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PubMed2002

Host defense and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation.

We made the hypothesis that donor and recipient gene polymorphisms that drive the host response to microorganisms could be associated with infections after bone marrow transplantation (BMT). HLA-identical BMT was performed for patients with acute (n = 39) or chronic leukemia (n = 68). Genotyping was performed in 107 D/R DNA pairs for gene polymorphisms of cytokines (tumor necrosis factor-alpha [TNF-alpha] and TNF-beta, interleukin-1 receptor antagonist [IL-1Ra], IL-6, and IL-10), adhesion molecules (CD31 and CD54), Fcgammareceptors (FcgammaRIIa, IIIa, IIIb), mannose-binding lectin (MBL), and myeloperoxidase (MPO). First infection (overall) and first episodes of bacterial, viral, or invasive fungal infection were studied retrospectively for 180 days after BMT. Univariate and multivariate analyses, using death as a competing event, were performed to study risk factors. In multivariate analysis, first overall infections were increased in patients with the FcgammaRIIa R-131 genotype (hazard ratio [HR] = 1.92; P =.04), and severe bacterial infections were increased when the MPO donor genotype was AG or AA (HR = 2.16; P =.03). Viral and invasive fungal infections were not influenced by any genetic factor studied. Interestingly, we also found that (1) time to neutrophil recovery was shorter when donors were FcgammaRIIIb HNA-1a/HNA-1b (HR = 1.77; P =.002); (2) donor IL-1Ra (absence of IL-1RN*2) increased the risk for acute graft-versus-host disease (GVHD) (II-IV) (HR = 2.17; P =.017); and (3) recipient IL-10 (GG) and IL-1Ra genotypes increased the risk for chronic GVHD (P =.03 and P =.03, respectively). Finally, 180-day transplantation-related mortality rates were increased when donors were FcgammaRIIIb HNA-1a/HNA-1a or HNA-1b/HNA-1b (HR = 2.57; P =.05) and donor MPO genotype was AA (HR = 5.14; P =.004). In conclusion, donor and recipient gene polymorphisms are informative genetic risk factors for selecting donor/recipient pairs and could help in the understanding of mechanisms involved in host defenses of BM transplant recipients.

Adolescent↗
PubMed2001

Tumour necrosis factor alpha (-238 and -308) and beta gene polymorphisms in pulmonary tuberculosis: haplotype analysis with HLA-A, B and DR genes.

SETTING: A study of tumour necrosis factor alpha and beta (TNFalpha and beta) gene polymorphism and haplotype analysis with HLA in pulmonary tuberculosis. OBJECTIVE: To determine whether TNFalpha (-238 and -308) and TNFbeta (Nco I polymorphism in intron 2) genes either alone or in combination with human leucocyte antigens (HLA) as haplotypes afford susceptibility or resistance to pulmonary tuberculosis as well as bacteriological relapse of the disease. DESIGN: Tumour necrosis factor alpha -238, -308 (TNFalpha -238, -308) and TNFbeta (Nco I) gene polymorphisms were carried out in HLA-A,B and DR typed pulmonary tuberculosis patients (n=210) and 120 normal healthy control subjects. RESULTS: No difference in the genotype frequencies of TNFalpha-238 and -308 and TNFbeta was seen between control subjects and pulmonary tuberculosis patients. Of the HLA-TNF haplotypes analysed, the infrequent allele (A) of TNFalpha238 was in strong linkage disequilibrium with HLA-A1 (P corrected: Pc=0.001), B17 (Pc<0.0001) and DR7 (Pc=0.01) in control subjects and with B17 (Pc<0.0001) in pulmonary tuberculosis. The infrequent allele 2 of TNFalpha-308 and the infrequent allele 2 of TNFbeta were in strong linkage disequilibrium with HLA-B21. An increased haplotype frequency of HLA-B17-TNFalpha-238/A (P=0.05), B17-TNFalpha308/2 (P=0.03) and B17-TNFalpha308/2 (P=0.01) was observed in bacteriological relapse patients than quiescent patients. CONCLUSION: The present study suggests that TNFalpha (-238 and -308) and TNFbeta gene variants are not associated independently with the susceptibility to pulmonary tuberculosis. However, in combination with the HLA genes/gene products such as HLA-A1, B17, B21 and DR7, the TNFalpha and beta genes as haplotypes are associated with protection against the disease as well as an increased susceptibility to bacteriological relapse.

Adult↗
PubMed2005

Risk association between human leukocyte antigen-A allele and high-risk human papillomavirus infection for cervical neoplasia in Chinese women.

