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PubMedDate not supplied

Progressive autoimmune beta cell insufficiency: occurrence in the absence of high-risk HLA alleles DR3, DR4.

In a prospective screening program for type I diabetes mellitus, we identified a unique family in which several members (mother and three siblings) expressed an unusual set of HLA-DR alleles (DR2+, DR3/4-) and were in different phases of immunologically mediated islet beta cell dysfunction. Immunologic and/or clinical manifestations of type I diabetes were absent in all siblings not sharing both HLA haplotypes in common with the proband. This article illustrates: the clinical utility of prospective family screening for predictive markers, such as islet cell antibodies, progressive autoimmune beta cell destruction can occur in the absence of the "high-risk" alleles HLA-DR3 and DR4, and HLA identity with the proband, rather than specific HLA alleles, i.e., presence of DR3, DR4 and absence of DR2, is an essential factor.

Adolescent↗

PubMed1999

Haplotype analysis in the Collaborative Study on the Genetics of Alcoholism data: double recombinants.

The presence of close double recombinants in genotyping data may help identify genotyping errors. Alternatively, putative double recombinants may be associated with genetic mechanisms that may be related to disease. Phase-known apparent double recombination events were identified in the Collaborative Study on the Genetics of Alcoholism data, and compared to the sex-specific genetic map at each region. A number of double recombinants occurred within a short genetic distance. Also, in some families multiple double recombinants were observed flanking the same genetic marker, both suggesting possible genotyping error. An excess of paternal double recombinants was identified, which is consistent with reports of sex-specific differential meiotic interference.

Alcoholism↗

PubMed1993

Detection by reversed-phase HPLC of trace amounts of the alpha 113His globin chain in a sheep homozygous for a quadruple alpha-globin gene chromosome.

1. In sheep alpha alpha 113His and alpha D alpha alpha 113His globin gene haplotypes, the percentage gene efficiencies, from the 5' to the 3' end, are about 32-18 and 30-14-6, respectively. 2. We previously found that in a alpha alpha alpha alpha homozygote there may be a 1-2% alpha 113His chains, which however were difficult to resolve from alpha 113Leu chains by CMC chromatography. 3. We report here the experimental conditions which allowed a neat resolution of the 1% alpha 113His chain peak by RP-HPLC. 4. This finding strongly suggests the occurrence of the alpha D alpha alpha alpha 113His haplotype where the percentage gene efficiencies are 30-(14-5)-1, supporting the existence of a gradient of decreasing expression in multiple alpha-globin gene haplotypes.

Animals↗

PubMed1991

Aspartic acid at position 57 of the HLA-DQ beta chain is protective against future development of insulin-dependent (type 1) diabetes mellitus.

Insulin-dependent (Type I) diabetes mellitus is a chronic autoimmune disease. From studies in discordant twins and multiplex families a long prediabetic period has been reported. In a population-based program started in 1983, fifteen individuals at possible risk for future Type I diabetes were followed for up to 74 months. Two individuals (13%) developed Type I diabetes. These probands were characterized by the presence of high-level cytoplasmic islet cell antibodies (ICA), complement-fixing ICA, and an impaired first-phase insulin response after intravenous glucose load. Both were homozygous for a high-risk immunogenetic marker of Type I diabetes, i.e., non-Asp at codon 57 of the HLA-DQ beta chain. In all other subjects studied, the immunogenetic marker that confers "dominant resistance", aspartic acid at codon 57, was found. On the basis of our data we conclude that a combination of assays which determine ICA, first-phase insulin release, and HLA-DQB1 polymorphisms will identify individuals with a high probability of developing Type I diabetes at the population level. Conversely, HLA haplotypes positive for aspartic acid seem to confer resistance to the disease.

Adult↗

PubMed2005

Add-back of allodepleted donor T cells to improve immune reconstitution after haplo-identical stem cell transplantation.

