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Z L Awdeh

Publications and source records attributed to Z L Awdeh.

At least 37 records · Page 2Linked to original sources
PubMed1991

Specific association of HLA-DR4 with increased prevalence and level of insulin autoantibodies in first-degree relatives of patients with type I diabetes.

First-degree relatives of patients with insulin-dependent (type I) diabetes (n = 264 from 106 families) were evaluated with HLA typing and determination of competitive insulin autoantibodies (CIAAs) and islet cell autoantibodies (ICAs). The levels of CIAAs in 30 relatives exceeded our upper limit of normal (greater than or equal to 39 nU/ml), and 30 had high-titer ICAs (greater than or equal to 40 Juvenile Diabetes Foundation units [JDF U]). Eleven of the HLA-typed relatives developed diabetes during follow-up. Twenty-three percent (28 of 123) of the relatives with at least one HLA-DR4 allele were CIAA+ (CIAA greater than or equal to 39 nU/ml) versus 4% (6 of 141) among DR4- relatives (P less than 0.0001). Twenty-one of 22 of the highest CIAA values were all in the DR4+ group (DR4+ vs. DR4-, P = 0.003, Wilcoxon's rank-sum test). HLA-DR3 did not correlate with the level of CIAAs, and neither DR3 nor DR4 correlated with titer of ICAs measured in JDF U. We conclude that, in first-degree relatives of patients with type I diabetes, there is a striking association with HLA-DR4 in both the prevalence of relatives exceeding the normal CIAA range and in the level of CIAAs. These data suggest that a gene on HLA-DR4 haplotypes contributes to the level of anti-insulin autoimmunity, and we hypothesize that DR4-associated diabetes susceptibility, distinct from DR3-associated susceptibility, may be secondary to this influence.

Autoantibodies↗
PubMed1989

Complotypes and extended haplotypes in laboratory medicine.

The region on the short arm of the sixth human chromosome encoding class I and class II histocompatibility antigens involved in immune recognition also encodes a group of molecules unrelated to HLA termed class III which includes C2, C4, and factor B. The four genes encoding the complement proteins occupy about 120 kb of genomic DNA between HLA-B and HLA-DR and are closer to HLA-DR. The four genes are inherited as a single unit, without observed crossover, called a complotype, designated by its BF, C2, C4A, and C4B alleles. There are about fifteen complotypes with frequencies of 0.01 or higher on normal caucasian chromosomes. Analysis of linkage disequilibrium between HLA-B, HLA-DR alleles, and complotypes reveals that about 30% of normal caucasian chromosomes consist of fixed sets called extended or fixed haplotypes. There are over a dozen such extended haplotypes defined by their HLA-B, DR and complotype alleles. They appear to contribute most of the previously described linkage disequilibrium between HLA-A/HLA-B and HLA-B/HLA-DR allelic pairs as well as most of the known HLA marker-disease associations. It is postulated that extended haplotypes consist of fixed DNA over at least the 10(6) base pairs of the HLA-B-DR interval, and independent examples in apparently unrelated individuals are thus identical or nearly identical over this interval. A practical consequence of this concept is the possible prediction of successful tissue transplantation donor-recipient pairs.

Chromosome Mapping↗
PubMed1988

The distribution of human C4 DNA variants in relation to major histocompatibility complex alleles and extended haplotypes.

A C4 DNA polymorphism that can subdivide C4 allotypes and major histocompatibility complex-linked complement gene cluster allele combinations (complotypes) that are not distinguishable by standard electrophoretic means was used to assess further the distribution and linkage association of C4 variants. Segregation of the DNA polymorphism in family studies allowed assignment of particular variants to particular major histocompatibility complex haplotypes. These studies revealed that some complotypes were exclusively correlated with a particular C4 DNA variant, whereas others were not and could be subdivided according to which particular C4 DNA variant was observed. When complotypes that could be subdivided at the DNA level were considered in relation to flanking major histocompatibility complex markers, it was apparent that complotypes associated with major histocompatibility complex "extended haplotypes" had an exclusive correlation with a particular C4 DNA variant. This finding supports the hypothesis that "extended haplotypes" are unique associations of major histocompatibility complex allele combinations and are genetically similar, stably inherited units.

Alleles↗
PubMed1988

Two variants of DRw52, DR3, and DQw2 specificities distinguish two different DR3-bearing extended haplotypes.