To examine the association between human leukocyte antigen-A (HLA-A) allele polymorphism, human papillomavirus (HPV) infection, and risk for cervical neoplasia in Chinese women, 263 patients (155 with cervical intraepithelial neoplasia [CIN] II/III and 108 with invasive cervical cancer [ICC]) were compared with 572 controls. Overall, regardless of HPV status, a decreased risk for ICC was observed for patients with A*0207/0215N or A*2402, and an increased risk was observed for patients with A*1104. The protective association of A*0207/0215N was reproduced in HPV-16-positive patients with ICC, but not in subgroups infected with other HPV types. The risk association between A*1104 and both HPV-16 and HPV-18 was reproduced in the subgroups with CIN III/ICC. The protective association between A*2402 and HPV-16, HPV-18, HPV-52, and HPV-58 was consistently observed in all subgroups with CIN III/ICC, suggesting a linkage with a general antioncogenic genetic factor. The results of the present study indicate that HLA-A polymorphism is one of the host genetic factors that alter the risk for the development of cervical cancer in Chinese women.

Adult↗
PubMed2005

A new HLA-DRB1 genotyping method using single nucleotide polymorphism (SNP) analysis with multiplex primer extension reactions and its application to mixed samples.

We have improved on conventional methods for HLA-DRB1 genotyping and devised a new method that is simple, cost-effective, and adequately applicable to routine forensic practice. This method consists of group-specific polymerase chain reaction (PCR) of the exon 2 region of the HLA-DRB1 gene and simultaneous detection of single nucleotide polymorphisms (SNPs) at multiple sites using multiplex primer extension reactions. With this method, we successfully detected HLA-DRB1 genotypes from the following materials: the peripheral blood of 142 donors, 6 aged saliva stains of known DRB1 genotype stored for 5-10 years at room temperature, 10 aged bloodstains of unknown DRB1 genotype stored for 29 years at room temperature, and minimal bloodstains and saliva stains from 3 donors of known DRB1 genotypes. Furthermore, we were able to type DRB1 alleles of the minor component in mixed samples at a proportion of 1/1,000 or 1/10,000. In a criminal case, DRB1 alleles detected from mixed bloodstains on a sword found at the scene enabled us to explain the case. This method is expected to be useful for forensic medicine.

Alleles↗
PubMed1988

HLA-A, B, C, DR and DQ polymorphisms in three South African population groups: South African Negroes, Cape Coloureds and South African Caucasoids.

The HLA class I and II phenotypes of the three population groups in the Cape Province of South Africa were determined. The HLA-A,B, and C antigens were tested in 1027 South African Negroes (Xhosa), 3716 Cape Coloureds and 1059 South African Caucasoids. This is the first study which has also included the class II antigens in the Southern African Negroes (Xhosa). The numbers tested for the DR and DQ antigens were smaller, as only typings done after the 8th Histocompatibility Workshop were included. A comparison was made between the frequencies in the Xhosa, the Cape Coloureds and the South African Caucasoids as well as the Nigerians, another group who also belong to the Bantu-speaking division of African Negroes and who were recently studied. The antigen, gene and haplotype frequencies were estimated in all three groups, and the genetic distances calculated. Striking differences in gene and haplotype frequencies between the various populations were seen. For example, Bw42 had a phenotype frequency of 0.062 in the Cape Coloureds, 0.213 in the Xhosa and 0.004 in the South African Caucasoids. The Xhosa showed marked differences in HLA distribution compared to the other Negro group (Nigerians), which can be attributed to a Khoisan admixture, e.g. HLA-DR4 had a phenotype frequency of 0.134 in the Xhosa and only 0.010 in the Nigerians. The haplotype B8,DR3, seen in association with many autoimmune diseases, had a significant delta value in all three populations.

Black People↗
PubMed1987

Two alleles detected for HLA-DZ alpha on the basis of a polymorphic restriction site in the third exon.

The restriction enzyme ApaI has been used to define Restriction Fragment Length Polymorphism (RFLP) within the DZ alpha gene. Digestion of genomic DNA of 96 individuals with ApaI reveals the existence of two different patterns. Both homozygous and heterozygous individuals were detected. Hardy-Weinberg analysis indicates that DZ alpha is part of a di-allelic system with allele frequencies of 50%. DZ alpha polymorphism in the population studied does not correlate with serologically determined class I and HLA-DR, DQ and cellular DP typing data. A limited family study demonstrates that DZ alpha polymorphism segregates with HLA-class II phenotypes.

