Bf Types of HLA Haplotyped Individuals in an Isolated Newfoundland Population

Five hundred and fourteen individuals from an isolated NewFoundland population have been typed and haplotyped for HLA and Factor B (Bf locus). The Bf gene frequencies were: S0.704, F0.226, F1 0.052 and S1 0.018. Tracing the haplotypes backwards on the various pedigrees it was shown that 202 HLA/Bf haplotypes had been introduced into the study population. Some HLA alleles always appeared in association with particular Bf alleles and vice versa. Bf S1 had entered the population four times, always with HLA--A9, B12. Bf F1 had entered three times, always with HLA--B18. There were 17 entries of HLA--Al, B8 that had given rise to the 78 such haplotypes that were now present in the population; all were Bf S. There were 68 family units informative for Bf. They accounted for 240 children and 304 informative meioses. There were three recombinants in the HLA region but none could be shown to have occurred between the HLA-B and Bf loci.     

HLA-linked genetic markers in Chinese and other Oriental populations

The polymorphic variants of the HLA-linked genetic markers Bf, C2, C4 and GLO—I were studied in three mongoloid populations. Analysis of linkage disequilibrium between these markers and HLA-A, B, C and DR antigens was carried out on test results from 140 unrelated Chinese individuals. The phenotypes BfS and GLO-2 were found at significantly higher frequencies than in Caucasians. BfS was associated with B12 in Japanese but not in Chinese. A single individual with the rare Bf variant SI was found. No C2 deficient individuals were observed. The C2C (common) allele occurred at a gene frequency of 0.949 and the more basic allele C2B at 0.039. The acidic variant, C2A, was observed at a frequency of 0.011 and appeared to be associated with BfF. Eighty-nine per cent of the Chinese were phenotypically C4FS. In contrast to Bf and C2, each of which is coded for by codominant alleles at a single genetic locus, C4 is coded for by two genes, C4F (Rodgers) and C4S (Chido). The C4F locus allele, C4F1 (extra fast), was strongly associated with HLA-B17, as has been found in other populations, but a new association of the C4S locus deficiency allele, C4s° (Ch-), with B17 was also observed. All HLA-B17;C4s° haplotypes were BfS positive. As has been previously found in Caucasian populations, individuals of the C4F phenotype (i.e. genotypically Fs°Fs°) were all found to be Chido negative. The frequencies of the various HLA-linked genetic markers, however, as much as the frequencies and associations of the HLA antigens themselves, distinguish these populations from other ethnic groups.     

Bf group system in the Polish population

In a sample of the Polish population including 890 subjects, the five common types BfSO, BfF, BfFS, BfSSO 7, BfFSO 7 and one phenotypic variant BfF1S were met. The frequencies of genes determining the common types were: BfS = 0.8337, BfF = 0.1506, BfSO, 7 = 0.0112 and BfF1 = 0.0045, respectively. Examination of 38 newborns and their mothers has revealed that Bf types are formed during the fetal life. Inheritance of Bf types was studied on 84 families with 187 children and 449 mother-child pairs. The results obtained have confirmed that Bf system is determined by a single genetic locus in which multiple codominant, autosomal alleles are situated. The occurrence of phenotypic variant Bf FIS observed in two and three generations, confirmed its hereditary character and its dependence on the rare BfF1 gene occurring with the BfS gene.     

Prevalence and inheritance of C3 types in the Polish population.

In a sample of the Polish population numbering 1,458 subjects, the three common types, C3S, C3F and C3FS, were found with frequencies of 0.6790, 0.0295 and 0.2901 respectively, besides two rare variants, C3FO, 7S and C3SO, 25S. Frequencies of C3S and C3F genes were 0.8248 and 0.1746 respectively, and of the CSFO,7 and C3SO,25 genes, 0.0003 each. Distribution of types in 695 mother-child pairs was consistent with the hypothesis that the C3 system depends on a single genetic locus in which codominat alleles are situated. No children of C3S and C3F mothers with opposite homozygous types were encountered. Hereditary character of the C3FO, 7S variant was confirmed by family studies in which the rare C3FO,7 gene, in combination with C3S or C3F genes, occured in three generations.     

