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Gene expression profiling is a promising tool for classification of pediatric acute lymphoblastic leukemia (ALL). We analyzed the gene expression at the time of diagnosis for 45 Danish children with ALL. The prediction of 5-year event-free survival or relapse after treatment by NOPHO-ALL92 or 2000 protocols resulted in a classification accuracy of 78% and a Matthew's correlation coefficient of 0.59 independently of immunophenotypes. The sensitivity and specificity for prediction of relapse were 87% and 69% respectively. Prediction of high vs low levels of the minimal residual disease (MRD) on day 29 (?0.1% or ?0.01%) resulted in an accuracy of 100% for precursor-B samples. The classification accuracy of precursor-B- vs T-lineage immunophenotypes was 100% even in samples with as little as 10% leukemic blast cells, and the immunophenotype classifier constructed in this study was able to classify 131 of 132 samples from a previous study correctly. Our study indicates that the Affymetrix Focus Array GeneChip may be used without loss of classification performance compared to previous studies using the far more extensive U133A+B GeneChip set. Further studies should focus on prediction of MRD, as this prediction would relate strongly to long-term outcome and could thus determine the intensity of induction therapy.Leukemia (2004) 18, 1270-1277. doi:10.1038/sj.leu.2403392 Published online 20 May 2004 [ABSTRACT FROM AUTHOR]

In order to analyze whether loci in the human leukocyte antigen (HLA) class I region may contribute to the HLA class II-associated genetic susceptibility to multiple sclerosis (MS), we examined selected microsatellite markers in 177 Nordic sib-pair families, 222 British sib-pair families, 323 sporadic Norwegian MS patients and 386 Norwegian controls. All samples were, in addition, genotyped for the HLA-DR DQ haplotype, and the Norwegian case-control samples were also typed for HLA-A and -B loci. In the Norwegian sporadic MS patients association was seen with HLA-A, HLA-B, and with the D6S265 marker, located 100 kb centromeric to HLA-A. Associations with HLA-A and D6S265 loci were also suggested when restricting the analysis to HLA-DR15 haplotypes. In the sib-pair data a similar trend was seen with marker D6S265. Higher genotypic relative risk (GRR) was found for individuals who carry both HLA-DR15 and -A3 (GRR = 15), compared to those who carry only HLA-DR15 (GRR = 7), only HLA-A3 (GRR = 3) or none of these alleles (GRR = 1). The highest risk was conferred by a combination of HLA-DR15 and -A3 (odds ratio (OR) = 5.2). These results suggest that HLA-A or a gene in linkage disequilibrium with it may contribute to the HLA class II-associated genetic susceptibility to MS. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that development of childhood acute lymphoblastic leukaemia may often be initiated in utero. To provide further evidence of an prenatal origin of childhood leukaemia, we conducted a molecular biological investigation of nine children with B-precursor acute lymphoblastic leukaemia carrying the chromosomal translocation t(12;21), the most common subtype of all childhood acute lymphoblastic leukaemia. Specifically, for each child we identified the non-constitutive chromosomal sequences made up by the t(12;21) fusion gene. From these, leukaemia clone-specific DNA primers were constructed and applied in nested polymerase chain reaction analyses of DNA extracted from the patients' Guthrie cards obtained at birth. Leukaemia clone-specific fusion gene regions were demonstrated in Guthrie card DNA of three patients, age 2 years 11 months, 3 years 4 months, and 5 years 8 months at leukaemia diagnosis. Our findings are consistent with previous observations, and thus provide further evidence that the development of t(12;21) B-precursor acute lymphoblastic leukaemia may be initiated in utero. Review of the current literature moreover indicates that age at leukaemia may be inversely correlated with the burden of cells with leukaemia clonal markers, i.e. leukaemia predisposed cells at birth, and that certain types of childhood acute lymphoblastic leukaemia develop as a multiple step process involving both pre- and postnatal genetic events. [ABSTRACT FROM AUTHOR]

Genetic factors influence susceptibility to multiple sclerosis but the responsible genes remain largely undefined, association with MHC class II alleles being the only established genetic feature of the disease. The Nordic countries have a high prevalence of multiple sclerosis, and to further explore the genetic background of the disease, we have carried out a genome-wide screen for linkage in 136 sibling-pairs with multiple sclerosis from Denmark, Finland, Norway and Sweden by typing 399 microsatellite markers. Seventeen regions where the lod score exceeds the nominal 5% significance threshold (0.7) were identified—1q11-24, 2q24-32, 3p26.3, 3q21.1, 4q12, 6p25.3, 6p21-22, 6q21, 9q34.3, 10p15, 10p1213, 11p15.5, 12q21.3, 16p13.3, 17q25.3, 22q12-13 and Xp22.3. Although none of these regions reaches the level of genome-wide significance, the number observed exceeds the 10 that would be expected by chance alone. Our results significantly add to the growing body of linkage data relating to multiple sclerosis. [ABSTRACT FROM AUTHOR]