Alleles↗
PubMed1997

Oligotyping for HLA-DQA, -DQB, and -DPB in idiopathic nephrotic syndrome.

Associations of human leukocyte antigens (HLA) with the idiopathic nephrotic syndrome (NS) have mainly been described for alleles of the HLA-DR locus. In the present study the polymorphism of HLA-DQ and -DP at the molecular level was investigated in 167 children with NS (129 steroid-sensitive) using the polymerase chain reaction and sequence-specific oligonucleotides in a French and a German cohort. HLA-DR typing was also performed by classical serology. In steroid-sensitive patients we observed an increased frequency of the alleles HLA-DQA1*0201 and -DQB1*0201 in both populations with relative risks ranging from 3.8 to 8.5 (Pb < 0.01 to Pb < 0.00001 after Bonferoni's correction). In contrast, the frequency of HLA-DQA1*0102 and DQB1*0602 was significantly decreased. In children with frequent relapses the HLA associations were generally more pronounced than in those with infrequent or no relapses. Applying logistic regression analysis, a nephrotic child bearing DQA1*0201 or DR7 was five times more likely to be in the steroid-sensitive group of patients than in the steroid-resistant group compared with nephrotic children not bearing one of these alleles. These HLA alleles therefore seem to be useful indicators of a steroid-sensitive frequently relapsing course of NS. No associations with DPB alleles were observed, which narrows the region genetically involved in the disease susceptibility to the DR-DQ region. Steroid-resistant NS was not associated with HLA.

Adolescent↗
PubMed1984

Evidence for polymorphism of MB3 antigens among three HLA-D clusters associated with HLA-DR4.

In a previous study, we showed that the three hitherto serologically indistinguishable HLA-D specificities associated with HLA-DR4, HLA- DYT , HLA- DKT2 , and HLA-Dw4 can be distinguished on the basis of their reactivity with two distinct Ia-like-specific monoclonal antibodies, HU-18 and HU-23. In this study, we attempted to identify and characterize Ia-like molecules recognized by HU-18 and HU-23 on a molecular level because Ia subsets (HLA-DR, MB, MT, or SB) identified by them remained unknown. The results of sequential coprecipitation assays and two-dimensional gel analyses showed that both HU-18 and HU-23 recognize antigenic determinants borne on MB3 but not on HLA-DRw6.2 molecules. Because the two monoclonal antibodies, specific for determinants carried on MB3 molecules, show distinct reactivity against homozygous typing cells defining HLA- DYT , HLA- DKT2 , and HLA-Dw4, all of which share DR4- MB3 , the data indicate that these three HLA-D clusters associated with HLA-DR4 possess distinct MB3 molecules, suggesting the existence of polymorphism in MB3 antigens.

Antibodies, Monoclonal↗
PubMed1986

A DR3-related DX alpha gene polymorphism strongly associates with insulin-dependent diabetes mellitus.

HLA-DQ alpha and HLA-DX alpha gene polymorphisms were analyzed by Southern blot techniques in 78 Caucasoid insulin-dependent diabetes mellitus (IDDM) subjects and 55 control subjects. Five restriction fragment length polymorphisms of the HLA-DQ alpha gene correlated with HLA-DR typing. Two allelic DX alpha-related gene fragments, of 2.1 kb (U) and 1.9 kb (L) in size were identified. Genotype frequencies in the IDDM group for UU, UL, and LL were 54%, 38.5%, and 7.5%, respectively, whereas the corresponding frequencies in the control group were 24%, 40%, and 36% (P less than 0.00005 for differences in genotype frequencies). The U allele was associated particularly with IDDM patients who were DR3, with healthy controls who were DR3, as well as with IDDM patients who were not DR3. Thus, if this DX alpha U allele is not the DR3-associated IDDM susceptibility gene, it is the closest marker hitherto studied.

Chromosome Mapping↗
PubMed1998

Is the expression of classical HLA class I antigens on trophoblast of importance for human pregnancy?