Poor immune reconstitution after haplo-identical stem cell transplantation results in high mortality from viral infections and relapse. One approach to overcome this problem is to deplete alloreactive cells selectively by deleting T cells activated by recipient stimulators, using an immunotoxin directed against the activation marker CD25. However, the degree of depletion of alloreactive cells is variable following stimulation with recipient PBMC, and this can result in GvHD. We have shown that using recipient EBV-transformed LCL as stimulators to activate donor alloreactive T cells results in more consistent depletion of in vitro alloreactivity while preserving T-cell responses to viral and potential myeloid tumor Ag. Based on these data, we have embarked on a phase I clinical dose escalation study of add-back of allo-LCL-depleted donor T cells in the haplo-identical setting, to determine if the allodepletion we achieve to allow infusion of sufficient T cells to restore useful antiviral/anti-leukemic responses without causing GvHD. Fifteen patients have so far been treated. The incidence of significant acute or chronic GvHD has been low (2/15), as has mortality from infection (1/15). Preliminary data show accelerated immune reconstitution in dose level 2 patients. Infused allodepleted donor T cells appear able to expand significantly in the face of viral reactivations, and doses as low as 3 x 10(5)/kg may be sufficient to confer useful antiviral immunity in this setting. At a median follow-up of 19.5 months, nine of 15 patients are alive and disease-free. Five patients have relapsed, all of whom have died.

Clinical Trials, Phase I as Topic↗

PubMed2006

Prediction of IBD based on population history for fine gene mapping.

A novel multiple regression method (RM) is developed to predict identity-by-descent probabilities at a locus L (IBDL), among individuals without pedigree, given information on surrounding markers and population history. These IBDL probabilities are a function of the increase in linkage disequilibrium (LD) generated by drift in a homogeneous population over generations. Three parameters are sufficient to describe population history: effective population size (Ne), number of generations since foundation (T), and marker allele frequencies among founders (p). IBDL are used in a simulation study to map a quantitative trait locus (QTL) via variance component estimation. RM is compared to a coalescent method (CM) in terms of power and robustness of QTL detection. Differences between RM and CM are small but significant. For example, RM is more powerful than CM in dioecious populations, but not in monoecious populations. Moreover, RM is more robust than CM when marker phases are unknown or when there is complete LD among founders or Ne is wrong, and less robust when p is wrong. CM utilises all marker haplotype information, whereas RM utilises information contained in each individual marker and all possible marker pairs but not in higher order interactions. RM consists of a family of models encompassing four different population structures, and two ways of using marker information, which contrasts with the single model that must cater for all possible evolutionary scenarios in CM.

Alleles↗

PubMed1982

Genetic regulation of delayed-type hypersensitivity responses to poly (Tyr,Glu)-poly(DLAla)--poly(Lys): expression of the genetic defect in the induction and manifestation phases in H-2s and H-2f mice.

The genetic defect of H-2s and H-2s non-responder mouse strains in both the induction and manifestation phases of delayed-type hypersensitivity (DTH) responses to poly(LTyr,LGlu)-poly(DLAla)--poly(LLys)[(T,G)-A--L] was analysed. Utilizing an in vitro system to activate DTH effector T cells, we observed that non-adherent T cells of (H-2f X H-2b) F1 or (H-2s X H-2b)F1 responder mice, could not be activated on antigen bearing adherent cells of H-2f or H-2s haplotypes. On the other hand, these T cells were effectively sensitized on adherent cells derived from either F1 or parental (H-2b) responder mice. These results indicate that in these mouse strains the genetic defect, in the induction phase of DTH, is expressed at the level of the antigen presenting cell. In subsequent experiments, we were able to "correct' the non-responsiveness of H-2s recipients by transfer of educated and irradiated (H-2s X H-2b)F1 T cells together with normal F1 adherent cells. Normal non-adherent and nylon wool enriched T cells failed to restore these responses. Similarly, antigen-pulsed F1 irradiated peritoneal exudate cells could stimulate DTH responses in SJL recipients of (SJL X C57BL/6)F1 (T,G)-A--L educated cells. The genetic defect of H-2s mice in the manifestation phase of the DTH reaction is thus also expressed on the antigen presenting cell.

Animals↗

PubMed2006

Vascular endothelial growth factor gene haplotypes in Kawasaki disease.

