Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Complete HLA and Bf typing of 18 families with juvenile diabetes mellitus (J.D.M.) showed that of 68 children, 9 bore recombinant haplotypes (13%). This frequency is significantly higher than the currently accepted 1.6% for intra-HLA recombinations with a p of 1.3 X 10(6) (binomial expansion) and may be related to the J.D.M. gene itself. Five of the nine crossovers were between HLA-A and B, and four between HLA-B and D. In one informative A/B recombination, Bf segregated with the HLA-B-D segment while in another two, it segregated in cis with HLA-A. This suggests the existence of two genetic sequences within the HLA region, one with Bf on the A site and a second one with Bf on the D site.
 ...
PMID:Intra-HLA recombinations in juvenile diabetes mellitus. 91 52

The major histocompatibility complex (MHC) contains multiple and diverse genes which may be relevant to the induction and regulation of autoimmune responses in insulin dependent diabetes mellitus (IDDM). In addition to HLA class I and II, the possible candidates include TNF, C4, and several other poorly defined polymorphic genes in the central MHC region. This study describes two approaches which take advantage of the fact that the relevant genes are carried by highly conserved ancestral haplotypes such as 8.1 (HLA-B8, TNFS, C4AQ0, C4B1, DR3, DQ2). First, three "diabetogenic" haplotypes (two Caucasoid and one Mongoloid) have been compared and it has been shown that all three share a rare allele of BAT3 as well as sharing DR3, DQ2. In 43 sequential patients with IDDM the cross product ratio for BAT3S was 4.8 (p less than 0.01) and 6.9 for HLA-B8 plus BAT3S (p less than 0.001). Second, partial or recombinant ancestral haplotypes with either HLA class I (HLA-B8) or II (HLA-DR3, DQ2) alleles were identified. Third, using haplotypic polymorphisms such as the one in BAT3, we have shown that all the patients carrying recombinants of the 8.1 ancestral haplotype share the central region adjacent to HLA-B. These findings suggest that both HLA and non-HLA genes are involved in conferring susceptibility to IDDM, and that the region between HLA-B and BAT3 contains some of the relevant genes. By contrast, similar approaches suggest that protective genes map to the HLA class II region.
 ...
PMID:Ancestral haplotypes reveal the role of the central MHC in the immunogenetics of IDDM. 135 98

Tumour necrosis factors alpha and beta (TNF-alpha and TNF-beta) and gamma interferon (IFN-gamma) were measured by ELISA in the supernatants of phytohaemagglutinin (PHA)-activated peripheral blood mononuclear cells (PBMNC) from 98 individuals (60 controls and 38 patients with insulin-dependent diabetes mellitus [IDDM]). The PBMNC were incubated with varying concentrations of PHA (0, 1, 5, and 10 micrograms/ml) for 72 h. In our population study we observed a correlation between the levels of secretion of TNF-alpha and IFN-gamma but not TNF-beta. The complete data set was analysed by non-parametric tests, and no associations with HLA phenotypes existed. Reduced levels of TNF-beta, but not TNF-alpha or IFN-gamma, secretion were found in IDDM patients stimulated with 1 and 5 micrograms/ml of PHA (P = 0.001 and 0.02 respectively). None of the lymphokine secretion levels at any PHA concentration correlated with particular HLA phenotypes. Analysis of the natural log-transformed data indicated that only for the TNF-beta levels (at 5 micrograms/ml PHA) could subjects be divided into high and low secretors, which also did not correlate with a particular HLA-B or -DR antigen.
 ...
PMID:The effect of HLA and insulin-dependent diabetes mellitus on the secretion levels of tumour necrosis factors alpha and beta and gamma interferon. 212 64

The human major histocompatibility complex (MHC)-linked genes C2,BF,C4A,C4B occur in populations and segregate in families as single genetic units or complotypes. Analysis for significant three-point linkage disequilibrium between HLA-B, DR and complotype on normal caucasian chromosomes 6p yields about a dozen haplotypes that account for most of the known HLA-B/HLA-DR linkage disequilibrium pairs previously noted in normal caucasian populations. We refer to the HLA-B/DR/complotype sets with significant linkage disequilibrium as extended haplotypes since they often show limited variation at other MHC-linked loci. From the study of MHC haplotypes in 21-hydroxylase deficiency, C2 deficiency and type 1 diabetes, it is becoming apparent that it is extended haplotypes rather than their individual alleles that are markers for these MHC-associated diseases.
 ...
PMID:Complement genes of the major histocompatibility complex (complotypes), extended haplotypes and disease markers. 349 6

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)
 ...
PMID:Complotypes, extended haplotypes, male segregation distortion, and disease markers. 351 38

