risk HLA-DQA1*0301-DQB1 *0302/DQA1*0501-DQB1*0201 genotype. Our study provides strong evidence that two regions in the major histocompatibility complex contribute to IDDM susceptibility or protection. First, despite selection for highest IDDM-associated risk DQ genotypes, this region displays extensive linkage disequilibrium (LD) differences between IDDM patients and control subjects. A second critical region was mapped around the microsatellite locus D6S273 centromeric of TNF, and it is approximately 200 kb in size. LD analysis shows that "diabetogenic haplotypes" may have resulted from a recombination telomeric of D6S1014 in the region of D6S273 and TNFa. Haplotype analysis using HLA and microsatellite loci refines IDDM risk assessment in carriers of the HLA-DQ highest risk genotype.

Adult↗
PubMed1997

Evidence for genetic heterogeneity in inflammatory bowel disease (IBD); HLA genes in the predisposition to suffer from ulcerative colitis (UC) and Crohn's disease (CD).

Family and epidemiological studies support a genetic susceptibility to UC and CD. Conflicting reports regarding associations between UC and HLA-DR2 and between CD and various HLA alleles have been published. The aim of this study was to determine whether molecularly defined HLA-DR genes are associated with these diseases in a Dutch group of patients. Fifty-nine unrelated Dutch UC patients and 89 CD patients were typed using DNA-based methods. A total of 2400 healthy local blood donors served as controls. The phenotype frequency of the HLA-DRB1*15 allele was increased in UC patients compared with controls (42% versus 26% in controls; P = 0.006; odds ratio (OR) = 2.1), and was predominantly found in female patients (53% versus 24%; P = 0.001; OR = 3.5). The DRB1*15 allele was increased in UC patients having a positive family history (P = 0.01; OR = 5.8). Among the 16 patients who showed an increase in extent of disease during follow up, 10 were DRB1*15+ (P = 0.002; OR = 4.8). The frequency of the DRB1*13 allele was decreased in patients with UC (15% versus 28% in controls; P = 0.04; OR = 0.5). In CD, no association was observed between disease or particular clinical subgroups and any allele tested. The present study provides additional evidence for the genetic association between UC and HLA-DRB1*15, and supports recent findings that the susceptibility gene(s) for CD is not located in the HLA class II region.

Adolescent↗
PubMed1997

HLA and elephantiasis revisited.

A recent case-control study in Indonesia suggested that the course of Brugian filariasis and in particular resistance to the development of elephantiasis was associated with certain HLA class II alleles. In order to see whether these data could be confirmed we conducted a similar study in another Indonesian population from South Sulawesi. We could not confirm our earlier results and therefore concluded that HLA-DR and -DQ alleles are at least not strongly associated with progression to elephantiasis in Brugian filariasis. The complete data are presented also for anthropological reference purposes.

Alleles↗
PubMed1997

Associations between HLA-DRB1 alleles and leprosy in an Indonesian population.

To investigate whether the susceptibility to leprosy (type), subclinical infection with Mycobacterium leprae and the antibody response against M. leprae-specific antigens are associated with HLA-DR phenotypes sequence-specific oligonucleotide HLA-DRB1 and DQA1 typing and antibody assays have been performed in 79 leprosy patients (41 TT/BT and 38 LL/BL) and 50 healthy controls from a Javanese population in Yogyakarta, Indonesia. DRB1*02 was associated with LL/BL [odds ratio (OR) 2.54, 95% confidence interval (CI) 0.97-9.78, p = 0.037 and attributable risk (AR) 41.5%] but not with TT/BT leprosy (p > 0.05). HLA-DRB1*12 was negatively associated with leprosy (either LL/BL or TT/BT [OR 0.33-0.35, p < 0.05, prevented fraction (PF) 58.8%-65.3%]. No significant association was found between HLA-DRB1 or DQA1 type, anti-M. leprae antibody level and subclinical infection with M. leprae. These data indicate that in this population susceptibility to lepromatous leprosy is associated with HLA-DRB1*02, while resistance to leprosy is associated with HLA-DRB1*12. These associations are not paralleled with associations of the same HLA types with anti-M. leprae antibody level. Finally, the results of this study also support the notion that infection with M. leprae per se is not associated with HLA-DRB1 or DQA1 alleles.

