HLA/Bf haplotypes in a Newfoundland family

HLA/Bf haplotypes were examined in a large three-generation Newfoundland family with a high incidence of Graves' disease. In that family Graves' disease was inherited in association with the haplotype HLA Aw24, Bw39 in some instances and with HLA B8-containing haplotypes in other instances. As all seven members of the family who suffered from Graves' disease were homozygous for the Bf S allele, the study for Bf was uninformative. However, the examination of other HLA/Bf haplotypes disclosed some interesting associations. One-hundred-and-five out of 168 HLA-A, -B, -Bf haplotypes were Bf S. Although numerically deviant, no unusual HLA B/Bf associations were observed. Bf F entered the family only once. A new finding is the association between HLA B27 and Bf S1; the haplotype entered the family once and was passed on to eight family members over three generations. Bf S1 was previously reported in association with HLA B12 or W21. None of these family members had ankylosing spondylitis. The Bf allele F1 entered the family three times, always in association with HLA B18.     

Studies on an Isolated West Indies Population: I. Analysis of HLA Genotypes

The transmission of HLA genes was studied in an isolated population of French origin on the lesser Antilles islands in the West Indies. The study of 74 unrelated individuals, 44 of whom were genotyped, was carried out for the alleles of HLA loci: A, B, C and Bf (proactivator factor of properdin).
As a result of the founder effect and the inbreeding process, the HLA haplotypcs were noted to be less polymorphic than in a French continental population. Two haplotypes: A2, Cw5, B12, BfS and A3, C-, B14, BfF represent 24% of the observed haplotypes, and only 2% of the reference haplotypes in France.
No significant excess or deficit of homozygotes was observed at the A and B loci.     

HLA Antigen Frequencies in an Irish Population

Two-hundred-and-fifty-three unrelated Irish adults were typed for 24 alleles at the HLA-A and B loci. A high frequency of HLA-B8 (34.8%) was observed compared with results published for other populations. Results of other gene frequencies, haplotype frequencies and linkage disequilibrium values were similar to those of Caucasian population studies. Close similarity of HLA polymorphism distribution was seen in relation to another relatively homogeneous Celtic population from the islands of the Outer Hebrides, off the coast of Scotland.     

HLA antigens and Bf allotypes in lichen sclerosus et atrophicus

A study of the HLA-A, B and DR antigens and properdin factor B allotypes of 26 patients with lichen sclerosus et atrophicus and a normal control population showed an increase in the HLA-Aw31 antigen only. However, when the HLA-A and B frequencies were combined with the results of a previous independent study a significant increase in both HLA-Aw31 and HLA-B40 was noted. These findings suggest an association between lichen sclerosus et atrophicus and the HLA system.     

Bf Polymorphism and its Relationship with HLA Antigens in a Sample of the Spanish Population: High BfF1 Frequencies

Bf allele frequencies were studied in a sample of the normal Spanish population and in family haplotypes. BfF1 shows a frequency higher than in other Caucasoid populations and closer to that found in Negroids. Basques show an even higher BfF1 frequency. BfF1 is in strong linkage disequilibrium with B18. HLA-Bw44 is found to be the B12 split in linkage disequilibrium with BfF and Bw50-BfS1 association is confirmed. DR3-BfF1 are not in linkage disequilibrium in the normal Spanish population, in contrast to DR3-BfF1 linkage found in a diabetic Spanish population.
Results are discussed on the bases of the paleo-North African Iberian population origins and of the use of Bf to define B12 and Bw21 splits.     

Tuberculosis Associated with HLA—B8, Bf S in a Newfoundland Community Study

In three adjacent Newfoundland communities comprising some 1500 people, 589 people have been HLA typed. Forty-six of the typed people gave a history of previous clinical tuberculosis which required treatment. Fifty-six percent of the TB patients carried HLA B8 compared with 20% of the remainder of the population. This is a highly significant difference ( P < 0.01). In each community the frequency of B8 as an epidemiological marker correlated with the incidence of tuberculosis. B8 is associated with TB in this study with a relative risk of 5.2 which compares with combined relative risks in the literature for coeliac disease and Addison's disease of 9.5 and 6.4, respectively, and which is greater than the risks for all the other B8-related diseases. The factor B allele, Bf S, was found on all the B8 haplotypes, but the overall Bf gene frequencies in tuberculosis patients did not deviate from expected values.     

The Association of HLA with Juvenile Diabetes Mellitus in Newfoundland

In view of the reported variation in the association between HLA antigens and Juvenile Diabetes Mellitus (J.D.M.) among different Caucasian populations, we have undertaken a study of these antigens among 44 Caucasian Newfoundlanders and 135 matched controls. We have also studied the allotypic markers for Immunoglobulin G (Gm) and variants of C3 among 36 of these patients. We found that both HLA--B8 and B15 were increased among the patient group, resulting in a relative risk of 3.9 and 4.4 respectively. While these values are the highest to be described for J.D.M. among Caucasians, and fell outside the 95% confidence intervals for the combined relative risk calculated from published series, it is still possible that they can be accounted for by sampling. The combination of the two antigens increased the relative risk for J.D.M. in an additive fashion. Additionally, we also found that the combination of HLA B8 and B18, but not B15 and B18, also appear to act in an additive manner. The incidence of Gm allotypes and variants of C3 were not different in the J.D.M. group from those observed among controls.     