OBJECTIVE: To investigate whether common genetic variants in the vascular endothelial growth factor (VEGF) gene are associated with Kawasaki disease (KD) and the subsequent development of coronary artery lesions. METHODS: Common genetic variants in the VEGF gene were analyzed in an association study in a Dutch cohort of 170 KD patients and 300 healthy Dutch Caucasian controls. Genotyping was done with 5'-nuclease TaqMan assays and 3'-hybridization-triggered fluorescence minor groove binder Eclipse assays. RESULTS: An association with susceptibility to KD was observed with 2 of the 6 single-nucleotide polymorphisms analyzed in VEGF: -2594 A>C (rs699947) and the 236 bp 3' of STP C>T (rs3025039). Also for an 18-bp deletion in the promoter of VEGF a significant difference in the genotype and allele frequencies was observed between the KD patients and the controls. The haplotype CGCC (based on rs699947, rs2010963, rs25648, and rs3025039) was significantly associated with the development of KD (hap score 3.8; P = 0.0002). VEGF plasma levels were significantly higher in patients with the early phase of KD than in the healthy controls, and there was a trend toward higher VEGF plasma levels in KD patients with the -2594 CC and 236 bp 3' of STP CC genotypes. CONCLUSION: Our results suggest that polymorphisms of the VEGF gene may play a role in the pathogenesis of KD.

Adolescent↗

PubMed2004

Genetic analysis of the growth curve of Rous sarcoma virus-induced tumors in chickens.

White Leghorn chicks homozygous for B19 MHC haplotype were selected for 18 generations on tumor regression after inoculation in the wing web with an SR-D strain of Rous sarcoma virus (RSV) at 4 wk of age. Each chick was assigned a tumor profile index (TPI) based on age at death and size of the tumor. During 18 generations, 2,010 birds were divergently selected on TPI for either progression or regression of the tumor (P and R lines). A Brody growth curve was fitted for each bird. Brody function parameters included the asymptotic tumor volume (A), the factor for increased growth in progression phase (K1), the factor for decreased growth in regression phase (K2), age at maximum volume (Tmax), and maximum volume of the tumor (Vmax). Tumor growth curves were found to be different according to line, sex, and restriction fragment pattern Y complex Rfp-Y MHC haplotype (Yw*15, Yw*16, and Yw*17). Within the P line, birds from the Yw*16 haplotype reached Vmax at an earlier age than Yw*15 and Yw*17, but with a lower Vmax value. Within the R line, tumor growth curves of birds from Yw*16 and Yw*17 haplotypes were similar. Rank correlations between the different parameters and TPI were low (between -0.26 and 0.36). Heritability estimated by the sire component was high for Vmax (0.73). Heritabilities of Tmax and K2 were moderate (0.20 to 0.23 for Tmax and 0.18 to 0.21 for K2) allowing these traits to be used as selection criteria. Heritabilities of A and K1 were lower than 0.12. Modeling the growth curve should contribute to better distinction between progressors and regressors.

Animals↗

PubMed2000

Giant axonal neuropathy locus refinement to a < 590 kb critical interval.

Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder, characterised clinically by the development of chronic distal polyneuropathy during childhood, mental retardation, kinky or curly hair, skeletal abnormalities and, ultrastructurally, by axons in the central and peripheral nervous systems distended by masses of tightly woven neurofilaments. We recently localised the GAN locus in 16q24.1 to a 5-cM interval between the D16S507 and D16S511 markers by homozygosity mapping in three consanguineous Tunisian families. We have now established a contig-based physical map of the region comprising YACs and BACs where we have placed four genes, ten ESTs, three STSs and two additional microsatellite markers, and where we have identified six new SSCP polymorphisms and six new microsatellite markers. Using these markers, we have refined the position of our previous flanking recombinants. We also identified a shared haplotype between two Tunisian families and a small region of homozygosity in a Turkish family with distant consanguinity, both suggesting the occurrence of historic recombinations and supporting the conclusions based on the phase-known recombinations. Taken together, these results allow us to establish a transcription map of the region, and to narrow down the GAN position to a < 590 kb critical interval, an important step toward the identification of the defective gene.

Axons↗

PubMed1996

The 1591C mutation in triosephosphate isomerase (TPI) deficiency. Tightly linked polymorphisms and a common haplotype in all known families.