PROBLEM: Human leukocyte antigen (HLA)-C and possibly also HLA-B seem to be expressed on the extravillous trophoblast. These antigens carry epitopes that function as ligands for natural killer (NK)-cell-inhibitory receptors. Antitrophoblast cytotoxicity mediated by decidual NK cells might be involved in miscarriage. We thus found it relevant to elucidate whether parental HLA-C and -Bw polymorphism play a role in recurrent miscarriage (RM). METHOD OF STUDY: HLA-C and -Bw investigations by DNA-based techniques were undertaken in 35 couples with unexplained RM and in 30 couples with normal fecundity. The number of HLA-C- and -Bw-related supertypic specificities that can bind NK-cell-inhibitory receptors was evaluated in selected couples. RESULTS: The proportions of couples with RM and control couples carrying four HLA-C alleles with the same NK-cell-inhibitory supertypic specificities were equal. In 46% of studied couples with RM, all four HLA-B alleles carried the HLA-Bw6 supertypic specificity, which was significantly higher than the corresponding frequency (17%) in the control couples (P < 0.02). CONCLUSIONS: The expression of polymorphic HLA-C on trophoblasts does not seem to play a role in RM. Assuming that HLA-B is expressed on trophoblasts, we may suggest that the revealed predominance of HLA-Bw6 expression (which excludes the presence of HLA-Bw4-protective antigens) may predispose a particular couple to the RM phenomenon.

Abortion, Habitual↗
PubMed1999

Association of HLA and T-cell receptor gene polymorphisms with Semple rabies vaccine-induced autoimmune encephalomyelitis.

Semple rabies vaccine is derived from brain tissue infected with rabies virus that is subsequently inactivated with phenol. Semple rabies vaccine-induced autoimmune encephalomyelitis (SAE) occurs in 1 in 220 immunized individuals. The immune response to myelin basic protein and pathological changes of demyelination in SAE suggest that this disease is the human homologue of experimental autoimmune encephalomyelitis (EAE). SAE and EAE are frequently studied as models for the human demyelinating disease multiple sclerosis. Major histocompatibility complex (MHC) class II and T-cell receptor (TCR) gene polymorphisms play important roles in rodent susceptibility to EAE and were analyzed to determine if the same was true in humans with SAE. HLA-DRB1, HLA-DQB1, and TCRBV gene polymorphisms were studied in Thai individuals with SAE (n = 18), with vaccination without neurological complications (n = 43), and without vaccination (n = 140). The allele frequencies of HLA-DR9 (DRB1*0901) and HLA-DR17 (DRB1*0301) were increased in SAE patients (DR9 = 22%, DR17 = 14%) compared with vaccinated controls (DR9 = 13%, DR17 = 6%) and with unvaccinated controls (DR9 = 9%, DR17 = 4%). The allele frequency of HLA-DQ7 (DQB1*0301) was decreased in SAE patients (8%) compared with vaccinated controls (15%) and with unvaccinated controls (25%). These susceptibilities are distinct from those associated with multiple sclerosis. The frequencies of TCRBV alleles and haplotypes were similar in SAE patients and vaccinated controls. These data suggest that genetic susceptibility associated with MHC class II alleles may have a role in the pathogenesis of SAE and its mechanism may be different from those involved in multiple sclerosis.

Alleles↗
PubMed2001

TNF-238A promoter polymorphism contributes to susceptibility to ankylosing spondylitis in HLA-B27 negative patients.

OBJECTIVE: To investigate the relative contribution of MHC loci in their susceptibility to primary ankylosing spondylitis (AS) in HLA-B27 negative patients and to compare the clinical features and genetic factors with those of HLA-B27 positive AS. METHODS: DNA from patients with B27 negative primary AS (n = 28), B27 positive primary AS (n = 77), and matched healthy controls (B27-, n = 100; B27+, n = 70) were analyzed to investigate whether HLA genes determine the disease susceptibility, or whether other closely linked loci might play a role in disease development. HLA typing was carried out by serology and PCR/SSP (HLA-B, -DR), MICA-TM polymorphism in the transmembrane region by radioactive PCR, and tumor necrosis factor-alpha (TNF-alpha) promoter polymorphism at positions -238 and -308 by PCR-RFLP. RESULTS: Subtle clinical differences were found for primary AS, the B27 negative patients being less frequently complicated by acute anterior uveitis and more associated with peripheral arthritis than B27 positive. Differences were found in the distribution of TNF-alpha -238 genotypes among patients with primary AS (B27- vs B27+). The TNF-alpha -238(A) polymorphism was present in 50% of the B27 negative patients carrying the -238 G/A and A/A genotypes and was significantly increased compared with B27 positive AS (odds ratio 4.3) and with the B27 negative control group (OR 5.9). The TNF-alpha genotypes were equally prevalent in B27 positive AS and healthy matched B27 positive controls. No significant HLA and MICA typing differences were found between the populations under study. CONCLUSION: Our results indicate that the polymorphism variation in the TNF-alpha promoter -238.2(A) influences disease susceptibility in B27 negative primary AS but had no effect in our B27 positive AS population.