Alleles↗
PubMed1996

Polymorphism of HLA-DRB, -DQA1, and -DQB1 in rheumatoid arthritis in Asian Indians: association with DRB1*0405 and DRB1*1001.

We investigated the DRB, DQA1, and DQB 1 polymorphism and haplotypes in sporadic and familial RA subjects of Asian Indian origin by PCR oligotyping using biotinylated SSOPs. Molecular subtyping of DRB 1*04 in RA patients showed strongest association with highest relative risk with DRB 1*0405, followed by DRBI*0401. A significant decreased frequency of DRBI*1502 was observed in patients compared to controls (chi 2 = 4.5). Among other alleles, DRBI*1001 was found to be significantly increased. A total of 73.3% of patients carried the shared sequence of the third HVR (67-74) of DRB1 domain compared to its presence in only 37.6% of controls. A significant number of patients carried DR4 haplotypes on DQBI*0302 (58%) as against DQBI*0301 which was present only on 10.5% of the haplotypes. When compared to controls, the difference was significant for the latter allele only. Few unique DRDQ haplotypes were observed in Asian Indians. Among DR-DQ haplotypes, DRB1*0401-DQB1*0302 gave the highest risk whereas DRB1*0403-DQB1*O301 was negatively associated. Alleles with negative charge at position 70 confer protection or are negatively associated with RA whereas among the associated alleles, glycine at position 86 resulted in higher risk than those with valine at this position. A heterogenous association of DQB1 alleles with DR4 subtypes, influencing susceptibility to RA, suggests the DQB locus is not primarily associated with RA and susceptibility lies in the sequence 67-74 of the DRB1 loci.

Alleles↗
PubMed1996

Secretion of tumour necrosis factor alpha and lymphotoxin alpha in relation to polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory bowel disease.

The genes for tumour necrosis factor alpha (TNF alpha) and lymphotoxin alpha (LT alpha; TNF beta) are tandemly arranged in the central region of the MHC. They may, therefore, be of importance for the aetiology of MHC-associated diseases. The authors have prospectively studied the secretion of TNF alpha and LT alpha in relation to polymorphisms at positions -308 and -238 in the TNF alpha gene (TNFA), and two polymorphisms in the first intron of the LT alpha gene (LTA), as well as HLA-DR in 30 patients with chronic inflammatory bowel diseases (IBD) and 12 healthy controls. In the Dutch population, the alleles of these four polymorphisms are present in only five combinations, called TNF-haplotypes: TNF-C, -E, -H, -I, and -P. Significant associations between TNF haplotypes and TNF alpha and LT alpha secretion were found when PBMC were cultured with T-cell activators, irrespective of disease. Mean TNF alpha secretion of individuals carrying the HLA-DR3 associated TNF-E haplotype was significantly higher, as compared to individuals without this haplotype (26 441 pg/ml versus 19 629 pg/ml; P = 0.014). Individuals carrying the TNF-C haplotype produced the lowest amount of TNF alpha (17 408 pg/ml; P=0.022). The TNF-C and TNF-E haplotypes differ only at position -308 in the promoter of TNFA. Individuals carrying the HLA-DR1 associated TNF-I haplotype produced significantly less LT alpha when compared to those who lack this haplotype (1979 pg/ml versus 3462 pg/ml; P = 0.006). As the TNF-I haplotype is also associated with low TNF alpha secretion, this haplotype thus defines a 'low secretor phenotype'. In conclusion, this is the first study to show associations between TNF haplotypes and TNF alpha and LT alpha secretion when T-cell stimulators are used. These findings will contribute to define disease heterogeneity in IBD and may be of relevance for understanding the pathogenesis of autoimmune diseases.