In order to investigate the basis of the repeated occurrence of the 1591C mutation (TPI 1591C, 105 Glu-Asp) in multiple unrelated families throughout the world, we studied five microsatellite and short tandem repeat markers that lie within a 1.77 megabase region which includes the TPI gene. We also studied an intragenic polymorphic marker that lies within intron 5 of the TPI gene. This polymorphism, recently described by others, is characterized by either an A or a G at position 2262 (the A in the initiation ATG is designated as +1 for both genomic and cDNA nucleotides). With very minor exceptions, all of the known families in the world with the 1591C mutation were available for study. These included five families from the U.S., three from France, one from Greece, one (of Turkish origin) from Germany, and two from Australia. Although we did not have the opportunity to directly study five families from the U.K., key data concerning the 2262 intragenic polymorphism in these subjects were made available to us. Four of the microsatellite and short tandem repeat markers were linked, but in apparent equilibrium. In contrast, a polymorphic repeat pentamer in the CD4 gene, thought to lie telomeric to TPI, was in apparent complete linkage disequilibrium with the TPI 1591C mutation. The intragenic polymorphism was also in apparent complete linkage disequilibrium with the mutation. In unrelated persons of known phase (1591C homozygotes or normal controls), the comparative allele frequencies for the CD4 pentameric repeat were 1.0 (14/14 alleles) in homozygous TPI 1591C subjects and 0.412 (28/68 alleles) in normal subjects (p < 0.0001). Again, in persons of known phase, the comparative allele frequencies for the A form of the intragenic 2262 A or G polymorphism were 1.0 (14/14 alleles) in 1591C homozygotes and 0.130 (7/54 alleles) in normals (p < 0.0001). Haplotypes were discernible in all of the 1591C homozygotes and in several of the heterozygotes and normals. The CD4 162, TPI 2262A haplotype was found on only two of thirty-eight normal chromosomes, but was universally associated with 1591C. The data indicate that all TPI 1591C subjects are descendants of a common ancestor who probably lived in what is now England or France. The original mutation probably occurred well in excess of 1000 years ago.

Australia↗

PubMed1993

Influence of genes within the MHC on mortality and brain cyst development in mice infected with Toxoplasma gondii: kinetics of immune regulation in BALB H-2 congenic mice.

Previous work has shown that genes within the major histocompatibility complex (MHC) of the mouse influence resistance and susceptibility to Toxoplasma gondii infection. Initial studies presented here using B10 H-2 congenic and recombinant haplotype mice inoculated via the oral route with the low virulence Beverley strain of T. gondii confirm the D region localization of MHC-linked control of brain cyst number. All B10 mice were, however, exquisitely sensitive to minor changes in virulence of the parasite inoculum resulting in high mortality during the early acute phase of infection. Further experiments examining mortality and brain cyst number in BALB MHC congenic mice inoculated via different routes indicated that the BALB background would provide a more favourable genetic environment in which to analyse kinetics of MHC controlled immune regulation following infection via the natural (oral) route. In studies comparing d and k haplotype mice a dramatic inverse relationship between splenic CD4:CD8 T cell ratios and brain cyst number was observed, particularly in the strain (BALB/K; H-2k) most susceptible to high brain cyst numbers and subsequent toxoplasmic encephalitis. Of particular interest was the observation that splenomegaly and the relative increase in the splenic CD8 T cell population preceded and accompanied the very dramatic and rapid increase in brain cyst formation. The results suggest that the too rapid development of a potent anti-parasite response in the viscera may drive the parasite to encyst in the brain.

Animals↗

PubMed1993

Predominant and stable T cell responses to regions of myelin basic protein can be detected in individual patients with multiple sclerosis.

