An HLA study in 74 Danish haemochromatosis patients and in 21 of their families

HLA-A and -B alleles in 74 Danish patients and 21 homozygous relatives with idiopathic haemochromatosis (IH) were compared with those in a sample of 1719 chromosomes from healthy Danish control subjects. The following alleles occurred with higher frequencies in IH compared to controls: A3: 53.6% vs. 15.1% (Pc less than 0.001); B7: 33.1% vs. 15.6% (Pc less than 0.001); B14: 6.9% vs. 3.0% (Pc greater than 0.05); B38: 5% vs. 0.9% (Pc greater than 0.05); B47: 4.0% vs. 0.4% (Pc greater than 0.05). Pedigree analyses disclosed 19 different haplotypes in IH subjects, compared to 286 haplotypes in controls. The following haplotypes occurred with higher frequency in IH compared to controls: A3,B5: 10.3% vs. 0.3% (Pc less than 0.001); A3,B7: 25.6% vs. 6.6% (Pc = 0.001); A3,B14: 3.4% vs. 0.6% (Pc greater than 0.05); A3,B47: 6.9% vs. 0.2% (Pc greater than 0.05). The major IH marker HLA-A3 was found in 56% of the haplotypes. The patterns of HLA-alleles associated with IH in Denmark show similarities to those in Central Europe, Australia, USA and Canada, being A3,B7 dominated and those in Central Sweden, England and Ireland, being A3,B14 dominated.     

HLA determinants in idiopathic haemochromatosis

HLA-antigens were determined in 21 unrelated patients with idiopathic haemochromatosis and in eight siblings and 13 children of the probands. The prevalences of HLA-A3, B7, and B14 in patients compared to 1967 healthy control subjects were: A3, 76.2% versus 26.9% (p less than 0.0001); B7, 57.1% versus 26.8 (p less than 0.001); B14, 9.5% versus 4.5% (n.s.); A3 and B7, 42.9% versus 12.2% (p less than 0.0001); A3 and B14, 9.5% versus 1.4% (p less than 0.001). Siblings (n = 3) that were HLA-identical with the proband were considered to be homozygotes for the haemochromatosis allele and presented with preclinical haemochromatosis. Siblings and children (n = 17) having only one HLA-haplotype in common with the proband were considered to be heterozygotes. Biochemical markers for haemochromatosis (transferrin saturation and serum ferritin) were higher in homozygous than in heterozygous subjects (p less than 0.0001). The results confirm the association between the HLA-A and B loci and the haemochromatosis gene. HLA-typing is a valuable tool in the identification of the haemochromatosis genotype in a family, and it is an adjunct to the biochemical screening procedure in relatives of patients with this iron overload disorder.     

HLA antigens and Graves' disease in Black South Africans

This study concerns the frequencies with which 36 HLA-A, -B and -C antigens occurred in 84 Black Africans with Graves' disease and in 311 Black controls. In the hyperthyroid patients significant reductions were found in the frequencies of HLA-B7 ( P <0.001, relative risk (RR) 0.33), HLA-Bw42 ( P <0.001, RR 0.32) and the HLA-B7-Bw42 crossreactive group (CREG) ( P <0.0001, RR 0.27), and in the frequencies of the phenotypic combinations HLA-A1, B7 ( P <0.001) and Aw30, B7-Bw42 ( P <0.001). HLA-B8 was increased in frequency ( P <0.01, RR 2.84). In patients without circulating antithyroglobulin or antimitichondrial antibodies the frequencies of HLA-A2 and B17 were increased when compared to those with antibodies or to the controls. In patients with and without clinically evident infiltrative ophthalmopathy the frequencies of HLA antigens were similar. In 62 Caucasian patients with Graves' disease, no antigens or phenotypic combinations occurred with increased or decreased frequency when compared to 278 controls.
Analysis of the frequencies of 9 HLA antigens and phenotypic combinations common in Caucasians but rare in Blacks revealed that only two antigens (A2 and B8) occurred with increased frequency in Black patients, suggesting that a contribution of Caucasian genes to the Black thyrotoxic subjects was unlikely.
Similarly, only one common Black antigen (A28) of 8 common antigens and phenotypic combinations, occurred in Caucasian patients with a frequency similar to that of Black controls. Thus it is unlikely that Black genes contributed to the lack of a significant increase of HLA antigens in the Caucasian thyrotoxic patients. The possession of HLA-B7-Bw42 CREG or related genes may be a protection against Graves' disease in Black Africans.     