The Association of HLA with Autoimmune Thyroid Disease in Newfoundland. The Influence of HLA Homozygosity in Graves' Disease

Forty-seven patients with Graves' disease, 73 with thyroiditis and 128 controls drawn from the same geographical area of Newfoundland were HLA typed. The frequency of HLA-B8 was significantly increased in the Graves' disease patients when compared to the control group giving a relative risk of 3.9. There were no significant HLA differences between the thyroiditis and control groups.
Homozygosity for the HLA haplotype, which is common in this island population, was more common in Graves' disease patients (12.8%) than in controls (5.5%) but did not reach statistical significance in this sample. Homozygosity was due in five of the six cases to either an A1;B8 haplotype or an A2;B8 haplotype. This contrasted with an apparently random assortment of haplotypes in the control and thyroiditis groups. Calculations suggest that homozygosity for a B8 haplotype confers an additional risk over heterozygosity for B8 of about 3.5 fold; however, homozygosity had no observable influence on the severity of the disease.
These results strengthen the idea that B8, or an allele in linkage disequilibrium with it, determines in part the susceptibility of an individual to developing Graves' disease.     

Study of a family with Cerebrotendinous Xanthomatosis. No HLA linkage, but an informative recombination between HLA-B and Bf

A large family with three children affected with the autosomal recessive disease of Cerebrotendinous Xanthomatosis (CTX) was studied for class I (HLA-A,B,C) and class II antigens (HLA-DR,D,SB), properdin factor B and glyoxalase. The extensive typing revealed an informative cross-over between HLA-B and Bf, indicating that Bf is located centromeric to the HLA-B locus and segregated in this family with HLA-D/DR. The parents in this family were first cousins and their parents were also first cousins. Three of their four haplotypes share B14, BfS, DR1, Dx and SB4 and may be identical by descent. The three affected children carried among them all four parental haplotypes, indicating that close linkage of the CTX locus to HLA is unlikely.     

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.     

HLA Haplotypes in a Genetic Isolate in Newfoundland. A Population Showing 8% Homozygosity and a Familial Aggregate of Lymphoma and Immunodeficiency Cases

HLA typing was performed on 384 individuals of an isolated population of 1,500 people with a.familial aggregate of lymphoma and immunodeficiency cases. Eighty-five % of the total population were descendants of the founding couple. First cousin marriages were common. There was a three-fold or higher increase of the following haplotypes as compared to the frequencies in Sheffield: HLA-A28, Bw35, HLA-A28, B18, HLA-A10, B18, HLA-A2, B18, HLA-A11, Bw40 and HLA-A11, B7. The frequency of HLA-A1, B8 was low (5.4%). The most common genotype was HLA-A2, B12/A2, B12 followed by HLA-A2, B12/A28, Bw35. We found 30 HLA homozygous individuals, of these 15 were HLA-A2, B12/A2, B12. There were two possible HLA cross-overs which may be confirmed and three postulated cross-overs which can never be confirmed as one or both parents of the individuals in question are deceased. Some of the haplotypes could be traced back to the first, second and third generations, i.e. to the first half of the nineteenth century. No single haplotype or antigen was shared by the patients.     

Extractable nuclear antigen (ENA) autoantibodies in SLE: an immunogenetic relationship with HLA, C4 and Bf alleles.

Sera from 36 subjects with systemic lupus erythematosus (SLE) were examined for extractable nuclear antigen (ENA) autoantibodies by immunoassay with the ribonucleoprotein (RNP) subset being determined by immunodiffusion. The prevalence of the genetic markers of HLA, the fourth complement component (C4) and properdin factor (Bf), which are all coded for within the major histocompatibility complex on chromosome 6 were analysed in relation to various parameters of these autoantibodies. The following associations were observed: The lowest ENA antibody titres of the RNP negative group were associated with HLA A9 (P less than 0.05), while the lowest RNA-ase sensitive ENA (RSE) subset antibody levels were associated with HLA Dr 1 (P less than 0.05). For the complement markers, C4 AQo was associated with the lowest affinity ENA antibodies (P less than 0.05), while the BF F allele and Fs phenotype had lower RSE antibody levels than did the S allele (P less than 0.05) and the SS phenotype (P less than 0.05) respectively. This study demonstrated diverse association between various MHC markers and ENA antibody parameters, indicating that there are distinctive immunogenetic influences over ENA autoantibodies in SLE.     

HLA antigens and Bf allotypes in SLE: evidence for the association being with specific haplotypes

The clinical features and HLA types of 67 unrelated patients with Systemic Lupus Erythematosus (SLE) were analyzed. The results showed:
1. An increase in frequencies of A1, B8, and DR3. These antigens are in close linkage disequilibrium and our data show that susceptibility to SLE is associated with the presence of all three antigens, implicating the specific haplotype which bears these antigens.
2. An increase in frequency of DR2, but not A3 or B7, these latter two antigens being in linkage disequilibrium with DR2.
3. 73.3% of the 54 Caucasoid SLE group were either B8 and/or DR2. This is in comparison with 37.5% in the controls and the difference is significant (p < 0.001).
4. There was no association apparent between extent of disease, particular organ involvement and level of circulating antibodies to double stranded DNA with any HLA region product.     

