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PubMed1989

Direct observation of the gene organization of the complement C4 and 21-hydroxylase loci by pulsed field gel electrophoresis.

Pulsed field gel electrophoresis and enzymes that cut genomic DNA infrequently have been used to define large RFLPs at the human C4 loci. With the enzymes BssH II or Sac II, and C4 or 21-hydroxylase DNA probes, it has been possible to observe directly the number of C4 genes present on a haplotype, and also whether the C4 genes are long (6-7-kb intron present) or short (6-7-kb intron absent). Haplotypes that have either two long C4 genes or one long and one short C4 gene generate BssH II fragments of approximately 115 or approximately 105 kb, respectively. Haplotypes that have either a single long or a single short C4 gene generate BssH II fragments of approximately 80 or approximately 70 kb, respectively. This technique has been used to analyze the DNA isolated from PBMC and allows the complete definition of the C4 gene organization of an individual without the need for family studies.

Cell Line↗

PubMed1992

Analysis of complement C4 loci in Caucasoids and Japanese with idiopathic membranous nephropathy.

Deletion of the HLA class III complement gene, C4A, has been linked with susceptibility to a number of autoimmune diseases. In this study, we show a strong positive association between C4A gene deletion and development of idiopathic membranous nephropathy (IMN) in European Caucasoids [patients, 17/27 (63%); healthy controls, 13/65 (20%); RR 6.8; P = 0.003]. To clarify whether C4A deletion is an independent risk factor for IMN or is increased secondarily to the Caucasoid HLA A1, B8, DR3 extended haplotype, we examined the frequency of C4A deletion in Japanese patients, in whom the disease is associated with another HLA haplotype (DR2-DQw1). Analysis of 31 Japanese patients and 46 healthy controls showed that C4A deletion was present in only one patient (3%) and one control (2%). In addition, examination of the C4B locus in Japanese patients showed that there was no significant increase in the estimated frequency of C4B deletion in patients against controls (31 vs. 27%) and no difference in the frequency of the C4B long gene (73 vs. 87%) or C4B short gene (77 vs. 78%). We conclude that although C4A deletion confers significant risk of IMN in Caucasoids, there is no significant association between C4 polymorphism, as detected here, and risk of IMN in Japanese. This suggests that either C4A deletion is irrelevant to the pathogenesis of IMN or that more than one genetic mechanism is involved.

Asian People↗

PubMed1984

Gene and haplotype frequencies of the fourth component of complement (C4) in type 1 diabetics and normal controls.

C4 gene and haplotype frequencies were calculated from phenotype data of 380 unrelated Caucasian patients with insulin dependent (type 1) diabetes mellitus and were compared with analogous frequencies of 382 unrelated healthy Caucasian individuals. In diabetics, a significantly increased frequency of the rare allele C4B 3 (p less than 10(-7] and of the silent alleles C4A Q0 (p less than 10(-7] and B Q0 (p less than 0.002) was observed. Accordingly, insulin dependent diabetes is associated with partial C4 deficiency, which may contribute to the pathogenesis of the disease.

Alleles↗

PubMed1988

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.

Adolescent↗

PubMed1985

Complement C4 allotype association with and serum C4 concentration in an autoimmune disease in the dog.

Serum C4 concentrations and C4 allotypes were determined wherever possible on eight dogs with an autoimmune disorder characterized by antinuclear antibody (ANA) positivity, pyrexia, and seronegative arthritis. Three of the six dogs tested serially showed hypocomplementemia at disease onset with return to normal concentrations with clinical remission following steroid therapy. All five dogs C4 allotyped were phenotypically identical. The phenotype (C4-4) was significantly increased in the diseased dogs. Thus C4 allotype may provide a marker for susceptibility to development of an autoimmune disorder in the dog. Serum C4 concentrations may help in disease diagnosis and monitoring the effectiveness of therapy.

Animals↗

PubMed1989

An Eco RI polymorphic site in the human complement C4 gene distinguishes juvenile rheumatoid arthritis (JRA) susceptibility-bearing haplotypes.

Susceptibility to acquire Juvenile Rheumatoid Arthritis (JRA) is linked to HLA-DR5 and DRw8 antigens in Caucasoid populations. However, the frequency of HLA-DR5 is too high in the normal Spanish population and JRA cannot thus be found to be associated with this antigen. It has been found a 14.3 kb-C4-Eco RI restriction fragment length polymorphism which correlates significantly with JRA and may be used as a marker for this disorder in Spaniards.

Arthritis, Juvenile↗

PubMed1992

Lack of deletion of complement C4 and steroid 21-hydroxylase genes in Japanese patients with primary Sjögren's syndrome.