Protective and susceptible HLA polymorphisms in IgA nephropathy patients with end-stage renal failure

Idiopathic immunoglobulin A (IgA) nephropathy is characterised by an extreme variability in clinical course, leading to end-stage renal failure in 15-20% of adults. This subgroup of patients with IgA nephropathy is usually included in the waiting lists of organ exchange organisations. The frequency of HLA-A,B,DR antigens of this subset of IgA nephropathy patients was calculated and compared to controls. The antigens HLA-B35 and DR5 were significantly increased in the patients with relative risk values of 1.385 and 1.487, respectively. The antigens HLA-B7, B8, DR2, and DR3 were found in a significantly lower frequency in the patients as compared to the controls. The relative risk (RR) values ranged between 0.695 and 0.727. Consequently, the haplotypes HLA-A1, B8, DR3, HLA-A3, B7, DR2, HLA-A2, B7, DR2 together with HLA-A1, B15, DR4, HLA-A9, B12, DR7, and HLA-A10, B18, DR2 were found to be protective with RR values ranging from 0.309 to 0.587. The only susceptible haplotype observed was HLA-A2-B5, DR5 (RR=2.990).     

High frequency of HLA-DR5 in Greek patients with haemophilia A and haemophilia B

Sixty unrelated Greek patients with haemophilia (46 with haemophilia A and 14 with haemophilia B) were typed for HLA-A, B and DR antigens. A highly significant increase in the frequency of HLA-DR5 was observed in both groups of patients (58.6% vs 30.0%, chi 2 = 10.47, pc less than 0.03, RR = 3.31 for haemophilia A and 78.5% vs 30.0%, chi 2 = 12.32, pc less than 0.007, RR = 8.5 for haemophilia B). An increased frequency of HLA-B13 was also observed in patients with haemophilia A (15.2% vs 5.7%, chi 2 = 5.74, pc less than 0.4, RR = 2.9). Thirty of the 60 patients (50.0%) were positive for LAV/HTLVIII antibodies. HLA-DR5 was equally distributed in patients with and without these antibodies (63.3% and 63.3%, respectively). The presence of DR5 did not correlate with the severity of haemophilia A or B. These results may suggest an influence of gene(s) on chromosome 6 in haemophilia A and haemophilia B and no effect of HLA antigens in the susceptibility to LAV/ HTLVIII infection among haemophiliac patients.     

Idiopathic haemochromatosis and HLA antigens in Italy: is A3 Bw35 HLA haplotype a marker for idiopathic haemochromatosis gene in north east regions?

Thirty two unrelated Italian subjects with idiopathic haemochromatosis were studied. HLA-A3 was present in 26 of them (81% v 22% in controls; p less than 0.001) and HLA B7 in eight (28% v 9%; p less than 0.01). There was no important association between idiopathic haemochromatosis and HLA B14. Subdividing the patients on the basis of their regional origin a noticeably higher prevalence of HLA Bw35 in patients with idiopathic haemochromatosis from north eastern Italy was found than in those from Lombardy, or in the controls; there were no differences in the incidence of HLA A3 and B7 between patients with idiopathic haemochromatosis from different areas. A high prevalence of A3, Bw35, and A3, B7 haplotypes was found in our patients with idiopathic haemochromatosis. A3, Bw35 could be the haplotype most commonly linked to the idiopathic haemochromatosis gene in north eastern Italy.     

HLA and IgA deficiency in blood donors

We have identified 67 IgA deficient healthy blood donors in our region by systematic screening of 24,782 blood samples. HLA typing results on 36 of these donors indicated a significant association with both HLA-A1 and HLA-B14 antigens. The frequency of A29 and B8 antigens was also increased. However, B8 association may be secondarily involved due to linkage disequilibrium (e.g., A1-B8-DR3). The frequency of HLA-A1 and HLA-B8 antigens was increased in the group of IgA deficient donors who developed anti-IgA antibodies (53.9%) compared to those who did not (26.1%). Although the sample size appears to be too small to show a statistical significance (chi 2 = 2.76, 0.05 less than p less than 0.1), this is the first report to imply a possible HLA association with anti-IgA antibody formation by IgA deficient healthy individuals.     