The proinflammatory cytokine interferon (IFN)-γ has been shown to influence the course of multiple sclerosis (MS). The IFN-γ (IFNG) contains a multiallelic dinucleotide repeat in intron 1. To investigate whether alleles at this locus influence susceptibility to MS, we performed linkage and familial association analyses on 100 sibling pairs from four Nordic countries, and case-control association analysis on 220 intermediately disabled sporadic MS patients and 266 controls. To determine the effect of the polymorphism on disease outcome, we compared genotype frequencies in the most and least disabled octiles of a total cohort of 913 cases. We also measured IFN-γ mRNA levels in unstimulated peripheral blood mononuclear cells from 46 MS patients and 27 controls grouped according to IFNG intron 1 genotype. Both nonparametric linkage analysis and transmission disequilibrium testing of the 100 sibling pairs produced negative results. Genotype frequencies for intermediate-MS patients did not differ significantly from those for controls; nor did genotype frequencies in the benign-MS octile differ significantly from those in the severe-MS octile. Comparison of IFN-γ mRNA levels in genotype-conditioned subgroups revealed no significant differences. Thus, alleles at the IFNG intron 1 dinucleotide repeat appear to affect neither MS susceptibility and severity nor IFN-γ mRNA expression in vivo. [ABSTRACT FROM AUTHOR]

The CC-chemokine receptor 5 (CCR5) has recently been described as a surface marker of human T cells producing type 1 (Th1) cytokines. Here we confirm that CCR5 is expressed on human Th1 but not on Th2 T-cell clones. Using intracellular cytokine staining, we show that allo-antigen specific CD4[sup +] T-cell lines derived from a CCR5-deficient individual (Δ32 allele homozygote) contain high numbers of both interferon γ (IFN-γ) and interleukin (IL)-2 producing cells, low numbers of IL-10 producing cells and no IL-4 or IL-5 producing cells when stimulated with phorbol ester and ionomycin in vitro. These results were similar to those obtained from allo-antigen specific CD4[sup +] T-cell lines derived from CCR5 expressing individuals. An enzyme-linked immunoabsorbent assay (ELISA) confirmed that the Th1 cytokine-positive cells from the CCR5-deficient individual were able to produce equal amounts of cytokines when compared to T-cell lines from CCR5-expressing individuals. These results demonstrate that CCR5-negative T cells display the same capacity of Th1 T-cell differentiation as T cells derived from CCR5-expressing individuals. Thus, CCR5 expression is not essential for differentiation of human Th1 T cells. [ABSTRACT FROM AUTHOR]

Provides an overview of the genetics and function of the human leukocyte A (HLA) system to describe the relationships between HLA and disease, with special emphasis on the implications. Characteristics of the genetics of the HLA; Explanation of the biological categories in which the HLA factors fall.

Several studies indicate genetic involvement of Th2 cytokines in allergic diseases. Interleukin (IL)-13 has been mapped to the cytokine cluster on chromosome 5q31–33, which has been associated with atopic conditions. Recently, an association was reported between the T allele in a promoter polymorphism in the IL-13 gene (C to T exchange) at position −1055 and allergic asthma in a population study in the Netherlands. This observation was apparently confirmed in a case–control study using probands and spouses from a Dutch asthma family study, but the polymorphism in that study was reported to occur at position −1111. In the present study, we established that this polymorphism is located at position −1024 relative to the ATG translation initiation codon, and investigated whether it confers a genetic predisposition to atopic conditions and the Th1 condition multiple sclerosis (MS) in Caucasian subjects. We confirmed the association between the IL-13 −1024TT genoype and inhalation allergy ( P = 2.4E-02). By combining the data from the three studies, we demonstrated a strong association ( P = 1.09E-05) between the IL-13 −1024 marker and inhalation allergy. Furthermore, we showed for the first time that this association also exists in atopic dermatitis ( P = 2.0E-02). No association with MS was found. [ABSTRACT FROM AUTHOR]