A null allele at C4A (C4AQO) is associated with primary Sjögren's syndrome (SS) in Japanese. Since a deletion of the C4A and CyP21A genes is reported to account for C4AQO in patients with systemic lupus erythematosus (SLE) in Caucasians, we studied the restriction fragment length polymorphism (RFLP) of genomic DNA to determine whether similar deletions of the C4A and CyP21A genes occur in Japanese patients with SS. Patients with C4AQO did not show the extensive deletion of C4A and CyP21A, which would be recognized by the appearance of 8.5 kb/HindIII and 6.4 kb/TaqI fragments hybridizing with a C4 probe. It is yet to be shown whether the lack of expression of C4A genes in Japanese patients with primary SS is due to point mutations, or to small deletions or insertions that were not detected by the RFLP approach.

Alleles↗

PubMed1986

Location of the interchain disulfide bonds of the fourth component of human complement (C4): evidence based on the liberation of fragments secondary to thiol-disulfide interchange reactions.

Treatment of human C4 with chemical denaturants and heat produces rapid, autolytic peptide bond cleavage of the alpha-chain. These alpha-chain fragments are linked to the parent C4 molecule through disulfide bonds. On more prolonged heating, however, there is liberation of several peptides, including the beta-chain, the gamma-chain, and a C-terminal alpha-chain fragment. This reaction is inhibited by iodoacetamide. By using a fluorescent thiol reagent and 14C-iodoacetamide, the thiol group present on each peptide was analyzed. The results suggest that the thiol residue exposed by cleavage of the thioester bond induces thiol-disulfide interchange reactions to liberate the peptides. Based on the identification of fragments liberated, the kinetics of their appearance, their sulfhydryl content, and the reported primary structure of human C4, a model of the interchain disulfide bonds is proposed in which the amino terminal portion of the alpha-chain is disulfide-linked to both the beta- and gamma-chains, whereas the carboxyl terminal portion of the alpha-chain is disulfide-linked to only the gamma-chain.

Amino Acid Sequence↗

PubMed1995

Polymerase chain reaction analysis of the Xba I polymorphism of the human complement C4 genes provides evidence for strong haplotype conservation.

The genes coding for the two isotypes of the fourth component of human complement, C4A and C4B, are located between the HLA-B and -DR loci of the MHC. We studied the linkage relationship of the previously described XbaI RFLP to obtain further insight into the evolution of the tandemly arranged C4 genes. Using exon-specific PCR amplification followed by restriction analysis and direct DNA sequencing, the polymorphic site could be located in exon 40 of the C4 gene (cDNA position 5095). The polymorphism does not change an amino acid residue. Using nested PCR amplification with isotype-specific primers to amplify either C4A or C4B alleles the haplotype arrangement of the XbaI sites in both isotypic C4 genes was analyzed independently. It was observed that the XbaI restriction site was either present or absent in both C4 genes of a given haplotype. In a study of 106 Caucasian haplotypes, only two different haplotypes could be identified carrying a C4A gene with and a C4B gene without the XbaI restriction site. Also, the XbaI site could only be detected in long C4 genes possessing the 6.5-kb insertion in intron 9. Our findings provide evidence that the mutation creating the XbaI polymorphism occurred in an ancestral C4 gene already carrying the long intron 9. The duplicating resulting in the presence of two isotypic genes, C4A and C4B, must have taken place subsequently giving rise to haplotypes with or without the XbaI site.

Base Sequence↗

PubMed1982

Genetics of complement C4. Two homoduplication haplotypes C4S C4S and C4F C4F in a family.

A family in which two homoduplicated C4 haplotypes (or supergenes) segregate is described. One haplotype C4F*3 C4F*2.2 is composed of two C4F alleles and the other C4S*5.1 C4S*1 of two C4S alleles. The C4F duplication haplotype is a partial inhibitor of the Rodgers antigen, and judged from our family and population material, it seems to be rather frequent and associated with HLAB*35, Bf*F, and HLAD/DR*1. The C4S duplication haplotype is Rg(a-) and is not identified in individuals without another S, Ch(A+) variant.

Adult↗

PubMed1992

Complement C4 null alleles as a marker of gold or D-penicillamine toxicity in the treatment of rheumatoid arthritis.

C4 null alleles and HLA-DR antigens were defined in 48 rheumatoid arthritis (RA) subjects who had developed renal or heamatological side effects to gold or penicillamine, as compared to 33 RA subjects who had received the drugs for similar time periods without developing side effects. A C4A null allele was found in 56% of subjects with and 31% of those without side effects (P = 0.027, relative risk 2.8). A similar but statistically non-significant trend was observed with the C4B null allele (P = 0.64) resulting in a higher risk of drug toxicity in rheumatoid patients bearing either a C4A or C4B null allele (relative risk 5.7). Frequencies of DR3 and DR4 were similar in the two groups.