HLA-DR beta and DQ beta MHC antigens present on B-lymphoblastoid cell lines homozygous for either [HLA-B8,DR3,SC01] or [HLA-B18,DR3,F1C30] were studied by two-dimensional gel electrophoresis. Comparison of neuraminidase-treated DR proteins from these cells showed that DR3-bearing cells express two DR beta genes. However, one DR beta chain (beta a) is nonpolymorphic, whereas the other beta chain (beta b) is polymorphic. Two variants of DR beta (DR3 or DRw52) and two of DQ beta (DQw2) were found, with all the examples of each extended haplotype carrying only one of these sets of variants. The variants thus absolutely distinguished the two DR3-bearing extended haplotypes. These results support the hypothesis of extended haplotypes at the protein level, and demonstrate the fixity of alleles on them in the HLA-B-D/DR region.

Antigen-Antibody Complex↗
PubMed1988

An immunoblotting technique for direct visualization of Chido and Rodgers reactivity on C4 variants after electrophoresis.

An immunoblotting technique allows direct visualization of Chido and Rodgers antigenic determinants on intact C4 proteins. C4 molecules separated by electrophoresis are selectively transferred to nitrocellulose membranes saturated with goat antiserum to human C4. The membranes are then incubated in alloanti-Chido or anti-Rodgers followed by enzyme-conjugated goat antihuman IgG. Molecules with Chido or Rodgers reactivity are visualized by incubation with an indicator substrate for the bound enzyme.

Complement C4↗
PubMed1987

There are two C4 genetic loci and a null allele in the chimpanzee.

Genetic polymorphism in C4 in the chimpanzee was studied by agarose gel electrophoresis of desialated plasma and development of patterns by immunofixation with antiserum to human C4 and by a C4-sensitive hemolytic overlay. In general, immunofixation patterns showed multiple partially overlapping bands of which only the most cathodal had strong hemolytic activity. In analogy to human C4, the latter were designated C4B, whereas those detected by immunofixation which had little hemolytic activity were designated C4A. Chimp C4A and C4B reacted with human and mouse (monoclonal) anti-C4B and human anti-Ch1 but neither reacted with monoclonal anti-C4A or human anti-Ch2, Ch3, Rg1, or Rg2. On sodium dodecyl sulfate polyacrylamide gel electrophoresis, the alpha chain of C4B showed a slightly lower apparent relative mass than that of C4A at around Mr 93,000. There were three C4A variants and two C4B variants inherited in families as autosomal codominant traits, as C4A-C4B cosegregating pairs with no detectable crossing-over. These pairs were inherited with chimpanzee leukocyte antigen types C2 and BF variants without detectable crossing-over. Half-null C4 haplotypes with C4B QO were observed in family studies. Nine BF, C2, C4A, C4B allelic haplotypic combinations (complotypes) were identified among presumably unrelated chimpanzees.

Alleles↗
PubMed1987

Molecular analysis distinguishes two HLA-DR3-bearing major histocompatibility complex extended haplotypes.

We detected restriction fragment length polymorphisms that distinguish the extended haplotype HLA-B8,DR3,SCO1 from HLA-B18,DR3,F1C3O at the DR beta and DQ beta loci with five of seven restriction endonucleases used. One set of restriction fragments was always found on HLA-B8,DR3,SCO1 and associated with DRw52a, while the other was present on HLA-B18, DR3,F1C3O and correlated with DRw52b (the gene encoding the subtype of DRw52 associated with the BO1 or LB-Q1 antigen). Furthermore, using a full-length DQ beta gene probe, we found division in the DQw2 haplotype, in which DQw2a always associated with HLA-B8, DR3,SCO1, while DQw2b always occurred with HLA-B18,DR3,F1C3O. Our evidence thus indicates that serologically defined HLA-DR3, HLA-DRw52, and HLA-DQw2 are each produced by two structurally very different sets of genes, one set occurring in HLA-B8, DR3,SCO1, and the other in HLA-B18,DR3,F1C3O.

Alleles↗
PubMed1987

Sharing of MHC haplotypes among apparently unrelated patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

From the study of HLA, complement, and glyoxalase I alleles in 82 Venezuelan individuals belonging to 19 families of mixed ethnic origin having 20 affected newborns with salt-wasting congenital adrenal hyperplasia due to 21-hydroxylase (21-OH) deficiency, a total of 38 disease haplotypes and 53 nondisease haplotypes were found. Of the pathological haplotypes 47% were found to share the HLA-B39 or -Bw62 specificities, 55% of them in combination with the BFS, C2C, C4A4, C4B2 (SC42) complotype. The frequencies of HLA-B39 and -Bw62 among the affected haplotypes were 29 and 18% as compared with 6 and 0% among the nondisease haplotypes of the same families. Statistical associations (P less than 0.01) with salt-wasting adrenal hyperplasia were found with the SC42 complotype and with the combination SC42, HLA-B39. These results are markedly different from those reported in the literature which show an "association" at the population level among many Caucasoid samples of HLA-Bw47 and the extended haplotype (HLA-Bw47, DR7,FC91,0) with the salt-wasting form of the disease. Furthermore, four of the unrelated patients reported here were homozygous for all the major histocompatibility complex loci tested, while three others were homozygous for at least two HLA loci. Analysis of the geographical origin of the grandparents indicated clustering of the deficiency carrier HLA haplotypes. This observation, together with the fact that there is an excess of homozygotes among the patients in Venezuela, strongly suggests that salt-wasting 21-OH deficiency congenital adrenal hyperplasia is mostly the result of a founder effect of relatively hyperplasia is mostly the result of a founder effect identity by descent of a few abnormal alleles at the 21-OHB locus in most cases. The mutation marked by HLA-Bw47 was not observed in this population.

