Extended major histocompatibility complex haplotypes in type I diabetes mellitus.
01 Aug 1984-Journal of Clinical Investigation (American Society for Clinical Investigation)-Vol. 74, Iss: 2, pp 449-454
TL;DR: It is demonstrated that all of the previously recognized increases in HLA-B8, B18, B15, DR3, and perhaps DR4 could be ascribed to the increase among diabetic haplotypes of a few extended haplotypes, and the increased frequency or the decreased frequency of individual MHC alleles is largely explainable by these extended haplotype increases.
Abstract: We have studied major histocompatibility complex markers in Caucasian patients with type I diabetes mellitus and their families. The frequencies of extended haplotypes that were composed of specific HLA-B, HLA-DR, BF, C2, C4A, and C4B allelic combinations, which occurred more commonly than expected, were compared on random diabetic and normal chromosomes in the study families. We demonstrated that all of the previously recognized increases in HLA-B8, B18, B15, DR3, and perhaps DR4 could be ascribed to the increase among diabetic haplotypes of a few extended haplotypes: [HLA B8, DR3, SC01, GLO2]; [HLA-B18, DR3, F1C30]; [HLA-B15, DR4, SC33]; and [HLA-BW38, DR4, SC21]. In fact, HLA-DR3 on nonextended haplotypes was "protective", with a relative risk considerably less than 1.0. There was a paucity or absence among diabetic patients of several extended haplotypes of normal chromosomes, notably [HLA-B7, DR2, SC31] and [HLA-BW44, DR4, SC30]. The extended haplotype [HLA-BW38, DR4, SC21] is found only in Ashkenazi Jewish patients, which suggests that extended haplotypes mark specific mutations that arise in defined ethnic groups. The data show that no known MHC allele, including HLA-DR3 and possibly HLA-DR4, is per se a marker for or itself a susceptibility gene for type I diabetes. Rather, extended haplotypes, with relatively fixed alleles, are either carriers or noncarriers of susceptibility genes for this disease. Thus, the increased frequency (association) or the decreased frequency (protection) of individual MHC alleles is largely explainable by these extended haplotypes.
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TL;DR: It is concluded that the usual response to hepatitis B surface antigen is due to the presence of a dominant immune-response gene in the MHC and that a low response isdue to the absence of such a gene and the presence on both chromosomes of MHC haplotypes that indicate such a response.
Abstract: In previous studies of the antibody response to hepatitis B vaccine in 598 subjects who received a full course of vaccination, we observed a bimodal response, with about 14 percent producing less than approximately 1000 radioimmunoassay (RIA) units. An analysis of the major histocompatibility complex (MHC) HLA and complement types of 20 of the subjects with the lowest responses indicated a greater-than-expected number of homozygotes for the extended or fixed MHC haplotype [HLA-B8, SC01, DR3]. This finding suggested that the lack of a normal response was a recessive MHC-linked trait. In this study, we prospectively vaccinated five homozygotes and nine heterozygotes for this haplotype in the expectation that the homozygotes would produce much lower levels of antibody than the heterozygotes. When the antibody response was assessed two months after the third injection, four of the five homozygotes had produced very low levels (approximately 1000 units or less) of antibody (mean, 467 RIA units; range, less than 8 to 1266), whereas all nine heterozygotes produced more than 2500 RIA units (mean, 15,608; range, 2655 to 28,900) (P less than 0.01). We conclude that the usual response to hepatitis B surface antigen is due to the presence of a dominant immune-response gene in the MHC and that a low response is due to the absence of such a gene and the presence on both chromosomes of MHC haplotypes (such as [HLA-B8, SC01, DR3]) that indicate such a response.
383 citations
TL;DR: It is found that IDDM is approximately equally associated with alleles of the DRB1 locus (Dw4 and Dw10, combined relative risk, RR = 6.4) and the DQB1 locu (DQ3.2), and there is significant interaction, in a statistical sense, between these DR and DQ alleles in IDDM.
