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F Pociot

Publications and source records attributed to F Pociot.

At least 55 records · Page 3Linked to original sources
PubMed2000

IDDM7 links to insulin-dependent diabetes mellitus in Danish multiplex families but linkage is not explained by novel polymorphisms in the candidate gene GALNT3. The Danish Study Group of Diabetes in Childhood and The Danish IDDM Epidemiology and Genetics Group.

The insulin-dependent diabetes mellitus (IDDM) susceptibility locus IDDM7 on 2q31 links to IDDM in some but not other populations. Linkage of D2S152, the marker for IDDM7, has hitherto not been demonstrated in Danish patients. GALNT3 that encodes the UDP-GalNAc: polypeptide N-acetyl-galactosaminyltransferase-T3 (GalNAc-T3), was recently identified and mapped to a region 5-25 cM from D2S152. The GalNAc transferases may play a role in immune mediated diseases by glycosylating autoantigens. Hence, the aims of the present study were to investigate by means of extended transmission disequilibrium testing (ETDT) and transmission disequilibrium testing (TDT) of the marker for IDDM7, D2S152, the marker for GALNT3, D2S2363, and novel polymorphisms identified through mutation screening of the entire GALNT3 for linkage with IDDM in 241 Danish IDDM multiplex families. ETDT analysis demonstrated linkage between IDDM and D2S152 (P(ETDT)=0.034). A prevalent T-->A polymorphism, T284A, was found in the GALNT3 3'UTR. Analysis of the D2S2363 and the T284A GALNT3 transmission patterns did not show linkage to IDDM in Danish patients (P(ETDT)=0.15 and P(TDT)=0.76, respectively). In conclusion, IDDM7 (D2S152) links to IDDM in Danish patients, but D2S2363 and the identified T284A polymorphism in the GALNT3 3'UTR did not. Hence, it is unlikely that the GALNT3 is an IDDM susceptibility gene.

Adult↗
PubMed2000

Linkage disequilibrium testing of four interleukin-1 gene-cluster polymorphisms in Danish multiplex families with insulin-dependent diabetes mellitus.

The molecules of the interleukin 1 (IL-1) system have been suggested to play a role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM), and polymorphisms in the genes encoding IL-1beta (IL1B), the IL-1 Type 1 receptor (IL1RTI) and the IL-1 receptor antagonist (IL1RN) molecules have been associated with IDDM in case-control studies. It can be difficult to exclude selection biases in case-control studies leading to spurious association. This risk is eliminated when using the transmission disequilibrium test (TDT). Hence, by means of the TDT we have investigated four intragenic IL-1 gene-cluster polymorphisms, the IL1B AvaI, the IL1B TaqI, the IL1RTI PstI and the IL1RN 2(nd)intron polymorphisms, for linkage and intra-familial association with IDDM in Danish IDDM multiplex family material comprising 245 families. We found no evidence for overall linkage or intra-familial association between any of the polymorphisms and IDDM. In addition, we did not find linkage between any of the polymorphisms and IDDM in HLA-DR3/4 heterozygous or HLA-non-DR3/4 heterozygous IDDM subjects, respectively. In conclusion, by means of intra-familial TDT analysis we found no linkage or intra-familial association between IDDM and the four IL-1 gene-cluster polymorphisms in Danish IDDM multiplex family material.

Denmark↗
PubMed2000

Complete molecular scanning of the human Fas gene: mutational analysis and linkage studies in families with type I diabetes mellitus. The Danish Study Group of Diabetes in Childhood and The Danish IDDM Epidemiology and Genetics Group.

AIMS/HYPOTHESIS: The human Fas gene (FAS) on chromosome 10q24.1 encoding a cell surface receptor involved in apoptosis was evaluated as a candidate susceptibility gene for Type I (insulin-dependent) diabetes mellitus. Apoptosis mediated by Fas is important in maintaining peripheral self-tolerance and in down-regulating the immune response and could have a role in immune-mediated beta-cell destruction. METHODS: We did a molecular scan of the entire human FAS (promoter, exons 1-9 including exon-intron boundaries and the 3'UTR) using single strand conformational polymorphism-heteroduplex analysis. RESULTS: We identified 15 mutations, of which 11 are new. Of these a g-1194A-->T and a g-295Ains give rise to alterations of transcription-factor-binding consensus sequences for c-Myb, SP-1 and NF-kappa B, respectively. A total of 1068 people from a Danish family collection comprising 138 Type I diabetic sib-pair families (289 affected and 121 unaffected offspring) and 103 Type I diabetic parent-offspring multiplex families (103 affected and 112 unaffected offspring) were typed for the three most frequent polymorphisms with high heterozygosity indices and for a FAS microsatellite. Haplotypes were established and data analysed using the extended transmission disequilibrium test, ETDT. CONCLUSION/INTERPRETATION: We found no overall evidence for linkage of the FAS polymorphisms to Type I diabetes. We conclude that it is unlikely that the Fas gene does contribute to genetic susceptibility for Type I diabetes.