Unbalanced regulation of the expression of HLA-A and -B antigens in metastatic melanoma cells compared to autologous PBMC: A quantitative analysis of fourteen patients.

The quantitative cell surface expression of the gene products of HLA-A and -B loci is genetically predetermined (following Mendelian inheritance) in a given individual; in addition, the regulation of their expression is tightly coordinated since the ratio of HLA-A and -B antigens expression is constant on different cell types and the expression of HLA-B antigens is lower than that of HLA-A antigens. In view of these considerations and of the potential relevance of the quantitative expression of the gene products of HLA-A and -B loci in antigen presentation and for T cell-based specific immunotherapy, levels of cell surface HLA-A (mAb A131) and -B (mAb YTH) antigens were investigated by flow cytometry on fourteen primary cultures of melanoma cells (analyzed between in vitro passages 5 to 10) derived from unrelated melanoma patients and compared to those obtained with autologous PBMC. All melanoma cells and PBMC investigated were stained by mAb A131 and YTH (samples were considered positive when the mean value of fluorescence intensity with specific mAb was at least double than negative control mAb). The mean values of mean fluorescence intensity obtained for HLA-A and HLA-B antigens were 275±247 and 35±30 on melanoma cells and 1520±490 and 780±340 on PBMC and were both significantly different in a paired test between melanoma cells and PBMC (HLA-A, P=2×10⁻⁶; HLA-B, P=1×10⁻⁶); thus, the expression of HLA-A and -B antigens was 5.5 and 22.1 times lower on melanoma cells than on autologous PBMC. Simple linear regression analysis showed a high correlation (r=0.9; P=1×10⁻⁵) between the mean values of fluorescence intensity observed for HLA-A and -B antigens in PBMC; in contrast, a low correlation (r=0.6; P=1×10⁻²) was found in melanoma cells. Therefore, we calculated the ratio between the mean values of mean fluorescence intensity obtained for HLA-A and -B antigens in melanoma cells and autologous PBMC. The ratio HLA-A vs HLA-B was 10.9±8.0 (range: 2.1 to 32.6) and 2.1±0.7 (range: 1.28 to 3.58) in melanoma cells and PBMC, respectively (p=1×10⁻³, paired t test). Results similar to those obtained with mAb YTH were also obtained with the anti-HLA-B antigens mAb Q6/64 and H2-89-1. Our data, altogether, strongly suggest the existance of an alteration involving the coordinated regulation of the expression of HLA-A and HLA-B loci in melanoma cells.     

HLA linked immune response to S and pre-S2 gene products in hepatitis B vaccination

In order to detect a possible HLA linked genetic control of human immune responses to hepatitis B virus, forty healthy adult persons of the same age typed for HLA-A, -B and -DR antigens, were vaccinated against virus hepatitis B and sequentially tested for anti-HBs and anti-pre-S2 antibodies. They received three injections of Hevac-B Pasteur vaccine, the second 1 month and the third 3 months after the first. Following the third immunization, 38 individuals (95%) had a protective level of anti-HBs antibodies and 17 (42.3%) had a positive level of anti-pre-S2 antibodies. HLA-A11 antigen was significantly more frequent (pc = 0.007) among anti-HBs high responders than low responders. In addition, anti-HBs high responders were more frequently HLA-DR1, and less frequently HLA-DR4 and DR7 positive; corrected values, however, were not significant. Anti-pre-S2 high responders showed an apparent increase of HLA-B7, B14 or DR3 antigens, when compared to low responders (pc not significant).     

Human leukocyte antigen-A, -B, and -DRB1 alleles and sarcoidosis in Chinese Han subjects