Abstract: HLA-DR4 is associated with insulin-dependent diabetes mellitus (IDDM) in many populations. Many recent studies suggest that the DR4 effect is really due to DQ3.2, an allele of the nearby DQB1 locus. We used T cell clones, MAb, and allele-specific oligonucleotides to test IDDM and control subjects for DR4 subtypes (Dw4, Dw10, Dw13, and Dw14) and for DR4-associated DQB1 alleles (DQ3.1 and DQ3.2). We find that (a) IDDM is approximately equally associated with alleles of the DRB1 locus (Dw4 and Dw10, combined relative risk, RR = 6.4) and the DQB1 locus (DQ3.2, RR = 5.9); and (b) there is significant interaction, in a statistical sense, between these DR and DQ alleles in IDDM. The only IDDM-associated DR4 haplotypes were those carrying the IDDM-associated alleles at both loci (RR = 12.1); haplotypes with Dw4 or 10 but not DQ3.2, or vice versa, had a RR less than 1. Alternative explanations include: (a) that susceptibility requires specific allelic products of both DR and DQ loci; (b) that the combination of certain DR and DQ alleles marks haplotypes with the true susceptibility allele at a third locus; or (c) that Dw4 and 10 mark haplotypes with an allele at another locus that interacts with DQ3.2. As discussed, this third locus is unlikely to be DQA1 (DQ alpha). The data thus are not easily reconciled with an exclusive effect of HLA-DQ. This information increases our ability to predict IDDM by genetic typing: in the population studied, heterozygotes DR3/[DQ3.2, Dw4] or DR3/[DQ3.2, Dw10] had a relative risk of 38.0 and an absolute risk of 1 in 15.
262 citations
TL;DR: It is postulate that gene products contained in the haplotype may be involved in mediating drug toxicity and genetic factors marked by major histocompatibility complex haplotypes may be associated with the susceptibility of Jewish schizophrenic patients treated with clozapine to develop agranulocytosis.
Abstract: • Agranulocytosis develops in approximately 1% of patients with chronic schizophrenia treated with the atypical neuroleptic drug clozapine. Previous studies have not identified the mechanism or risk factors for this adverse reaction. Because of an observed association between Jewish ethnic background and the development of agranulocytosis in our patient sample treated with clozapine for refractory symptoms, HLA typing was performed in 31 patients (19.4% of whom had developed agranulocytosis). The HLA-B38 phenotype was found in 83% of patients who developed agranulocytosis and in 20% of clozapine-treated patients who did not develop agranulocytosis. Because B38 is part of a haplotype known to occur frequently in the Ashkenazi Jewish population, the frequencies of the combined alleles HLA-B38, DR4 and DQw3 were examined. The incidence of HLA-B38, DR4, DQw3 was significantly increased in patients with agranulocytosis (five of five patients) compared with control patients of Ashkenazi Jewish ancestry (two of 17 patients). These findings indicate that genetic factors marked by major histocompatibility complex haplotypes may be associated with the susceptibility of Jewish schizophrenic patients treated with clozapine to develop agranulocytosis. We postulate that gene products contained in the haplotype may be involved in mediating drug toxicity.
197 citations
TL;DR: HLA-DR4, Dw4- associated haplotypes associated with IDDM and JRA were compared using genomic DNA restriction fragment analysis to distinguish among DQ beta and alpha alleles linked to DR4, implicating different HLA genetic contributions in these two DR4-associated diseases.
Abstract: HLA-DR4, Dw4-associated haplotypes associated with IDDM and JRA were compared using genomic DNA restriction fragment analysis to distinguish among DQ beta and alpha alleles linked to DR4. DQ beta polymorphisms that subdivide the HLA-DQw3 specificity into DQ3.1 and 3.2 alleles were identified. More than 90% of DR4+ IDDM patients express one of these alleles, DQ3.2; restriction enzyme mapping indicates that the presence of this allele also accounts for the genomic fragment patterns previously reported in IDDM. Furthermore, haplo-identical siblings of DQ3.2 IDDM patients also carry the DQ3.2 allele, regardless of clinical presentation. In contrast, DR4+ JRA patients show no allelic preference at DQ beta, implicating different HLA genetic contributions in these two DR4-associated diseases.
186 citations
Cites result from "Extended major histocompatibility c..."
...This conclusion is consistent with reports of associated haplotypes in IDDM in which DR3 + extended haplotypes frequently occur, but most DR4 + haplotypes are "nonextended" (15)....