Adult↗
PubMed2000

The intercellular adhesion molecule-1 K469E polymorphism in type 1 diabetes.

Type 1 (insulin-dependent) diabetes is a complex trait. The region harboring the ICAM1 gene on 19p13 links to type 1 diabetes, and a growing body of evidence indicates that intercellular adhesion molecule-1 (ICAM-1) could play a role in type 1 diabetes development. Recently, association studies of an ICAM-1 K469E polymorphism in type 1 diabetes populations have reported conflicting results. Hence, we performed a transmission disequilibrium test analysis of the ICAM-1 K469E variations in 253 Danish type 1 diabetes families. Linkage and association was not found between the ICAM-1 K469E variation and type 1 diabetes in Danish patients (P(tdt)> or =0.48), and our data did not indicate an interaction between ICAM1 and IDDM1 in predisposition to type 1 diabetes in Danes (P=0.78). We did not observe significant association with late-onset type 1 diabetes (P(tdt)> or =0.12) or differences in transmission patterns between groups of affected offspring stratified for age at onset (P> or =0.19), as suggested in Japanese patients. Combined analysis of the present and previously reported transmission data comprising 728 affected offspring of Romanian, Finnish, and Danish ancestry suggested association between the ICAM-1 E469 allele and type 1 diabetes (P(tdt)=0.013), but association was not found in the combined Scandinavian material. In conclusion, we found no association of the ICAM-1 K469E polymorphism with type 1 diabetes or its subsets stratified for age at onset and HLA risk in Danish patients. Analysis of ICAM-1 K469E transmissions reported in three populations suggested association to type 1 diabetes, but also demonstrated heterogeneity between populations.

Adolescent↗
PubMed2000

CTLA-4 in autoimmune diseases--a general susceptibility gene to autoimmunity?

For most autoimmune disorders, the pattern of inheritance is very complex. The major histocompatibility complex (MHC) gene complex has been implicated as the major genetic component in the predisposition to these diseases but other genes are likely to be involved. Based on function and experimental data, the gene encoding cytotoxic T lymphocyte-associated antigen 4 (CTLA4) has been suggested as a candidate gene for conferring susceptibility to autoimmunity. In this review, we critically evaluate the evidence for pathogenetical involvement of CTLA-4 in the different autoimmune diseases with focus on the possible role of genetic variation of the CTLA4 locus.

Abatacept↗
PubMed2000

No evidence for linkage in the promoter region of the inducible nitric oxide synthase gene (NOS2) in a Danish type 1 diabetes population.

Exposure of human pancreatic islets to a mixture of cytokines induces expression of inducible nitric oxide synthase (iNOS), impairs beta-cell function and induces apoptosis. Exposing human islets to high amounts of NO from chemical NO-donors causes DNA strand breaks and mitochondrial damage, suggesting that NO is deleterious to human beta-cells. Hence, we consider the gene encoding iNOS in beta-cells, NOS2, a candidate gene for type 1 diabetes in humans. In the present study we have tested three identified polymorphisms within the promoter sequence of the human NOS2 gene in a type 1 diabetic family material comprising 154 affected sib-pair families and 103 affected simplex families (1143 individuals in total). PCR-based amplification of the polymorphic loci were established. Linkage analysis was performed using the extended transmission disequilibrium testing (ETDT). A Bsal RFLP was found not to be polymorphic in 20 type 1 diabetic patients and 14 healthy control subjects and was not analysed further. In affected cases a nine allele CCTTT repeat and a bi-allelic TAAA repeat revealed allelewise Petdt of 0.52 and 0.60, respectively. ETDT applied to (TAAA)n; (CCTTT)n haplotypes demonstrated random transmission from heterozygous parents to affected offspring. In conclusion, the tested polymorphisms within the NOS2 gene promoter did not show evidence for linkage to type 1 diabetes in a Danish family material.

Base Sequence↗
PubMed2000

Characterization of new polymorphisms in the 5' UTR of the human interleukin-1 receptor type 1 (IL1R1) gene: linkage to type 1 diabetes and correlation to IL-1RI plasma level.