Human leukocyte antigens (HLA) play a key role in antigen presentation. HLA genes, especially HLA-A, -B, and -DRB1, which are highly polymorphic, have been thought to be candidate loci for the etiology of sarcoidosis. This study aimed to assess the association between the polymorphism of HLA-A, -B, and -DRB1 alleles and sarcoidosis in Chinese Han subjects. Genomic DNA was extracted from 131 patients with sarcoidosis and 122 healthy controls. The polymorphisms of the HLA-A, -B, and -DRB1 alleles were determined using a polymerase chain reaction sequence-specific primer method. The frequency of allele HLA-DRB1*11 in sarcoidosis patients was significantly higher than that in controls (24.43% vs 4.92%, p/p_c = 0.0001/0.002), whereas the frequencies of allele HLA-B*13 and HLA-DRB1*07 were markedly lower in sarcoidosis patients than in controls (12.21% vs 27.87%, p/p_c = 0.002/0.045; 7.63% vs 22.95%, p/p_c =0.001/0.009). HLA-B*51 was overrepresented in patients with erythema nodosum and Löfgren's syndrome (p < 0.001 [p_c = 0.015], p < 0.0001 [p_c < 0.001], respectively). These results support the hypothesis that HLA-A, -B, and -DRB1 polymorphisms may play a role in susceptibility and manifestation of sarcoidosis.     

HLA and Bf in idiopathic nephrotic syndrome in children: differences between corticosensitive and corticoresistant forms

An association between HLA-DR7 and the steroid sensitive idiopathic nephrotic syndrome in the children has already been reported. Immunogenetic data in the less frequent steroid resistant form of this disease have never been published. In this study, we analyse HLA-A, B and DR typing in 99 cases of nephrotic children divided in 72 with the steroid sensitive (SS) form and 27 with the steroid resistant (SR) syndrome, in comparison with those of 207 healthy controls; Bf allotypes were determined in 53 of the patients. The results show the increased frequency of DR7 in the SS syndrome (75% vs 30%, RR = 6.9, pc less than 10(-6), while the SR one is more associated to DR3 (52% vs 27%, RR = 3, p less than 0.004). In the SS patients, atopy is associated to DR7 (p less than 0.001), which is not the case in the SR group. Furthermore, a high relative risk is associated to the phenotype DR3/DR7 (30% vs 4%; RR = 9.3; pc less than 0.0004), for the SR disease; besides, this phenotype is associated to an early onset of the disease and to lesions of focal sclerosis. Thus a heterozygous effect in the SR form of idiopathic nephrotic syndrome of children has been demonstrated; the steroid sensitive and the steroid resistant forms of the disease seem to have different immunogenetic components.     

Polymorphisms of HLA genes in Western Javanese (Indonesia): close affinities to Southeast Asian populations

Identification of human leukocyte antigen (HLA) antigens that are known as the highest polymorphic genes has become a valuable tool for tissue transplantation, platelet transfusion, disease susceptibility or resistance, and forensic and anthropological studies. In the present study, the allele and haplotype frequencies of HLA-A, HLA-B, and HLA-DRB1 were studied in 237 unrelated healthy Western Javanese (Indonesia) by the high-resolution polymerase chain reaction-Luminex method. A total of 18 A, 40 B, and 20 DRB1 alleles were identified. The most frequent HLA-A, -B, and -DRB1 alleles were HLA-A*2407 (21.6%), HLA-B*1502 (11.6%) and HLA-B*1513 (11.2%), and DRB1*1202 (37.8%), respectively. The most frequent two-locus haplotypes were HLA-A*2407-B*3505 (7%) and HLA-B*1513-DRB1*1202 (9.2%), and three-locus haplotypes were HLA-A*3401-B*1521-DRB1*150201 (4.6%), HLA-A*2407-B*3505-DRB1*1202 (4.3%), and HLA-A*330301-B*440302-DRB1*070101 (4.2%). HLA allele and haplotype frequencies in addition to phylogenetic tree and principal component analyses based on the four-digit sequence-level allele frequencies for HLA-A, HLA-B, and HLA-DRB1 showed that Western Javanese (Indonesia) was closest to Southeast Asian populations.     