Adult↗
PubMed1996

Six newly identified HLA-DRB alleles: DRB1*1121, *1419, *1420, *1421, DRB3*0203 and DRB5*0103.

Seven samples with irregular PCR-SSO hybridization patterns, observed during routine HLA-DRB typing, were studied in more detail. Group-specific amplification, followed by hybridization with relevant SSOs strengthened the suggestion that these samples contained new DRB alleles. DRB exon 2 segments were amplified, cloned and sequenced and revealed: DRB1*1121 [MUL] is similar to DRB1*1102 in which codon 85 changed from GTT(V) into GTC(A); DRB1*1419 [AKKAL] is similar to DRB1*1402 with codon 71 changed from AGG(R) into AAG(K); DRB1*1420 [OND-52971] is a DRB1*1406 with codon 37 changed from AAC(N) into TTC(F); DRB1*1421 [TGI] is similar to DRB1*1417 with codon 71 changed from AGG(R) into AAG(K); DRB3*0203 [POS] is similar to DRB3*0202 in which codons 37-38 are changed from TAC GCG(YA) into TCC GTC(SV); DRB5*0103 was found in two unrelated individuals of Oriental origin [IND-24 and IND-59] and is similar to DRB5*0102 in which codon 71 AGG(R) changed into ACG(T). This particular sequence variation at position 71 has not yet been described. The new DRB sequences were confirmed using the sequencing based typing technique. Low resolution PCR-SSP typing failed to amplify two of the DRB1*14 variants, whereas high resolution PCR-SSP resulted in aberrant patterns. Class II alloantisera identify the codon 71 changes in DRB1*1419 and *1421 with respect to the MC1 ('DR1+DR4') epitope.

Alleles↗
PubMed1995

Irregular polymerase chain reaction-sequence-specific oligonucleotide hybridization patterns reveal seven new HLA-DRB1 alleles related to DR2, DR3, DR6, DR8, and DR11. Implications for sequence-specific priming.

In the past 3 years we have typed over 7000 individuals for HLA-DRB using a nonradioactive PCR-SSO method. The use of locally developed computer programs simplified data input and the interpretation of the DRB PCR-SSO readings. In this way we detected a number of samples with unexpected hybridization patterns. DRB1 exon 2 segments of these samples were amplified, cloned, and sequenced and appeared to identify seven new DRB alleles: DRB1*0304, a DRB1*0301 variant, was observed in three unrelated Caucasoid individuals; DRB1*1606, which is very similar to *1603; DRB1*1113 is a *1101 variant with some *1401 sequences; DRB1*1310 is *1301-like; DRB1*1311 is similar to *1305 and *1307; DRB1*1416 is a *1401 sequence with a HV3 derived from *1301; DRB1*0808 was found in an Ethiopian individual. Next, we studied the effectiveness of PCR-SSP typing of the newly defined DRB1 alleles. Only two variants were distinguished as odd by PCR-SSP and two were typed as regular specificities. Three alleles were not amplified by the primer sets used. As compared to PCR-SSO, the PCR-SSP typing method using currently available typing kits clearly has limitations as far as the recognition of new and variant alleles is concerned. The products of some of these new alleles may be distinguished using conventional serology.

Alleles↗
PubMed1995

Novel HLA-DPB1 alleles detected in the Ethiopian population.

The number of identified HLA-DPB1 alleles increased rapidly by application of DNA-based typing techniques. PCR-SSO typing indicated the presence of possible new HLA-DPB1 variants in the Ethiopian population. The use of the SBT technique, which considers polymorphic as well as constant regions in the second exon of HLA genes, allowed direct identification of two new allelic variants. Moreover, a recently identified HLA-DPA1 variant was also present in this population. The newly defined allelic HLA-DPB1 sequences found in five individuals of the Ethiopian population were confirmed by cloning and subsequent sequencing of the cloned DNA. One of the new alleles was shown to segregate in a family and was also present in unrelated individuals. Both new DPB1 alleles represent new combinations of existing polymorphism in the hypervariable regions. In different populations the frequency of these new HLA-DP variants remains to be determined.