Alleles↗

PubMed1983

Analysis of active and inactive complement C4 complotypes associated with subtypes of HLA-B17 in different racial groups.

HLA-A, B, and C antigens and the HLA-linked markers BF, C2, and C4 were determined in 1,799 unrelated Caucasians, 140 North American blacks, 140 Chinese, and 66 Japanese. One allele of the C4A locus (Rodgers), C4A*6, was found to code for a functionally inactive product in HLA-B17 (Bw57)-positive individuals, but for a functionally active product in HLA-B37- or HLA-B27-positive individuals. Further studies revealed that the functionally inactive C4A*6 gene product was found only in one subtype of HLA-B17, namely, 17.1 (Bw57, long). In addition, it was found that the frequency of the other subtype of HLA-B17, namely, 17.2(Bw58, short) varies greatly in different populations and that HLA-Bw58 is associated with either C4A*3,B*1 or C4A*3,B*Q0.

Alleles↗

PubMed1985

Liver mRNA probes disclose two cytochrome P-450 genes duplicated in tandem with the complement C4 loci of the mouse H-2S region.

A search for uncharacterized genes of the S region of the murine H-2 major histocompatibility complex was undertaken; a series of cosmid clones previously aligned by overlap hybridizations were used as radiolabeled probes. Sequences hybridizing with liver poly(A)+ RNA were found within a cosmid covering a region 3' to the C4-Slp gene (the gene encoding the hemolytically inactive isoform of the fourth component of serum complement). Radiolabeled, short cDNA complementary to liver poly(A)+ RNA was used to establish the transcriptional polarity of the newly detected gene and to define fragments containing its 3' end. DNA sequence analyses and comparisons with porcine peptides established that the gene encodes the enzyme steroid 21-hydroxylase (EC 1.14.99.10), a cytochrome P-450 often referred to as P-450(C21), whose major site of expression is the adrenal gland. Two copies of the P-450(C21) gene, very similar yet distinguishable by restriction endonuclease analysis, were found individually associated with C4 and C4-Slp, genes that encode isoforms of mouse fourth component of complement. One of the P-450(C21) genes is coamplified with C4-Slp in H-2w7, a haplotype carrying a rare elongation of the S region. Comparisons with other members of the P-450 gene family show that the P-450(C21) genes encode peptides of extraordinary evolutionary conservation. The detection of a liver transcript of P-450(C21) raises the issue of the specific metabolic role of this enzyme in this organ and may have implications for the interpretation of human congenital adrenal hyperplasia.

Amino Acid Sequence↗

PubMed1998

A study of the association of HLA DR, DQ, and complement C4 alleles with systemic lupus erythematosus in Iceland.

OBJECTIVE: To perform an exploratory analysis of the relative contribution of single MHC genes to the pathogenesis of systemic lupus erythematosus (SLE) in a homogenous white population. METHODS: MHC class II alleles and C4 allotypes were determined in 64 SLE patients and in ethnically matched controls. HLA-DR and DQ typing was performed by polymerase chain reaction amplification with sequence specific primers. C4 allotypes were determined by agarose gel electrophoresis. RESULTS: The frequency of C4A*Q0 was significantly higher in patients than in controls (46.9% v 25.3%, p = 0.002). HLA-DRB1, DQA1, and DQB1 alleles in the whole group of SLE patients were not significantly different from those of controls. On the other hand increase in DRB1*03 was observed in the group of patients with C4A*Q0, as compared with patients with other C4A allotypes (p = 0.047). There was no significant correlation between severe and mild disease, as judged by the SLEDAI, and HLADR, DQ alleles and comparing the patients with C4A*Q0 with those with other C4A allotypes there was no significant difference regarding clinical manifestations. CONCLUSION: The results are consistent with the argument that C4A deficiency contributes independently to susceptibility and the pathogenesis of SLE. C4A*Q0 in SLE patients in Iceland shows weaker linkage disequilibrium with DR3 genes than reported in most other white populations and emphasises the role of ethnicity.

Adolescent↗

PubMed1991

HLA DRw8 and complement C4 deficiency as risk factors in primary biliary cirrhosis.

