Heterozygous expression of insulin-dependent diabetes mellitus (IDDM) determinants in the HLA system.
Newton E. MortonA GreenT. S. DunsworthArne SvejgaardJ BarbosaStephen S. RichLennart IseliusP. PlatzLars P. Ryder
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Linkage Disequilibrium
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A large family with three children affected with the autosomal recessive disease of Cerebrotendinous Xanthomatosis (CTX) was studied for class I (HLA—A,B,C) and class II antigens (HLA‐DR,D,SB), properdin factor B and glyoxalase. The extensive typing revealed an informative cross‐over between HLA‐B and Bf, indicating that Bf is located centromeric to the HLA‐B locus and segregated in this family with HLA‐D/DR. The parents in this family were first cousins and their parents were also first cousins. Three of their four haplotypes share B14, BfS, DR1, Dx and SB4 and may be identical by descent. The three affected children carried among them all four parental haplotypes, indicating that close linkage of the CTX locus to HLA is unlikely.
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Although psoriasis vulgaris (PsV) is strongly associated with certain human leukocyte antigens, the pathogenetic nature of these associ- ations remains elusive. The objectives of this study were: (i) to determine whether HLA loci directly determine susceptibility or merely serve as markers for the susceptibility allele; and (ii) to identify additional disease- associated haplotypes. By applying maximum likelihood linkage disequilib- rium analysis (LDA) in cases vs. controls, we found the susceptibility gene to be more strongly associated with specific HLA haplotypes than with their component alleles. Stronger linkage disequilibrium between PsV and HLA alleles was detected at HLA-C and HLA-B than at DRB1 and DQB1. Para- metric linkage analysis accounting for marker-trait disequilibrium in pso- riasis vulgaris pedigrees yielded most significant results for a locus close to HLA-B and -C. Furthermore, we found that susceptibility is linked to at least three different ancestral HLA haplotypes; among them, HLA-Cw7-B8- DRB1*0301-DQB1*02 is linked to PsV for the first time. These results identify a major PsV susceptibility locus in the immediate vicinity of, but distinct from HLA-B or HLA-C, and suggest that multiple disease alleles have arisen during human evolution. 1 , 2 , 3 ,
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Abstract Familial predisposition to IgA deficiency (IgAD) suggests that genetic factors influence susceptibility. Most studies support a polygenic inheritance with a susceptibility locus (designated IGAD1) in the MHC, but its exact location is still controversial. This study aimed to map the predisposing IGAD1 locus (or loci) within the MHC by investigating the pattern of association of the disease with several markers in the region. DNA-based techniques were used to type individual alleles of four polymorphic HLA genes (HLA-DR, -DQA1, -DQB1, and HLA-B), six microsatellites (all located between HLA-DR and HLA-B), and three single nucleotide polymorphisms on the TNF gene. The frequencies of these alleles were compared among ethnically matched populations comprising 182 patients and 343 controls. Additionally, we investigated parents and siblings of 100 of these patients. All four parental haplotypes were established in each family (n = 400), and transmission disequilibrium tests were performed. Surprisingly, our results did not support the hypothesis of a unique susceptibility gene being shared by all MHC susceptibility haplotypes. On HLA-DR1 and -DR7-positive haplotypes IGAD1 mapped to the class II region, whereas on haplotypes carrying HLA-DR3 the susceptibility locus mapped to the telomeric end of the class III region, as reported previously. Our results show how, in complex diseases, individuals may be affected for different genetic reasons and a single linkage signal to a region of a chromosome may actually be the result of disease-predisposing alleles in different linked genes in different pedigrees.
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Simulation studies were undertaken with POPGEN, a new population simulation program, to explore strategies for detecting loci underlying rare and common disorders in a small population that has been partially isolated for 10 generations. Haplotype-sharing analysis (HSA) and non-parametric linkage analysis (NPL) were applied to the simulated haplotype and pedigree data for 100 cases, 100 controls, and an average of 28 multiplex pedigrees from cases' families, for a 2-5 cM map of markers. When identity by descent (IBD) status was known (using unique founder marker allele designations assigned during simulation), a linkage disequilibrium (LD) signal could be detected under disease-generating models predicting relative risk to sibs of 11.8 (high-RR) or 2.67 (mod-RR). Detection was more difficult when marker alleles were down-coded to resemble microsatellites (heterozygosities 0.75-0.80). False-positive peaks on nondisease chromosomes were uncommon. NPL analysis was more powerful than HSA at this marker density using down-coded alleles and assuming availability of all affected relatives. LD mapping of common disorders is likely to require denser maps of highly polymorphic markers to approximate full IBD information. LD and linkage mapping provide independent information, and strategies that combine these two methods could be useful in studies of small isolated populations.
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To identify the markers tightly linked to Machado-Joseph disease (MJD) and to investigate whether a limited number of ancestral chromosomes are shared by Japanese MJD pedigrees, a detailed linkage analysis employing D14S55, D14S48, D14S67, D14S291, D14S280, AFM343vf1, D14S81, D14S265, D14S62, and D14S65 was performed. The results of multipoint linkage analysis as well as detection of critical recombination events indicate that the gene for MJD is localized in a 4-cM region between D14S280-D14S81. We found strong linkage disequilibria at AFM343vf1 and D14S81, and association of a few common haplotypes with MJD. These results indicate that there is an obvious founder effect in Japanese MJD and suggest the possibility of the existence of predisposing haplotypes which are prone to expansions of CAG repeats. © 1996 Wiley-Liss, Inc.
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Recombinations defining centromeric and telomeric borders for the hereditary haemochromatosis locus.
Hereditary haemochromatosis (HFE) is a common inherited disorder, affecting approximately five per thousand white people of northern European descent. Genetic linkage and linkage disequilibrium studies indicate that the disease locus is tightly linked to HLA-A and D6S105. Recombination between HFE and HLA class I loci is known to be rare. We report here two pedigrees in which recombinations telomeric of HLA-A occurred. These recombinant events define new centromeric and telomeric borders for the HFE locus.
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