Adrenal Hyperplasia, Congenital↗
PubMed1986

Complotypes, extended haplotypes, male segregation distortion, and disease markers.

From our studies in Caucasian families of HLA, complement, and glyoxalase alleles have developed the concepts of the complotype and the extended haplotype. complotypes are clusters of the four genes for complement proteins encoded within the MHC designated (in arbitrary order) by their BF, C2, C4A, and C4B alleles. They are inherited in families and occur in populations as functionally single genetic units and exhibit linkage disequilibrium with HLA-B and HLA-DR alleles which are complotype, rather than complement gene allele, specific. In Caucasians, there are 10-12 common sets of HLA-B, DR, complotype sets that show significant linkage disequilibrium. These haplotypes constitute 25-30% of all MHC haplotypes in Caucasians. Because there is evidence for relative fixity of alleles on these chromosomes to an unknown extent beyond the HLA-B-DR interval, they have been called extended MHC haplotypes. It appears likely that it is these extended haplotypes that provide most of the known linkage disequilibrium pairs previously reported for MHC alleles as well as many of the known MHC allele-disease associations. The most common extended haplotype [HLA-B8, DR3, SC01], when it carries GLO2, is increased in type I diabetes mellitus and probably a number of other diseases, including gluten-sensitive enteropathy and membranoproliferative glomerulonephritis. In the families with these disorders studied by us, this haplotype exhibits male segregation distortion, a feature displayed by t-mutants found in wild mouse populations. This feature constitutes an important selective advantage for the chromosome and may contribute to the accumulation of susceptibility mutations for a variety of diseases.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Nonresponsiveness to hepatitis B vaccine in health care workers. Results of revaccination and genetic typings.

Twenty-eight health care workers who had a poor antibody response when initially vaccinated with hepatitis B vaccine were revaccinated with three additional 20-microgram doses. Eight of the twenty nonresponders, who had levels of antibody to hepatitis B surface antigen (anti-HBs) of less than 8 estimated radioimmunoassay (RIA) units, and all 8 of the hyporesponders, who had anti-HBs levels of 8 or 16 RIA units, attained anti-HBs levels of 36 RIA units or more after revaccination. Tests for HLA-A, B, C, and DR; for complement proteins C2, C4A, C4B, and BF; and for the erythrocyte enzyme glyoxalase I were done in 17 nonresponders and 3 hyporesponders. Nine (45%) had HLA-DR7 and 8 (40%) had HLA-DR3, compared with an expected rate of 23% in the general population. At least one of two extended haplotypes (B44, DR7, FC31 or B8, DR3, SCO1) were detected in 6 of the 9 who did not respond to revaccination, compared with 2 of 11 who responded to a second course of vaccine. Poor responders to vaccine may benefit from revaccination, and genetic factors may modulate the immune response to vaccination.

Adult↗
PubMed1985

Unrelated individuals matched for MHC extended haplotypes and HLA-identical siblings show comparable responses in mixed lymphocyte culture.

Extended haplotypes are specific HLA B, HLA DR, BF, C2, C4A, and C4B combinations in significant linkage disequilibrium in chromosomes of unrelated individuals. The possibility that matching unrelated individuals for extended haplotypes may match for the genes that cause mixed lymphocyte reactivity was tested. 22 of 26 unrelated extended-haplotype-matched subjects had similar mixed lymphocyte reactivity to HLA-identical siblings.

Alleles↗
PubMed1985

Possible human analogs of the murine T/t complex.

After a short description of the T-t complex of the mouse, a comparison between the MHCs of mouse and man and HLA marker-disease associations, possible candidates for human t-analogs are discussed. The hypothesis is put forward that some extended MHC haplotypes might be human analogs of murine t-mutants.

Animals↗
PubMed1984

MHC determinants of response to Rh immunization.