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TL;DR: The concept of the conserved extended haplotype (CEH) is updated using HLA allele identification and TNF microsatellites to show that specific combinations of the four blocks form single genetic units with a total haplotype frequency in the Caucasian population of 0.30.
Abstract: The difference in sizes of conserved stretches of DNA sequence within the major histocompatibility complex (MHC) in human individuals constitutes an underappreciated genetic diversity that has many practical implications. We developed a model to describe the variable sizes of stretches of conserved DNA in the MHC using the known frequencies of four different kinds of small ( /= 1.5 Mb) with a total haplotype frequency in the Caucasian population of 0.30. Some CEHs extend to the HLA-A and -DPB1 loci forming fixed genetic units of up to at least 3.2 Mb of DNA. Finally, intermediate fragments of CEHs also exist, which are, nevertheless, larger than any of the four small blocks. This complexity of genetic fixity at various levels should be taken into account in studies of genetic disease association, immune response control, and human diversity. This knowledge could also be used for matching CEHs and their fragments for patients undergoing allotransplantation.
168 citations
Cites background from "Extended major histocompatibility c..."
...Early examples of the use of family studies to identify CEHs associated with disease susceptibility include studies of type 1 diabetes (20) and IgA deficiency (18)....
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References
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TL;DR: The increase of HL-A8 in insulin-dependent diabetes, Graves' disease, and idiopathic Addison's disease is suggestive of a common pathogenesis of these endocrine autoimmune conditions.
705 citations
TL;DR: Electrophoretic studies of fragments from defined types of GBG suggested that GBG cleavage induced by complement or properdin activation in serum occurred through this C moiety, since two variants were detectable in one fragment and two were found in the other fragment.
Abstract: Extensive polymorphism of glycine-rich beta-glycoprotein (GBG) was found in human sera. In all instances, GBG consisted of at least five components on electrophoresis. Patterns were such that they provided evidence for four alleles (at a locus designated Gb) which were expressed as autosomal codominant traits. Gb(S) and Gb(F) were found in all populations but with different frequencies, Gb(F1) was found in Negroes, and Gb(S1) was found in Caucasians. From electrophoretic studies of GBG, evidence was obtained that suggested that the GBG molecule was a tetramer consisting of A and B subunits in a proportion of about 1.6:1. The genetically controlled differences in GBG embodied in the Gb system indicated the presence of a third moiety of the molecule (C), possibly a polypeptide subunit. Electrophoretic studies of fragments from defined types of GBG suggested that GBG cleavage induced by complement or properdin activation in serum occurred through this C moiety, since two variants were detectable in one fragment and two were found in the other fragment. On comparison of fetal-maternal Gb types, approximately one-half the pairs showed differences. This indicated that GBG did not cross the placental barrier.
489 citations
TL;DR: The distribution of HL-A antigens, and the incidence of lymphocytotoxic and tissue antibodies in the two patient groups was not different from that in the control population and specificity W15 was present in significantly higher frequency in the insulin-dependent diabetic patients.
Abstract: Diabetes mellitus is a genetically determined disorder of metabolism in which inherited susceptibility plays an important part. We studied the distribution of HL-A antigens, and theincidence of lymphocytotoxic and tissue antibodies in seventy-one adult diabetic patients—fifty insulin-dependent and twenty-one insulin-independent. Specificity W15 was present in significantlyhigher frequency in the insulin-dependent diabetic patients than either in the control group (P = 0.0005) or in the insulin-independent diabetic patient group (P
390 citations
TL;DR: In this paper, the distribution of alleles for HLA-A, B, C, D, BF, C2, C4A, and C4B markers were found to occur in haplotypes at frequencies significantly higher than expected.
Abstract: 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.
330 citations
01 Jan 2016
TL;DR: 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 and it is suggested that this GLO 2-marked chromosome is a human analog of a murine t mutant.
Abstract: 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 mark- ers 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 main- tenance 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, SCOI, GLO 2, was found to be transmitted from males to 83% of their offspring. The same haplotype with GLO I had no trans- mission bias. It is suggested that this GLO 2-marked chromosome is a human analog of a murine t mutant.
318 citations