Population of the HLA ligand database

We have established an HLA ligand database to provide scientists and clinicians with access to Major Histocompatibility Complex (MHC) class I and II motif and ligand data. The HLA Ligand Database is available on the world wide web at http://hlaligand.ouhsc.edu and contains ligands that have been published in peer-reviewed journals. HLA peptide datasets prove useful in several areas: ligands are important as targets for various immune responses while algorithms built upon ligand datasets allow identification of new peptides without time-consuming experimental procedures. A review of the HLA class I ligands in the database identifies strengths and deficiencies in the database and, therefore, the utility of the dataset for identifying new peptides. For instance, 212 HLA-A phenotypes exist of which 23 have a motif determined and 43 have peptides characterized. In terms of number of ligands, HLA-A*0201 has 258 characterized ligands, A*1101 has 25 peptides, while the remaining two-thirds of the HLA-A phenotypes have less than 10 associated peptide sequences. Characterization of ligands and motifs remains roughly the same at the HLA-B locus while the peptides of the HLA-C locus tend to be less characterized. These data show that 74% of HLA class I molecules do not have ligands represented in the database and thus algorithms based on the dataset could not predict ligands for a majority of the US population. Building upon this dataset and knowledge of HLA allelic frequencies, it is possible to plan a systematic expansion of the HLA class I ligand database to better identify ligands useful throughout the population.     

HLA Antigens in a Scottish Psoriatic Population

Sixty-one patients in the Dundee area suffering from psoriasis were typed for HLA-A and HLA-B antigens. On the basis of the typing results, the patients were divided into three groups, and studied with respect to sex, age of onset and familial incidence of the disease. The frequency of HLA-A1 appeared to be increased and HLA-B7 decreased but HLA-B13 and HLA-B17 were highly significantly increased (P less than 10(-6) and P less than 10(-10) respectively) in the psoriatic group compared to 204 controls. Of particular interest was a highly significant association of HLA-A1 with HLA-B17 in psoriatic patients. Family studies showed HLA-B17 to be a useful genetic marker for psoriasis in the families of B17 positive patients. Considerations of age of onset, familial incidence and typing data suggest that there is heterogeneity of genetic susceptibility to psoriasis and that one probable mechanism is the dominant inheritance of a "disease allele" in linkage disequilibrium with the allele coding for HLA-B17.     

HLA Frequencies in a Mexican Mestizo Population

The aim of the present study was to reevaluate the distribution of HLA antigens in Mexican Mestizos since, in our previous report, very few specificities were explored for this population. The Mestizos are primarly a mixture of Caucasians (Spaniards) and Mexican Indians and account at the present time for about 95% of the total Mexican population. A and B antigens were typed on isolated cells using a microlymphocytotoxicity technique. Antigen, gene and haplotype frequencies were calculated including the significance for delta values. The results clearly showed that the HLA distribution differs from other ethnic groups and the predominant antigens are A2, A9, B5, Bw35 and B40, but the general pattern clearly shows the participation in genetical composition of Spanish and Mexican Indian backgrounds. The most frequent haplotypes were A2-B5, A9-Bw35, A9-B40 and A2-B40, which are also the most common in some Mongoloid populations.     

HLA Frequencies in a Mexican American Population

HLA-A and -B antigens were determined for 300 unrelated Mexican-Americans and 300 unrelated Caucasians from San Antonio by the microlymphocytotoxicity technique, using lymphocytes isolated from freshly drawn peripheral blood. Haplotype frequencies for the Mexican American population were obtained directly, based on family studies, as well as estimated from phenotype data. The results revealed clear differences in the distribution of HLA antigens between Mexican American and Caucasian populations. The predominant HLA specificities in Mexican Americans were A2 and Bw35, while the most frequently observed haplotypes were A2-Bw35, A2-B12 and A2Bw40. Despite the distinct differences in HLA antigen distribution between Mexican American and Caucasian populations, genetic distance values, calculated from the HLA frequencies, were surprisingly low.     

Distribution of HLA Antigens in a Cuban Population

The frequencies of the HLA antigens were determined in a population of 160 unrelated Cubans from three different ethnic groups (white, mixed-blood and negro). We typed for antigenic specificities of the A and B loci, and also for the Cw1 specificity of the C locus. Phenotype and gene frequencies for the different ethnic groups are presented for comparison. The phenotype distribution, the haplotype frequencies for the white group and the genetic distance between this group and a Spanish population were calculated.     

Linkage of GLO with HLA and Bf. Effect of population and sex on recombination frequency.

Further data on the linkage relationships of red cell glyoxalase I(GLO) with HLA and Bf are reported. The most likely order of loci is GLO: Bf: HLA-B: HLA-A. No sex difference in the frequency of recombination between GLO and HLA was noted, but recombination was more frequent for both males and females in the American black population than in the white population.