Adult↗
PubMedDate not supplied

Genotyping: the HLA system and embryo development.

The human major histocompatibility complex (MHC), in addition to its role in the regulation of cell-cell interactions in the immune response, also influences reproductive success. Human leukocyte antigen-G (HLA-G) is an MHC class I gene of particular interest in reproductive biology because of its specific expression on fetal cytotrophoblast cells, and its reported involvement both in protection of the developing fetus from destruction by the maternal immune response and in the prevention of maternal pre-eclampsia. HLA-G has 15 known alleles at the DNA level, and allelic frequency varies among ethnic groups. This study describes the results of an inaugural attempt to correlate an HLA-G genetic polymorphism with pregnancy outcome in a patient population undergoing IVF. The study group was composed of 102 Caucasian women. A maternal HLA-G genetic polymorphism was investigated by polymerase chain reaction (PCR) analysis of DNA collected from granulosa cells surrounding oocytes harvested for the IVF procedure. While no statistically significant correlation was identified in this initial study, larger studies examining DNA from trios of mother, father and offspring are planned.

Adult↗
PubMed1998

[Frequency of the HLA-DPB1 allele in the Slovak population].

The polymorphism at the HLA-DPB1 locus was established in 146 unrelated persons. The polymerase chain reaction (PCR) in combination with restriction fragment length polymorphism (RFLP) technique was used. After PCR amplification of the second exon of the HLA-DPB1 locus, the PCR products were digested with seven allele specific endonucleases. The alleles DPB1*0401 (43.29%), DPB1*0402 (20.89%), DPB1*0201 (14.39%) and DPB1*0301 (9.25%) were the most common among 15 DPB1 alleles detected in the tested group. The least frequent alleles were DPB1 *0202, *0601, *1101 and *1501 (0.34%). The comparison with allele frequencies in Austrian and German populations showed no statistically significant differences. (Tab. 2, Ref. 18.)

Alleles↗
PubMed2001

Association of HLA-DR genotypes and IL-1ra gene polymorphism with treatment failure of budesonide and disease patterns in Crohn's disease.

OBJECTIVE: Associations between HLA-DR genotypes and susceptibility to Crohn's disease (CD) have been reported. However, it is not known whether certain HLA-DR genotypes or IL-1ra gene polymorphism are associated with responsiveness to treatment or different clinical patterns of disease. DESIGN/SETTING: In a large, randomized, controlled multicentre trial, 318 patients with CD were treated with daily doses of 6, 9 or 18 mg budesonide. Patients were stratified into two groups: patients without steroid pretreatment and with active CD (CDAI > 150) and patients with conventional steroid pretreatment of < or= 30 mg prednisolone per day, which was replaced by oral budesonide within 3 weeks. MAIN OUTCOME MEASURES: The HLA-DRB1 genotypes 1-16 and the IL-1ra gene polymorphism were examined for an association with budesonide treatment failure. RESULTS: Only HLA-DR 8 was associated with treatment failure of budesonide. HLA-DR 8 is not very common. Only 17/243 patients who could be evaluated expressed this genotype, and 13 of these 17 patients did not respond to budesonide (P < 0.00067). Neither the other HLA-DR genotypes nor the IL-1ra gene polymorphism had an influence on treatment outcome of budesonide therapy. No significant association of fistulas, perianal disease, need for bowel resections, and disease localization with certain HLA-DRB1 genotypes or the IL-1ra gene polymorphism were found. CONCLUSIONS: This is the first description of an association of a certain HLA-DR genotype (HLA-DR 8) with treatment failure in inflammatory bowel disease (IBD).

Adult↗
PubMed2004

The human leukocyte antigen genotype has a modest effect on the insulin gene polymorphism-associated susceptibility to type 1 diabetes in the Finnish population.

In addition to the known human leukocyte antigen (HLA)-associated risk, polymorphisms of insulin gene region show association with type 1 diabetes. We analyzed possible interactions between the HLA class II genotypes and -2221 MspI (insulin) INS gene polymorphism in Finnish population, using a series of 1331 diabetic children and 2222 healthy newborns. C/C genotype was increased among diabetic children compared to the controls (83.2 vs 70.1%). This genotype was slightly more common in diabetic children with low or moderate HLA-associated risk than in those with high risk, but INS gene effect was clear in all major HLA-risk genotypes and, thus, can be used as an additional risk prediction marker, irrespective of HLA genotypes.

Child↗