T lymphocytes from patients with multiple sclerosis (MS) recognize multiple myelin basic protein (MBP) epitopes. This situation complicates the design of specific immunotherapies. We investigated to which extent the T cell response to MBP is heterogeneous in single subjects in terms of preferentially recognized regions of the molecule, major histocompatibility complex (MHC) restriction, and stability over time. From each of nine patients with MS, a minimum of six MBP-specific T lymphocyte lines (TLL) were assayed for the proliferative response to a panel of overlapping peptides, encompassing the whole MBP. Predominant T cell recognitions of distinct MBP regions were present in three patients, all HLA-DR2+, independently of the clinical features of their disease. T cell reactivity was preferentially directed to residues 16-38 in one patient. In this case the response was also stable over time, during different phases of the disease. Predominant reactivity to residues 86-99 was detected in the two other DR2+ patients. In each of the patients with other HLA-DR haplotypes (DR2-), as well as in three DR2+ non-MS donors, the T cell response to MBP appeared to be considerably more heterogeneous. The HLA restriction element varied among TLL recognizing the same MBP region, even when raised from the same individual. The genomic HLA typing, performed on the DRB1 and DRB5 genes in the DR2+ subjects, showed no obvious correspondence between preferential responses to regions of MBP and HLA-DR2 subtypes. In this context, a simple, new method for the genomic typing of the HLA-DRB1 gene in individuals with the HLA-DR2 serological specificity is also described. We conclude that predominant and stable T cell responses to a single MBP region can be detected in some patients with MS. In these individuals, the MHC restriction of the T cell recognition of predominant regions appears to be variable. Polymorphisms of the HLA-DR2 gene products alone do not account for the selection of the dominant MBP T cell epitope.

Adolescent↗

PubMed1992

[Familial study for the early diagnosis of insulin-dependent diabetes mellitus].

BACKGROUND: Diabetes is more frequently found than expected in families of first grade with children with diabetes type I. METHODS: With the aim of identifying the potential candidates prone to develop diabetes type I, genetic and metabolic analysis was carried out on the members of 11 families with a diabetic type I child. They were distributed into three groups: 11 diabetic patients (IDDM); 22 progenitors and 13 unaffected siblings. The HLA haplotype was determined, the spectrum of autoantibodies and the intravenous glucose tolerance test (IVTT) were performed. RESULTS: In two progenitors postprandial glycemia values corresponding to intolerance to carbon hydrates were obtained. Moreover, in one the IVTT was found to be low in the normal values. Of a total of 12 non diabetic descendents studied, 4 shared identical HLA haplotypes as the diabetic, 5 were haploidentical and 3 unidentical. The DR 3 antigen was detected in 90% of the diabetics; in 68% of the progenitor group and in 50% of the non diabetic descendents. Sixty-two percent of the children inherited the DR 4 antigen of the father (p less than 0.05), while 37% do so from the mother. Of the siblings with a haplotype identical to that of the diabetic, 2 were also ICA positive; asymptomatic at the moment of the study but in one the diabetes type I became manifest after 2 years of evolution. CONCLUSIONS: Subjects at high risk of becoming type I diabetics may be identified at a preclinical phase by means of HLA typing and the detection of immunologic and metabolic markers associated with the disease.

Adolescent↗

PubMed2026

Development of molecular markers associated with saline-alkali tolerance in rapeseed (Brassica napus L.).

A total of 947 saline-alkaline tolerance-related molecular markers and a 5K cGPS genotyping chipwere developed, providing practical tools for marker-assisted selection and molecular design breeding of saline-alkaline-tolerant rapeseed. Rapeseed (Brassica napus L.) has relatively strong tolerance to saline-alkaline stress and shows great potential for the sustainable utilization and improvement of saline-alkaline soils. However, the breeding of highly tolerant cultivars still mainly depends on conventional hybridization combined with phenotype-based selection, which constrains breeding efficiency. In this study, previously reported saline-alkaline tolerance-related genes from rapeseed, rice, maize, wheat, sorghum, and Arabidopsis were collected. Candidate gene-based association analysis enabled the development of molecular markers and a genotyping chip. A total of 483 significantly associated genes were identified, among which 355 genes contained favorable haplotypes. Molecular markers were successfully developed for 275 genes, including 746 KASP and 201 InDel marker pairs, and four marker pairs were randomly selected for validation. In addition, a 5K cGPS liquid-phase chip (HZSW-cGPS-BRNAP-04), was developed and showed a high call rate and excellent reproducibility in genotyping. These markers and the chip are expected to improve the breeding efficiency of saline-alkaline-tolerant rapeseed cultivars. Overall, this study provides useful tools for early-generation evaluation and marker-assisted selection (MAS), and provides a foundation for molecular design breeding of saline-alkali-tolerant rapeseed.