Identification of two different HLA B49 DR4 extended haplotypes in the Sardinian population

Abstract: The HLA-B49 DR4 haplotype, which is rare in Caucasoid populations, has a frequency in Sardinia of approximately 6% and a very strong linkage disequilibrium (LD). To better understand its genetic structure, the Bf, C4A and C4B Class III alleles were studied in 56 healthy unrelated Sardinian subjects of B49 DR4 phenotype and in 24 of their families. Moreover, 14 sick subjects with the same phenotype were examined together with five of their families. A group of 285 haplotypes belonging to randomly selected individuals was used as a control population sampling. The distribution of the Bf, C4A and C4B alleles among the healthy probands revealed two main groups of association: one major group of 36 subjects (64.3%) with the BfF, C4A3 and C4B4 alleles and one minor group of 14 subjects (25%) with BfS, C4AQ0 and C4B1. A similar subdivision was also observed in the small group of patients. The family analysis confirmed these results and showed two different B49 DR4 extended haplotypes: one with the F34 complotype in 79.1% of the probands (Δ × 1000 = 49.0) and the other with the SO1 complotype in 20.8% of the probands (Δ × 1000= 17.3). The first one, in LD with the A1 and Cw7 alleles, has not yet been reported in other populations. The second one seems to be identical to a haplotype already reported in the Spanish population. The molecular analysis of the DRB1 locus carried out in 20 of the 70 probands demonstrated that, in both haplotypes, DR4 was represented by the DRB1*0405 allele. On the other hand, the study of the DQA1 and DQB1 loci in 11 probands revealed differences between the two haplotypes.     

Human 18 kDa phosphotyrosine protein phosphatase (ACP1) polymorphism: studies of rare variants provide evidence that substitutions within or near alternatively spliced exons affect splicing result

The mammalian low molecular weight phosphotyrosine protein phosphatase is expressed as two distinct isoforms. The human 'fast' and 'slow' isoforms differ only in the sequence of an internal segment of 34 residues, and the ACP1 gene contains two adjacent exons (E3F and E3S) which encode these segments. We have previously suggested that the fast and slow isoforms are generated by mutually exclusive pre-mRNA splicing of E3F and E3S. The common alleles ACP1 *A, *B and *C express the fast and slow isoforms in different ratios. The *A and *C alleles differ from *B by C → T transitions in E3S and E3F respectively. To test the idea that the fast:slow ratio is determined by nucleotide substitutions in the E3F-I3F-E3S region, four groups of rare ACP1 variants with unusual fast : slow ratios and the rare *E and *R alleles, expressing fast : slow ratios similar to *C and *B, respectively, were analysed. Gene segments of the I2-I3S region were amplified by PCR and analysed by SSCP and variant bands were excised and sequenced. For each of the rare isozymic variants one of six different nucleotide substitutions in E3F (nts+42, +85, +109, +110), I3F (nt+1) and I3S (nt+8) was observed. The *E and *R alleles showed C and B sequence, respectively, in accordance with the fast : slow ratio. The results support the hypothesis that the fast : slow ratio is constitutive.     

Polymorphism of C4 and factor B in type I diabetes

The haplotypic frequencies of the fourth component of complement (C4) and factor B (Bf) have been determined in 44 Alsatian type 1 diabetics. An increased frequency of the rare allele Bf F1 (9.1% vs 1.5%) and of the silent alleles of C4 (C4 AQO: 21.6% vers 15.5% -C4 BQO: 29.6% vs 16.0%) was observed in diabetics in comparison to the general population of the same geographic area. A complete HLA haplotype determination has been obtained in 24 type 1 French diabetics. Three haplotypes were associated with the diabetic susceptibility: HLA-A30 CW5 B18 BfF1 C4A3BQO DR3 (18.75% vs 0.86%), HLA-A1 CW7 B8 BfS C4AQOB1 DR3 (15.58% vs 4.17%), HLA-A2 CW3 BW62 BfS C4A3B3 DR4 (6.25% vs 0.45%). The authors suggest that the silent alleles of C4 could modulate the expression of the diabetic susceptibility genes by lowering of the serum C4 hemolytic activity.     

Autoimmune-associated HLA-B8-DR3 haplotypes in Asian Indians are unique in C4 complement gene copy numbers and HSP-2 1267A/G