HLA antigens in IGA deficient paediatric patients

HLA antigens (A, B, C and DR loci) were studied in 62 IgA-deficient (IgAd) paediatric patients: 17 with coeliac disease (CD), 13 with juvenile arthritis (JA), 27 with frequent respiratory tract infections (RTI) and five with other diseases. The frequencies of HLA antigens in IgAd patients were compared with those in healthy blood donors, and in CD and JA patients with normal serum IgA levels. The IgA deficiency in the patients showed significant associations with HLA A1, B8, B13, Cw6, DR3 and DR7 (P less than 0.0005, P corr less than 0.02 vs controls) and decreased frequencies of DR2 (P less than 0.0005, P corr less than 0.02 vs controls). The HLA associations typical of coeliac disease, increased frequencies of HLA-B8 and DR3, were evident among the IgAd coeliacs; in contrast to the coeliacs with normal IgA levels, the IgAd coeliacs showed a significant increase of the HLA-Cw6 allele (P less than 0.0005, P corr less than 0.02 vs control coeliacs). Increased frequencies of HLA-A1, B8, B13, Cw6, DR3 and DR7 were noted in the patients with RTI, which can be explained by the frequent occurrence of the haplotypes A1, B8, DR3 and B13, DR7, the latter haplotype often also having the Cw6 allele. Among the IgAd JA patients, the antigen frequencies were similar to those in the JA patients with normal serum immunoglobulins.     

HLA antigens in Asian Indians: HLA-D-DR relationships

Fifty-nine Asian Indians were typed for HLA-A, B, D, and DR antigens. Peculiar to the population that we have tested was the absence of HLA-A25, B13, B14, DR1, DW1, LD13 (a DR1-associated HLA-D allele), and LD12 (a DR4-associated HLA-D allele). Certain haplotypes that exhibit high frequencies in Caucasians (such as A2-BW50, AW24-B18, B8-DR3, BW44-DR7, B18-DR5) or in Blacks (such as A29-B7) also show significant delta in Asian Indians. The HLA-D-DR associations previously described in European and North American Causcasians were also found in Asian Indians. Additionally, however, Asian Indians exhibited two new HLA-D antigens, one associated with DR5 and the other with DRw6. The genetic distance between Asian Indians and Caucasians, Blacks, or Mongoloids is of the same order of magnitude.     

HLA-DP in rheumatoid arthritis

Frequencies of HLA-DR, Dw and DPw specificities were compared between rheumatoid arthritis (RA) patients, Felty's syndrome (FS) patients and normal controls. It was confirmed that the frequency of DR4 was increased in RA patients (54% (n = 111) vs 23% (n = 272), relative risk (RR) = 3.98, P less than 0.001). Cellular typing showed a highly significant increase in HLA-Dw14 in the entire RA population (17% (n = 32) vs 2% (n = 242), RR = 11.90, P less than 0.001), and a tendency towards an increase of HLA-Dw14 in DR4+ RA patients compared to DR4+ controls (28% (n = 32) vs 11% (n = 47), RR = 3.29, P less than 0.05). Regarding DPw specificities, the only significance was for a negative association with DPw3 (13% vs 22% (n = 254), RR = 0.51, P less than 0.05), with an additional tendential decrease of DPw1 (11% vs 19%, RR = 0.53, not significant (NS]. The decrease of DPw3 was more marked in DR4- RA patients (RR = 0.33, P less than 0.05) than in DR4+ RA patients (RR = 0.69, NS). In FS patients, 96% of whom were DR4+, decreased DPw1 was very marked, whereas the frequency of DPw3 was unaltered compared to DR4+ normals. These alterations in frequencies were not caused by linkage disequilibria between HLA-DR and -DP alleles. Thus, taken together, these data suggest that, in the presence of the major DR4-associated "susceptibility" gene(s) for RA, DPw1 may have "protective" effects, whereas in the absence of DR4, the presence of DPw3 has significant "protective" activity.     

Association of IgA deficiency with HLA A28 and B14

HLA typing was performed in two groups of individuals with low serum IgA concentrations. These consisted of 44 individuals identified from a blood donor clinic and 37 individuals attending an Immunology clinic with disorders associated with IgA deficiency. Both groups showed an increase in the frequency of HLA B14 (p less than 0.0001), HLA-A28 (P = 0.0007) and the combinations HLA-A1, B14 and HLA-A28, B14. The previously reported increase in HLA-A1, B8 was not apparent in either group. These data suggest that there is a gene within the human major histocompatibility complex which is relevant in IgA deficiency.     

