[Show abstract][Hide abstract] ABSTRACT: The human leukocyte antigen (HLA) is the main genetic determinant of multiple sclerosis (MS) risk. Within the HLA, the class II HLA-DRB1*15:01 allele exerts a disease-promoting effect, whereas the class I HLA-A*02 allele is protective. The CIITA gene is crucial for expression of class II HLA molecules and has previously been found to associate with several autoimmune diseases, including MS and type 1 diabetes. We here performed association analyses with CIITA in 2000 MS cases and up to 6900 controls as well as interaction analysis with HLA. We find that the previously investigated single-nucleotide polymorphism rs4774 is associated with MS risk in cases carrying the HLA-DRB1*15 allele (P=0.01, odds ratio (OR): 1.21, 95% confidence interval (CI): 1.04-1.40) or the HLA-A*02 allele (P=0.01, OR: 1.33, 95% CI: 1.07-1.64) and that these associations are independent of the adjacent confirmed MS susceptibility gene CLEC16A. We also confirm interaction between rs4774 and HLA-DRB1*15:01 such that individuals carrying the risk allele for rs4774 and HLA-DRB1*15:01 have a higher than expected risk for MS. In conclusion, our findings support previous data that variability in the CIITA gene affects MS risk, but also that the effect is modulated by MS-associated HLA haplotypes. These findings further underscore the biological importance of HLA for MS risk.Genes and Immunity advance online publication, 16 January 2014; doi:10.1038/gene.2013.71.
Genes and immunity 01/2014; DOI:10.1038/gene.2013.71 · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The total length of the two chromosomes (n = 2) which build the genome of Haplopappus gracilis is about 14.6 microns. A well-defined nucleolus organizer is found in chromosome No. 2. Heterochromatin is seen in interphase nuclei mainly associated with the nucleolus. This heterochromatin is late in replicating as shown by H3-thymidine incorporation. In the analytical ultracentrifuge Model E the DNA of Haplopappus shows a DNA satellite with a buoyant density of 1.699 g/ml corresponding to a guanine-cytosine content of 39.8 %, the corresponding values for the main band being 1.693 g/ml and 36.7 % GC.Hybridization between 28S hamster ribosomal H3-RNA and total Haplopappus DNA fractionated on CsCl gradients reveals that the ribosomal cistrons are present in the DNA satellite. When the fractions — of similar gradients — which contain the ribosomal DNA are collected and their DNA is centrifuged in the analytical ultracentrifuge, the DNA satellite increases appreciably in size. These results lead us to conclude that the ribosomal cistrons are localized in the DNA satellite. Moreover, there is a high level of redundancy of the genes for ribosomal RNA in Haplopappus. Since chromosome No. 2 contains the nucleolus it is suggested that the DNA sequences of this DNA satellite are located in this chromosome.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to compare the frequency of human leukocyte antigen (HLA) genotypes in 1-18-year-old patients with type 1 diabetes newly diagnosed in 1986-1987 (n = 430), 1996-2000 (n = 342) and in 2003-2005 (n = 171). We tested the hypothesis that the HLA DQ genotype distribution changes over time. Swedish type 1 diabetes patients and controls were typed for HLA using polymerase chain reaction amplification and allele specific probes for DQ A1* and B1* alleles. The most common type 1 diabetes HLA DQA1*-B1*genotype 0501-0201/0301-0302 was 36% (153/430) in 1986-1987 and 37% (127/342) in 1996-2000, but decreased to 19% (33/171) in 2003-2005 (P \ 0.0001). The 0501-0201/0501-0201 genotype increased from 1% in 1986-1987 to 7% in 1996-2000 (P = 0.0047) and to 5% in 2003-2005 (P > 0.05). This study in 1-18-year-old Swedish type 1 diabetes patients supports the notion that there is a temporal change in HLA risk.