Alleles↗
PubMed1995

Molecular analysis of HLA class II polymorphism in Croatians.

HLA-class II polymorphisms have been studied in a population of 141 unrelated healthy Croatians using PCR amplification, followed by non-radioactive oligonucleotide hybridization. Thirty one DRB1, 8 DQA1, 13 DQB1 and 16 DPB1 alleles were found in the tested population. DRB1*1601, 0701, 1501, 0101 and 1104 are the most frequent alleles at the DRB1 locus. At the DQA1 locus two alleles predominate: DQA1*0501 and 0102, while the most frequent DQB1 allele is *0301. Analysis of HLA-DPB1 polymorphism showed that, as in other Europeans, DPB1*0401 is the most frequent allele. Four different two locus haplotypic associations (DRB1-DRB3, DRB1-DRB5, DRB1-DQB1 and DQA1-DQB1) as well as three locus DRB1-DQA1-DQB1 haplotypic associations were assigned on the basis of known linkage disequilibria. Several unusual two-locus associations have been observed: DRB1*0301-DRB3*0202, DRB1*1501-DRB5*02, DRB1*1601-DRB5*0101, DRB1*1502-DRB5*0101, DQA1*0103-DQB1*0503 and DQA1*0501-DQB1*0302. Among 236 examined DRB1-DQA1-DQB1 haplotypic combinations, the most frequent was DRB1*1601-DQA1*0102-DQB1*0502 that was found with statistically significant higher frequency than in other Europeans. Twenty-eight distinct probable haplotypes were observed just once, suggesting that the main characteristic of Croatian population is great heterogeneity of haplotypes. This study will serve as a reference for further anthropology studies, HLA and disease associations studies and for donor/recipient matching in organ and bone marrow transplantation.

Alleles↗
PubMed1995

Variants of HLA-DR2/DR51 group haplotypes and susceptibility to tuberculoid leprosy and pulmonary tuberculosis in Asian Indians.

This study reports our observations on the correlation between HLA-DR2 subtypes and their DR-DQ haplotypes in patients with tuberculoid (TT) leprosy and pulmonary tuberculosis (PTB). DRB1*1501 was significantly increased in patients with PTB (90%) as compared to controls (p < 0.05); whereas the prevalence of DRB1*1502 was significantly increased in patients with TT leprosy (p < 0.05), suggesting allele-specific binding of the pathogen to form disease-causing motifs to the T-cell receptor. Among DR2-DQ haplotypes, the deviation was noted in the distribution of unique and common haplotypes in patients with TT leprosy and PTB. A significant decrease of haplotype DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0502 in TT leprosy and a significant increase of DRB1*1501-DRB5*0101-DQA1*0103-DQB1*0601 in PTB patients were observed. The occurrence of specific DR2 subtypes and their haplotypes in the two disease groups suggests their involvement in disease pathogenesis.

Adult↗
PubMed1994

Tumor necrosis factor alpha-308 gene variants in relation to major histocompatibility complex alleles and Felty's syndrome.

The location of the human TNF genes within the MHC complex has prompted much speculation about the role of TNF alleles in the etiology of MHC-associated autoimmune diseases. On sequencing the 5' regulatory region of the human TNFA gene a G (TNFA-308G) to A (TNFA-308A) transition polymorphism at position -308 was discovered. We have developed a simple PCR assay to facilitate the screening of the -308 polymorphism at the DNA level. In view of the possible linkage between the TNFA-308A allele and a certain MHC type, TNFA-308 genotypes in HLA-typed healthy individuals (n = 88) were determined. A statistically significant association between the TNFA-308A allele and HLA-DR3, DQB1*0201, DQA1*0501, A1, B8, and the NcoI 5.5-kb RFLP of the TNFB gene was observed. In addition, we determined the frequency of the TNFA-308A allele in patients with FS (n = 13), an HLA-DR4-associated disease. In this study, no association was found of Felty's syndrome with the TNFA-308A allele, indicating that this allele does not appear to be a susceptibility factor for FS.

Alleles↗