The demonstration of immune response genes in man has been difficult, although there is evidence for genes linked to the MHC in mouse and guinea pig that control both the specificity and magnitude of immune responses. A number of features of the antibody response to the Rh D antigen, such as the failure of some individuals at risk to respond, the restricted immunoglobulin class, subclass, and light chain type of the antibody produced, and the presumed minor structural difference between Rh D antigen and its allelic product, all suggest that one or at most a few immune response genes are involved. Typing for the four MHC-linked complement genes BF, C2, C4A, and C4B was carried out in 52 independently ascertained Caucasian individuals with significant anti-D titers. A control population of 623 normal Caucasian chromosomes was also studied. In patients with anti-D antibodies, the frequency of BF F1 (0.04 vs 0.0064 for 623 chromosomes, p less than 0.003); of C4A 3 (0.769 vs 0.631, p less than 0.006); and of C4B Q0 (0.25 vs 0.104, p less than 0.00004) were all increased. These three alleles are found in the common complotype BF 8F1,C2 C,C2A 3, C4B Q0, and presumably represent a single extended haplotype of 6p associated with (and presumably containing a gene for) the immune response to RhD. This complotype has a 0.6% frequency in 623 normal control chromosomes, but is also increased in patients with insulin-dependent diabetes mellitus and with membranous glomerulonephritis.

Blood Group Incompatibility↗
PubMed1983

Extended MHC haplotypes in 21-hydroxylase-deficiency congenital adrenal hyperplasia: shared genotypes in unrelated patients.

HLA, complement, and glyoxalase I alleles were studied in 29 families in which at least one member has classical 21-hydroxylase-deficiency congenital adrenal hyperplasia. A rare complement allele, C4B*31, was found in over 20% of the haplotypes defined in these families and was always part of the complement haplotype BF*F, C2*C, C4A*Q0, C4B*31 (abbreviated FCO,31). The haplotype containing this rare set of complement alleles always carried the rare HLA allele, HLA-Bw47, usually carried HLA-A3, and almost always had the alleles HLA-Cw6, HLA-DR7, and the glyoxalase I (GLO) allele GLO1. Thus over 20% of the haplotypes in the population studied contained all or almost all of the rare extended haplotype HLA-(A3), Bw47, Cw6,DR7, FCO,31, GLO 1. 3 other haplotypes were each found twice in unrelated patients concordant for their disease phenotype and ethnic background. Extended MHC haplotypes may be markers for different genetic mutations causing 21-hydroxylase deficiency.

Adrenal Hyperplasia, Congenital↗
PubMed1983

Extended HLA/complement allele haplotypes: evidence for T/t-like complex in man.

The chromosomal distribution of alleles for HLA-A,-B,-C, and -DR and the serum complement protein alleles of factor B and C2 and C4 was studied in normal Caucasian families. Eight combinations of HLA-B, DR, BF, C2, C4A, and C4B markers were found to occur in haplotypes at frequencies significantly higher than expected. In these combinations, which were defined as extended major histocompatibility complex haplotypes, HLA-A showed limited variation. A possible mechanism for the maintenance of extended haplotypes are human analogs of murine t mutants which are characterized by crossover suppression and male transmission bias. One human 6p haplotype, HLA-B8, DR3, SCO1, GLO 2, was found to be transmitted from males to 83% of their offspring. The same haplotype with GLO 1 had no transmission bias. It is suggested that this GLO 2-marked chromosome is a human analog of a murine t mutant.

Alleles↗
PubMed1983

Serum complement 'supergenes' of the major histocompatibility complex in man (complotypes).

The loci for the complement proteins C2 and BF, and the two loci for C4 are closely linked to one another. In many hundreds of meioses no crossing over has been detected between these loci. In addition, the alleles of these four loci occur in specific combinations not predicted by their gene frequencies in much the same way as alleles of the Rh and MNS systems. These units are termed complotypes. There are 14 complotypes with frequencies in excess of 1% in our study population of normal sixth chromosomes from Caucasians. Since they are also intimately associated with HLA-DR, comploytypes may also be of importance in screening programs for transplantation.

Chromosome Mapping↗
PubMed1981

The location of C2, C4, and BF relative to HLA-B and HLA-D.

The loci for HLA-A,B,C,D, and DR are known to be closely linked to the structural loci for the complement components C2, BF, and the duplicated loci for C4, C4A and C4B. Conflicting evidence has been presented for the order of these genes. However, new techniques have made possible identification of markers in the HLA-D and C4 region for nearly all identified haplotypes. In our population we have confirmed five HLA-B-D crossovers and in each case informative allotypes of C2, BF, or C4A and C4B segregated with HLA-D or DR suggesting that the loci for these proteins lie close to HLA-D and DR. These findings may be of importance for resolving problems encountered in the assignment of HLA-D alleles.

Complement C2↗