The classical AH8.1 (HLA-A1-B8-DR3-DQ2) is the most common Caucasian haplotype, associated with several autoimmune diseases, immunologic hyperreactivity and rapid progression to the acquired immunodeficiency syndrome. However, in Asian Indians, there are multiple unique B8-DR3 haplotypes that are associated with autoimmunity and differ significantly from the common Caucasian AH8.1. The Indian HLA-A1-B8-DR3 is therefore referred to as an AH8.1 variant. The aims of this study were to compare C4A and C4B copy numbers and to identify alleles in HSP70-2 and LTA in these haplotypes. The Indian B8-DR3 haplotypes differ from the Caucasian AH8.1 at C4A and HSP70-2 loci. The Indian B8-DR3 haplotypes have 1 copy each at C4A and C4B, while the Caucasian AH8.1 has 1 copy at C4B but no C4A gene. Moreover, the Indian and Caucasian B8-DR3 haplotypes had HSP70-2 1267 (*)A, and *G alleles, respectively. By contrast, the LTA 252 *G allele occurred both in the Indian and Caucasian haplotypes. The Indian haplotypes also contained Bf*F and TNF-308*G that were different from the Caucasian equivalents Bf*S and TNF-308*A. These differences and previous studies support the hypothesis that B8-DR3-DQ2 haplotypes in Asian Indian population might have originated independently of Caucasian AH8.1 selectively through recombination and mutations. Because autoimmune disease associations are shared among these otherwise diverse haplotypes, these data strongly suggest that some shared component(s) of all these associated haplotypes may be playing a key role in such associations.     

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.     

A DNA restriction fragment length polymorphism in the complement region of the human MHC shows an absolute correlation with polymorphism of complement factor B(Bf) defined by isoelectric focusing

The gene coding for properdin factor Bf is located in the human major histocompatibility complex and is closely linked to the genes coding for the complement components C2 and C4. Recently, by Southern blotting techniques, a restriction fragment length polymorphism was identified using the endonuclease Taq I, which subdivides haplotypes carrying the F allele of factor Bf. The F allotype has also been subdivided at the protein level by isoelectric focusing into two subtypes Fa and Fb. We have investigated the DNA of 41 healthy unrelated individuals with known BfF subtypes using the 2.3 kb factor Bf cDNA probe to determine if there is any correlation between the Taq I polymorphism and F subtype. We have found that in 23 individuals who carried the Fb subtype a 6.6 kb Taq I fragment was present. The remaining 18 individuals carried the Fa subtype and showed only the 4.5 kb Taq I fragment on Southern blotting (P = 10(-12). This striking correlation (r = 1) between the Fb protein and DNA polymorphism is surprising especially as the 4.5 kb and 6.6 kb Taq I fragments overlap the Bf and C2 genes and the polymorphic Taq I site is located within the C2 gene.     

A new cathodal Gc variant in Australia

A new cathodal Gc variant and a known rare variant were found in a study of 307 Australian caucasian blood donors, each with a gene frequency of 0.28%. The frequencies of the other alleles were 0.161 (Gc1F), 0.557 (Gc1S) and 0.279 (Gc2), and were comparable with those of two earlier surveys.     

Complement C2, C3, C4 and factor B allele distribution in the Gipsy population in Hungary

Allotype frequencies of four complement proteins (C3, C2, factor B, and C4) were tested in 150 healthy Hungarian and 126 healthy Gipsy individuals living in Hungary. We observed significant differences between the two ethnic groups in the incidence of C3*F, Bf*F, C4A*Q0, C4A*3, C4B*1 and C4B*2 allotypes. Bf*F occurred more frequently among Gipsies, while frequencies for the other three allotypes was lower in this group than in Hungarians. The similarities in the allotype frequencies of C3 and Bf among Gipsy and Gaddis (India) populations supports the Indian origin of the former ethnic group.     

贵州苗族补体Bf和C4B同种异型的多态性

用高压琼脂糖电泳后的免疫固定试验，检测了贵州苗族健康成人的补体旁路Ｂ因子（Ｂｆ）和Ｃ４Ｂ的同种异型。在检出的基因型中Ｂｆ有３个，Ｃ４Ｂ有１０个，最高基因频率的基因是Ｂｆ＊Ｓ０．９４４４。Ｃ４Ｂ＊２０．５０００．     

Genetic polymorphism of coagulation factor XIIIB subunit in Japanese

Genetic polymorphism of coagulation factor XIIIB subunit in Japanese has been described, using thin-layer agarose gel isoelectric focusing followed by immunofixation.
Phenotypes of factor XIIIB subunit were essentially classified into three common patterns A, B and AB. It is estimated that the phenotypes are determined by two codominant alleles. A new rare variant B' has been detected in Japanese.
Gene frequencies calculated from 304 individuals showed FXIII-B^A =0.735, FXIII-B^B = 0.252 and FXIII-B^B' = 0.013, respectively. The distribution of phenotypes fitted the Hardy-Weinberg equilibrium.     