[Show abstract][Hide abstract] ABSTRACT: In a large case-control study of Swedish incident type I diabetes patients and controls, 0-34 years of age, we tested the hypothesis that the GIMAP5 gene, a key genetic factor for lymphopenia in spontaneous BioBreeding rat diabetes, is associated with type I diabetes; with islet autoantibodies in incident type I diabetes patients or with age at clinical onset in incident type I diabetes patients. Initial scans of allelic association were followed by more detailed logistic regression modeling that adjusted for known type I diabetes risk factors and potential confounding variables. The single nucleotide polymorphism (SNP) rs6598, located in a polyadenylation signal of GIMAP5, was associated with the presence of significant levels of IA-2 autoantibodies in the type I diabetes patients. Patients with the minor allele A of rs6598 had an increased prevalence of IA-2 autoantibody levels compared to patients without the minor allele (OR=2.2; Bonferroni-corrected P=0.003), after adjusting for age at clinical onset (P=8.0 x 10(-13)) and the numbers of HLA-DQ A1*0501-B1*0201 haplotypes (P=2.4 x 10(-5)) and DQ A1*0301-B1*0302 haplotypes (P=0.002). GIMAP5 polymorphism was not associated with type I diabetes or with GAD65 or insulin autoantibodies, ICA, or age at clinical onset in patients. These data suggest that the GIMAP5 gene is associated with islet autoimmunity in type I diabetes and add to recent findings implicating the same SNP in another autoimmune disease.
Genes and Immunity 10/2007; 8(6):503-12. DOI:10.1038/sj.gene.6364413 · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: SUMO4 M55V, located in IDDM5, has been a focus for debate because of its association to type I diabetes (TIDM) in Asians but not in Caucasians. The current study aims to test the significance of M55V association to TIDM in a large cohort of Swedish Caucasians, and to test whether M55V is associated in those carrying human leukocyte antigen (HLA) class II molecules. A total of 673 TIDM patients and 535 age- and sex-matched healthy controls were included in the study. PCR-RFLP was performed to identify the genotype and allele variations. Our data suggest that SUMO4 M55V is not associated with susceptibility to TIDM by itself. When we stratified our patients and controls based on heterozygosity for HLA-DR3/DR4 and SUMO4 genotypes, we found that presence of SUMO4 GG increased further the relative risk conferred by HLA-DR3/DR4 to TIDM, whereas SUMO4 AA decreased the risk. From the current study, we conclude that SUMO4 M55V is associated with TIDM in association with high-risk HLA-DR3 and DR4, but not by itself.
Genes and Immunity 10/2007; 8(6):518-21. DOI:10.1038/sj.gene.6364406 · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The main band DNA of Phaseolus coccineus has a buoyant density of 1.692 g/ml. In roots, shoots, integuments and suspensors there is a DNA satellite with a buoyant density of 1.700 g/ml. The satellite of the roots, shoots and integuments represents approximately 28.2 %, 29.4 % and 34.7 % respectively of the total DNA. In suspensors, where polyteny occurs, besides the 1.700 g/ml satellite there is a second one at 1.696 g/ml. They represent about 32.9 % and 13.1 % of the total DNA.
H3-25S and H3-18S ribosomal RNA of Phaseolus coccineus were hybridized separately with DNA of shoots from CsCl gradient fractions. In both hybridizations the peak of labelling coincides with the position of the DNA satellite with a buoyant density of 1.700 g/ml. Thus the genes for 25S and 18S are mainly located in this DNA component.
Hybridization experiments at saturation inputs of H3-25S ribosomal RNA with DNA of shoots, integuments, roots and suspensors give saturation values of 0.72 %, 0.64 %, 0.51 % and 0.42 % respectively.
The lower saturation value in the suspensors may indicate an underreplication of ribosomal genes in this tissue. This is partly cancelled out by the amplification in another DNA: that of the second satellite at 1.696 g/ml which does not seem to be part of the ribosomal DNA.
[Show abstract][Hide abstract] ABSTRACT: In the cricket Acheta domesticus, the DNA of somatic tissues (heads and legs), centrifuged to equilibrium in CsCl gradients in the Model E ultracentrifuge, shows a DNA satellite with a buoyant density of 1.716 g/ml. This satellite occurs in the same amount (0.8% of the total DNA) and has the same buoyant density as the satellite found in testes. In ovaries (in which most oocytes are at pachytene) the satellite is 5% of the total ovarian DNA and has the same buoyant density. The amount of DNA complementary to ribosomal RNA has been determined using the low temperature formamide hybridization technique and by carrying out separate experiments involving 28S and 18S H 3 RNA of Acheta. The data indicate that the numerical ratio between genes for 28S and 18S rRNA is one, in ovaries, testes and somatic tissues. The degree of amplification found by saturation experiments in the ovaries agrees with the size of the high buoyant density satellite observed in the analytical centrifuge. Under the conditions of personal experiments there were 1,600 rRNA genes per ovarian cell (pachytene) whereas in somatic cells the value obtained was 342 sites. The amount of DNA non homologous to rRNA present in the high buoyant density satellite is approximately 96.3%. This may consist of 'spacer' and other DNA sequences.