Brassica napus↗

PubMed1989

Risks of fetal cystic fibrosis based on linkage disequilibrium data.

First-trimester prenatal diagnosis of cystic fibrosis depends on tissues being available from a previous affected child for determination of the phase relationship of DNA markers. If no such tissues are available, it is possible to estimate the risks of a couple producing an affected child from the distribution of haplotypes showing linkage disequilibrium with the cystic fibrosis gene. We have calculated all the fetal risk subsets from the various parental haplotype combinations for the restriction fragment length polymorphisms identified by the KM.19/PstI and XV-2c/TaqI systems. We conclude that only in a limited number of parental combinations are the fetal risks sufficiently high or sufficiently low to be used in prenatal diagnosis.

Cystic Fibrosis↗

PubMed2003

Intervening before the onset of Type 1 diabetes: baseline data from the European Nicotinamide Diabetes Intervention Trial (ENDIT).

AIMS/HYPOTHESIS: To set up a clinical trial to establish whether nicotinamide can prevent or delay clinical onset of Type 1 diabetes. METHOD: The European Nicotinamide Diabetes Intervention Trial is a randomised, double-blind, placebo-controlled intervention trial undertaken in 18 European countries, Canada and the USA. Entry criteria were a first-degree family history of Type 1 diabetes, age 3-40 years, confirmed islet cell antibody (ICA) levels greater than or equal to 20 JDF units, and a non-diabetic OGTT; the study group was further characterised by intravenous glucose tolerance testing, measurement of antibodies to GAD, IA-2 and insulin and HLA class II genotyping. RESULTS: ICA screening was carried out in approximately 30,000 first-degree relatives. A total of 1004 individuals fulfilled ICA criteria for eligibility, and 552 (288 male) were randomised to treatment. Of these, 331 were aged less than 20 years (87% siblings and 13% offspring of the proband with diabetes) and 221 were 20 years of age or more (76% parents, 21% siblings and 3% offspring). Oral glucose tolerance was normal in 500 and impaired in 52 (9.4%), and first phase insulin response in the IVGTT was below the 10(th) centile in 34%. Additional islet autoantibodies were identified in 354 trial entrants. Diabetes-associated HLA class II haplotypes were found in 84% of the younger age group and 80% of the older group. The protective haplotype HLA-DQA1*0102-DQB1*0602 was found in 10% overall. CONCLUSIONS/INTERPRETATION: ENDIT has shown that a trial of an intervention designed to halt or delay progression to Type 1 diabetes can be carried out on a multinational collaborative basis, as and when potentially safe and effective forms of intervention become available. Primary screening with biochemically defined autoantibodies will substantially reduce the number of lower risk individuals to be included in future intervention trials

Adolescent↗

PubMed2025

The reference genome of the human diploid cell line RPE-1.

Recent technological advances have facilitated the assembly of telomere-to-telomere (T2T) genomes. The current T2T CHM13 showcases the complete architecture of the human genome, yet its use in functional experiments is limited by discrepancies with the actual genome of the specific biological system under study. Access to reference assemblies for experimentally relevant cell lines is therefore essential in advancing sequencing-based analyses and precise manipulation, particularly in highly variable regions such as centromeres. Here, we present RPE1v1.1, the near-complete diploid genome assembly of the hTERT RPE-1 cell line, a non-cancerous human retinal epithelial model with a stable karyotype. Using high-coverage Pacific Biosciences and Oxford Nanopore Technologies long-read sequencing, we generate a high-quality de novo assembly, validate it through multiple methods, and phase it by integrating high-throughput chromosome conformation capture (Hi-C) data. Our assembly includes chromosome-level scaffolds that span centromeres for all chromosomes. Comparing both haplotypes with the CHM13 genome, we detect haplotype-specific genomic variations, including the translocation between chromosome 10 and chromosome X t(X;10)(Xq28;10q21.2) characteristic of RPE-1 cells, and divergence peaking at centromeres. Altogether, the RPE1v1.1 genome provides a reference-quality diploid assembly of a widely used cell line, supporting high-precision genetic and epigenetic studies in this model system.

Humans↗