Reference typing report for complement factor B

Factor B (BF) reference typing was carried out on the occasion of the VIIth Complement Genetics Workshop in Mainz, May 1998. Two different sets of samples were analysed by agarose electrophoresis and/or isoelectric focusing at the protein level, and by PCR-RFLP analysis at the DNA level. These results confirmed the reliability of the standard agarose electrophoresis technique for the identification of the major BF alleles as well as for the identification of cathodic and anodic variants. However, the exact alphanumeric designation of individual variants relative to the reference distance between alleles S and F1 turned out to be more difficult. Using PCR-RFLP analysis, the common alleles F and S as well as the FA and FB subtypes in 6 samples containing an F allele were all assigned correctly. However, the variants F1 and S07 were not detected by this method, as they could not be distinguished from the accompanying S allele. Therefore, a combined application of all three typing methods is recommended for a reliable identification of factor B alleles, variants and FA/FB subtypes.     

Human MHC Class III (Bf, C2, C4) genes and GLO: their association with other HLA antigens and extended haplotypes in the Spanish population

C4 allotype frequencies and their combination with factor B and C2 alleles (complotypes) were studied in a sample of the Spanish population in relation to MHC class I, class II and GLO alleles. The shorter genetic distances found for C4 between Spaniards and North Africans and the high frequency of extended HLA haplotypes (GLO 2) HLA-DR3 F1C30 HLA-B18 HLA-Cw5 (HLA-A30) and HLA-DR7 S1C21 HLA-Bw50 HLA-Cw6 are consistent with a paleo-North African ethnic origin (about 20,000 years B.C.) of a part of present Spaniards (Iberians), and with the effect of racial admixture during late Moslem invasions (from the 8th to the 15th century). The complotype null alleles C4A QO and C4B QO may be under natural selection pressure when found in cis position, since they are never in the same haplotype in families. The underestimation of these C4 null alleles' frequencies in unrelated individuals as compared to genotyped families is shown to be a very likely event and a serious hindrance for C4-disease association studies. We have not found any C4 duplications in the Spanish population; this may be due to sample size limitations or to the degree of admixture of our population. Strikingly, no positive linkage disequilibrium between C4A and C4B alleles is detected in unrelated individuals nor in families, although strong associations are maintained among Bf, C2, C4, HLA-A, HLA-B, HLA-C and HLA-DR markers. Assuming that all MHC polymorphisms have reached equilibrium, several explanations are proposed, including the possibility of no, different or additional natural selection mechanisms operating on some MHC class III genes (Bf, C2, C4 alleles combinations for most appropriate C3 convertases), as compared to those affecting class I and class II gene clusters (most advantageous immune response genes sets).     

HLA Antigens Associated with Properdin Factor B Allotype BfF1

Linkage disequilibrium has been described between HLA-B antigens and allotypes of properdin factor B (Bf). The association between HLA-B and DR antigens and the rare allotype BfF1 was investigated. In 27 HLA-A, B and DR typed individuals only one person was found who was DR3 negative but five who were B18 negative. Family studies showed that in nine cases B18, BfF1 and DR3 segregated as a haplotype; in another family which was B18 negative, BfF1 and DR3 segregated together. It is infered that the Bf locus is more strongly associated with HLA-DR than with HLA-B.     

C4 complement allotypes in juvenile dermatomyositis

Twenty probands with juvenile dermatomyositis and their relatives were studied to determine the inherited segregation patterns of class I, II, and III HLA region markers including C4A, C4B, Bf, and C2 complement polymorphisms. The extended haplotype B8, DR3, C4A*Q0, C4B*1, C2*C, and Bf*S was present in 13 of the 20 probands. Three other probands also carried a haplotype with a null allele for C4A and two further probands carried a null allele for C4B; only two probands had no detectable C4 null allele. These data confirm previous studies showing high frequencies of B8 and DR3 in patients with juvenile dermatomyositis, but show that there is a higher association with null alleles of C4. This suggests that the C4 genes are either themselves the disease-susceptibility genes or are in very strong linkage disequilibrium with such genes.     

Serum protein polymorphism in Bali (Indonesia)

Serum samples from Bali, obtained in three different ethnic groups and in one isolated village were tested by isoelectric focusing electrophoresis for Gc, Pi, Tf and Hp subtyping. In addition to the three common alleles Gc1F, Gc1S and Gc2, two variants Gc1A1 and Gc1A8 were observed. In the Pi system, five alleles were present: PiM1, PiM2, PiM3, PiM4 and PiX. The Tf variability was exceptional with the presence of eight alleles: TfB1, TfC1, TfC2, TfC3, TfC4, TfC8, TfD1 and TfDchi. For Hp, there were two common alleles Hp1S and Hp1FS and two rare ones: Hp1F and Hp2SS. As expected, the genetic polymorphism is reduced in the isolated community. The anthropological significance of these genetic data is discussed.