The families of 41 probands with type I (insulin-dependent) diabetes mellitus (IDDM) were typed for HLA-A, HLA-B, and HLA-DR antigens in addition to the complement polymorphisms C2, C4A, C4B, and Bf. All of these loci are encoded on the short arm of human chromosome 6 in a narrow region. Alleles at HLA-B (8, 15, 18, and 40), HLA-DR (3 and 4), and Bf (F1) have been associated with increased relative risk (RR) for IDDM, while HLA-B7 and HLA-DR2 have been associated with decreased RR for IDDM. This study confirms those significant risks in addition to confirming increased risk for the null (silent) allele for C4A (C4AQ0) and a rare C4B variant (C4B2.9). The significantly associated antigens (alleles) and risks were: HLA-B8 (RR = 3.1), HLA-DR3 (RR = 5.2), HLA-DR4 (RR = 4.3), and BfF1 (RR = 7.1), in addition to C4AQ0 (RR = 2.8) and C4B2.9 (RR = 12.6). Significantly low risk was associated only with HLA-DR2 (RR = 0.1). In a recent study, we defined five high-risk haplotypes that were determined solely by HLA-B, Bf, and HLA-DR (B8-BfS-DR3, B8-BfS-DR4, B15-BfS-DR4, B18-BfF1-DR3, and B40-BfS-DR4). By inclusion of information from the complement polymorphism, we have defined in greater detail three of these five high-risk haplotypes. One previously identified haplotype (B40-BfS-DR4) showed no complement clustering, while the rare high-risk haplotype (B8-BfS-DR4) was seen only once in this smaller sample.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Complement and HLA. Further definition of high-risk haplotypes in insulin-dependent diabetes. 398 76

For a preliminary estimation of the prevalence and significance of HLA antigens, tests were carried out on the A and B loci in an unselected group of 107 patients with type 1 diabetes in Bucharest. Monospecific antisera furnished by NIH, Bethesda were used. For HLA-A the following data were obtained: A2 (20.3% of the total specificities); A1 (18.4%); A3 (14.0%); A28 (10.1%). Provisional estimations in the healthy population also indicated HLA-A2 as being more frequent than followed by A30/31, A1, A9, A3. For HLA-B: B7 (38.2%); B5, B12 and B14 (14.0% each); B8 (11.1%). In the healthy subjects, the order was B12, B35, B5, B8 the same as B18, then B7 (which did not exceed 11%). The most frequently encountered haplotypes in the diabetic patients were: A2/B7 (8.4% of the total haplotypes); A3/B7 (6.9%); A1/B7 (6.6%); A10/B7 (3.8%); A9/B7 and A11/B7 (3.6% each). An unexpectedly high frequency of the HLA-B7 antigen was found in group of diabetic patients investigated, contrasting with its assumed "protector" role in the Caucasian population. The frequency of antigen HLA-A3 and haplotype HLA-A3/B7 infringes their listing in the "resistance axis" to diabetes.
 ...
PMID:Testing histocompatibility antigens (loci A and B) in a group of type 1 (insulin-dependent) diabetic patients in Bucharest. 404 1

Two hundred subjects with insulin-dependent (type I) diabetes mellitus (IDDM) were typed for HLA-B, HLA-DR, and properdin factor B (Bf). HLA and Bf antigen and haplotype frequencies in subjects were compared with control frequencies derived from the 8th HLA Workshop. Frequencies of extended haplotypes (defined by B-Bf-DR alleles on a chromosome) were also contrasted with control frequencies. Significant positive associations between IDDM and HLA-B8, DR3, DR4, BfS, and BfF1 were confirmed, as were significant negative associations between IDDM and HLA-B7, DR2, DR5, DR7, and BfF. One haplotype (B7-BfS-DR2) exhibited significant negative association, while five haplotypes (B8-BfS-DR3, B8-BfS-DR4, B15-BfS-DR4, B18-BfF1-DR3, and B40-BfS-DR4) exhibited significant positive associations with IDDM. In this sample, 64% of all probands carried at least one of the high-risk haplotypes. In conclusion, the occurrence of five "high-risk" haplotypes associated with IDDM provides evidence for previously undocumented genetic heterogeneity and suggests that possibly more than two HLA-region genes may be involved in IDDM susceptibility.
 ...
PMID:Genetic heterogeneity of insulin-dependent (type I) diabetes mellitus: evidence from a study of extended haplotypes. 659 40

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.
 ...
PMID:Extended major histocompatibility complex haplotypes in type I diabetes mellitus. 674 3

HLA frequency distributions in Fiji Indians with non-insulin dependent diabetes were compared with those in control subjects with confirmed two-hour plasma glucose levels less than 7.8 mmol/L. Antigen frequencies at HLA-A and HLA-DR loci were similar in patients and controls. At HLA-B, there was a significant increase in Bw61 (Bw40.2) in diabetics, with a relative risk for this antigen of 4.8. Since a similar finding has been reported previously in South African Indians with Insulin-dependent diabetes, it is possible that wer have defined yet another genetically-distinct form of diabetes, especially prevalent in Indians. Alternatively, definition of new HLA alleles such as Bw61, a new subdivision of an established antigen, may reveal HLA associations with non-insulin dependent diabetes in European Caucasians also.
 ...
PMID:HLA and non-insulin dependent diabetes in Fiji indians. 694 7


1 2 3 4 Next >>