HLA in familial and nonfamilial Mediterranean Kaposi's sarcoma in Greece

Abstract: Fifty-four (54) unrelated patients with Mediterranean Kaposi's sarcoma (MKS) and 8 patients members of 4 unrelated families with familial MKS were serotyped for HLA-A,B and DR antigens. The diagnosis was histologically confirmed and all patients were negative for anti-HIV antibodies. An increased frequency of HLA-B18 (44.4% vs 14.2% in the controls, p<0.001, RR=4.8) and HLA-DR5 (57.6% vs 37.2% in the controls, p<0.025, RR=2.29) was observed in the group of patients with MKS. Seven (7) of the 8 family members with FMKS possessed HLA-DR5, and the affected members in the 3 families shared a common haplotype which included HLA-DR5. These findings support the hypothesis that genetic factors linked to HLA-DR5 antigen may contribute to the pathogenesis of MKS.     

Myasthenia gravis patients with thymus hyperplasia and myasthenia gravis patients with thymoma display different HLA associations

Thirty myasthenia gravis (MG) patients (9 with thymoma, 12 with thymus hyperplasia and 9 with thymic atrophy) and 181 Norwegian healthy controls were serologically typed for HLA-A, -B and -DR antigens and genomically typed for HLA-DQA1 and HLA-DQB1 alleles by probing in vitro amplified DNA with sequence-specific oligonucleotides. In patients with thymus hyperplasia the frequency of the DQB1*0201 allele was increased compared to controls (RR = 3.5, p less than 0.05), whereas among the patients with thymoma this allele was not observed (RR = 0.06, p less than 0.01). The frequencies of HLA-B8, -DR3 and -DQA1*0501, which are in strong linkage disequilibrium with DQB1*0201, were increased in patients with hyperplasia and reduced in patients with thymoma. The data suggest that different HLA genes predispose to two different forms of MG.     

Association of HLA antigens with chronic active hepatitis (CAH) in children

HLA-A and -B antigen frequencies were investigated in a group of 46 children with chronic active hepatitis (CAH) and in a control group of 100 healthy children. The diseased group comprised 43 HBsAg positive and 3 HBsAg negative children. From the antigen frequencies relative risks (RR) were calculated according to the method of Woolf. The A1 and B8 antigens, known to be associated with autoimmune diseases, were only moderately more frequent in the CAH group than in the control. The relative risk for B8 antigen was 2.23 which is near to a significance level of p = 0.05. When the calculations were performed for 43 HBsAg positive CAH children the RR decreased to 1.70. Additionally, observations were performed on associations of HLA antigens with the occurrence of antinuclear antibodies (ANA) and anti-smooth muscle antibodies (SMA). Positive associations were found for ANA with B13 antigen (RR = 14.13) and for SMA with B5 antigen (RR = 13.66) with X2 4.85, and 5.51 respectively, at 1 degree of freedom. The p values, situated between 0.05 and 0.01 were insignificant after the correction for the number of antigens studied.     

HLA-DR4 associated Dw types in rheumatoid arthritis

Frequencies of HLA-DR4 and its related Dw types were compared between randomly selected normal controls and the index cases of multiplex rheumatoid arthritis (RA) families. A DR4 frequency of 68.3% was observed in index cases (n = 57) compared to 31.2% in normal controls (n = 96). Cellular typing with homozygous typing cells (HTCs) revealed significant increases of Dw4 (49.1% vs 22.9% RR = 3.2 p less than 0.001) and Dw14 (22.8% vs 2.1% RR = 13.9 p less than 0.001) in the index cases. A non-significant increase was seen for Dw13 (8.8% vs 4.1%). When DR4 positive patients and controls were compared, a significant increase was seen only for Dw14 (34.2% vs 6.6% RR = 7.3 p less than 0.01). Data from HLA genotyped RA and normal families allowed an examination of haplotype combinations of HLA-B antigens and DR4/Dw types to be made. HLA-Dw4 was predominantly found with B44 and Bw62 with nearly all DR4/Bw62 haplotypes being Dw4 positive. HLA-Dw13 was associated with B44 and Dw14 with Bw60, B44 and B27. Based on HTC and normal family data. Dw10 was found to be strongly associated with B38 containing haplotypes. Analysis of 69 C4A, C4B complement typed DR4 haplotypes failed to show any statistically significant association between Dw type and "complotype". However, there was a suggestion of C4A3. BQO being associated with Dw4 (34.2% vs 16.1% X2 = 2.9 p = ns) and C4A3, B1 with Dw14 (45.5% vs 27.6% X2 = 2.1 p = ns).(ABSTRACT TRUNCATED AT 250 WORDS)