HLA class I, II, and III alleles were investigated in 25 consecutive unrelated German patients with primary biliary cirrhosis and in two families with two primary biliary cirrhosis patients in each. In primary biliary cirrhosis patients, HLA class I antigens did not differ significantly from in health controls. For HLA class II antigens, a highly significant increase of HLA DRw8 was found in patients with primary biliary cirrhosis compared with controls. Thirty-six percent vs. 3.6% were DRw8 positive [relative risk = 15.28; P (corrected) = 0.00013]. The genetic typing of HLA class III alleles revealed an increased incidence for C4AQ0 alleles [72% vs. 34.5%, relative risk = 4.89: P (corrected) = 0.0056]. A highly significant proportion of primary biliary cirrhosis patients carrying both DRw8 and C4A-Q0 alleles (relative risk = 183.75; P = 9.7 x 10(-7)) were found. In one family, a mother and her daughter had primary biliary cirrhosis, both sharing the major histocompatibility complex haplotype HLA-A1, -B8, -DR3, -C4AQ0B1. In the other family, two sisters with primary biliary cirrhosis shared the major histocompatibility complex haplotype HLA-A24, -B8, -DRw8, -C4A4B2. These studies contribute to the further elucidation of the immunogenetic background of primary biliary cirrhosis.

Alleles↗

PubMed1986

Complement C4 fixation by the anti-La(SSB) found in normal donors and in patients with systemic lupus erythematosus.

The discovery that a common systemic lupus erythematosus (SLE) autoantibody (anti-La/SSB) occurs in normal individuals has made it possible to compare the specific complement binding capacity of normal autoantibody with SLE patient autoantibody. Normal donors with elevated levels of anti-La(SSB) binding were compared to negative normal donors and to 3 patients with SLE with high levels of anti-La(SSB) binding in assays for anti-La(SSB) and for the capacity of anti-La(SSB) to bind C4. The anti-La(SSB) found in normal sera and in SLE patient sera had no identical specific capacity to fix C4. For the case of anti-La(SSB), the autoantibody structure in relation to its specific capacity to activate complement, at least to the extent of fixing C4, does not differentiate SLE patients from normal individuals with this autoantibody.

Antibodies, Antinuclear↗

PubMedDate not supplied

HLA and complement C4 studies in psoriasis vulgaris.

BACKGROUND: Psoriasis vulgaris is known to be associated with the presence of certain HLA antigens and complement factors but only studies of Western populations have been reported. We investigated the HLA and complement profile in Indian patients with psoriasis vulgaris. METHODS: Sixty-seven patients and 132 normal subjects were typed for class I antigens using 262 sera, and 55 patients and 104 normal subjects were typed for class II antigens using 174 sera. The sera from patients and normals were sent to Japanese laboratories for the study of class III antigens. RESULTS: The study revealed that patients had an increased frequency of A1 (p < 0.0025), B17 (p < 0.0025), Cw6 (p < 0.001) DR7 (p < 0.05) and DQw3 (p < 0.005) when compared to normal controls. Analysis of two and three antigen haplotypes revealed a significant increase in the incidence of all haplotypes involving those antigens which showed a high frequency among patients. A significant association was also found with complement factors C4A6.3 and C4A6,X. However, the relative risk was high for C4BQO (10.73). CONCLUSIONS: Psoriasis in Indians is associated with the A1, B17 and Cw6 but not with B13 antigens and the complement allotypes mentioned above. The strong association with C4 factors may be as a result of a close linkage between the class III region and Ir genes.

Adolescent↗

PubMed1986

Polymorphism of the human complement C4 and steroid 21-hydroxylase genes. Restriction fragment length polymorphisms revealing structural deletions, homoduplications, and size variants.

Several autoimmune disorders as well as congenital adrenal hyperplasia (CAH) are either associated or closely linked with genetic variants of the fourth component of complement (C4A and C4B) and the enzyme steroid 21-hydroxylase (21-OH). These proteins are encoded by genes that are located downstream from the genes for complement proteins, C2 and factor B (BF) between HLA-B and -DR in the major histocompatibility complex (MHC). Previous studies of variants and null alleles were based on electrophoretic mobility of C4 protein and linkage with disease phenotypes. These data did not permit analysis of the basis for the observed null alleles and duplicated variants. We studied this region of the MHC in 126 haplotypes for a structural analysis of the four adjacent loci, C4A, 21-OHA, C4B, and 21-OHB. About half of the C4 genes typed as C4 null are deleted and several unrecognized homoduplicated C4 alleles were detected. Hence the frequencies of different C4 structural variants must be recalculated based on a direct analysis of the genes. Analysis of the C4/21-OH genes of patients with the classical (salt-wasting) form of CAH showed that some involve a deletion of the C4B and 21-OHB genes; whereas for two only the 21-OHB gene is deleted, i.e., the C4B gene is present. Together, these data provide a better understanding of the mechanisms generating and importance of deleted C4 and 21-OH null alleles in human disease.

Adrenal Hyperplasia, Congenital↗