The human interleukin-1 type I receptor (IL-1RI) is the signal transducing receptor for IL-1, a principal proinflammatory cytokine, which is cytotoxic to pancreatic islet beta cells. The IL-1RI gene, IL1R1, maps to chromosome 2q12. We have previously examined part of the IL1R1 promoter region and in the present study we further characterized the promoter region demarcating exon 1B and 1C by sequencing and mutation scanning. New sequence was obtained 1762 bp upstream and 1609 bp downstream the known region. Within this sequence, we identified four frequent single nucleotide polymorphisms (SNPs). PCR-based RFLP assays were established and three of the polymorphisms were typed in a Danish Type 1 (insulin-dependent) diabetes mellitus (T1DM) family collection comprising 103 simplex and 150 sib-pair affected families. Linkage was evaluated by the sib-TDT (transmission disequilibrium test). One of the polymorphisms, defined by a Hinfl RFLP assay, demonstrated linkage to T1DM, P(sTDT) = 0.026. Random transmission was observed to unaffected offspring from heterozygous parents, P = 0.87. No evidence for positive linkage was seen for the other tested polymorphisms, P = 0.14 and P = 0.21, respectively. To evaluate the possible functional significance of the Hinfl polymorphism, we measured circulating IL-1RI plasma level in 30 T1DM patients and in 30 control subjects--10 with each genotype in both groups. Significant differences in plasma levels in relation to genotype--independent of disease status--were found (P = 0.04). In both diabetic and non-diabetic subjects, the wt/wt genotype correlated with the highest IL-1RI plasma level, whereas the plasma levels were lowest for the mt/mt genotype.

5' Untranslated Regions↗
PubMed2000

Interferon-gamma induces interleukin-1 converting enzyme expression in pancreatic islets by an interferon regulatory factor-1-dependent mechanism.

Whereas nitric oxide (NO) production is associated with the toxic effect of cytokines on rodent pancreatic beta-cells, cytokine-induced apoptosis in human islets may occur independently of NO. The cysteine protease interleukin (IL)-1 converting enzyme (ICE) is a key proapoptotic caspase. Our aim was therefore to analyze the effect of cytokines on ICE expression in human, rat, and mouse islets and rat insulinoma cells. ICE messenger RNA (mRNA) expression was highly up-regulated after 6-, 24-, and 72-h exposure of human islets to interferon (IFN)gamma, tumor necrosis factor (TNF)alpha + IFNgamma or IL-1beta + TNFalpha + IFNgamma, paralleled by increased iNOS (the inducible form of NO synthase) expression and NO production after exposure to the combined cytokines but not to IFNgamma or TNFalpha + IFNgamma. Cytokine-induced NO-independent ICE transcription was confirmed using iNOS inhibitors. Exposure of rat and mouse islets, or rat insulinoma cells, for 24 h to IFNgamma alone or in combination with the two other cytokines also resulted in a highly significant ICE mRNA expression. ICE transcription was not inducible in islets from IFN regulatory factor-1 knock-out mice, suggesting a key-role of this transcription-factor in cytokine-mediated ICE expression in pancreatic islets. In conclusion, cytokines and IFNgamma in particular increase ICE mRNA expression in pancreatic islet cells and beta-cell lines, independently of NO synthesis, suggesting that ICE up-regulation may be involved in cytokine-induced NO-independent apoptosis of human islets.

Adult↗
PubMed2000

Cytokine- or chemically derived nitric oxide alters the expression of proteins detected by two-dimensional gel electrophoresis in neonatal rat islets of Langerhans.

Interleukin-1beta (IL-1beta) treatment of neonatal rat islets for 24 h induces changes in the expression of 105 of 2,200 proteins, as determined previously by two-dimensional (2D) gel electrophoresis. Nitric oxide (NO) has been implicated as one of the mediators of IL-1beta effects in insulin-containing cell lines and rat islets. The aims of this study were 1) to determine the involvement of NO in IL-1beta-induced alterations in protein expression and 2) to investigate the effects of chemically generated NO on protein expression by 2D gel electrophoresis of neonatal rat islet samples. IL-1beta-induced NO production was prevented by incubation of islets in arginine-free medium supplemented with the arginine analog NG-nitro-L-arginine. [35S]methionine-labeled islet proteins were separated using 2D gel electrophoresis and analyzed using the BioImage computer program. Analysis revealed that the expression levels of 23 protein spots of the 105 protein spots, altered by prior treatment with IL-1beta (60 U/ml) alone, were significantly affected (P < 0.01 [n = 4] and P < 0.05 [n = 19]) when NO production was prevented. The effects of chemically generated NO were investigated by exposing islets to the NO donor GSNO (100 micromol/l) for 24 h before labeling with [35S]methionine and 2D gel electrophoresis. Computer-based analysis identified alterations in the expression of 19 of a total of 1,600 detectable proteins in GSNO-treated islets (P < 0.01). We conclude 1) that the expression of up to 42 proteins is altered by cytokine-induced or chemically generated NO in the precise experimental conditions chosen and 2) that the majority of proteins altered by prior treatment with IL-1beta may be the result of NO-independent IL-1beta-mediated regulation of gene expression. This study demonstrates that the combination of 2D gel electrophoresis and mass spectrometry is a powerful tool in the identification of beta-cell proteins involved in the response to toxic mediators.

Animals↗
PubMed2000

NeuroD/BETA2 gene variability and diabetes: no associations to late-onset type 2 diabetes but an A45 allele may represent a susceptibility marker for type 1 diabetes among Danes. Danish Study Group of Diabetes in Childhood, and the Danish IDDM Epidemiology and Genetics Group.

Mutations in the NeuroD/BETA2 gene have been shown to associate with type 2 diabetes. In the present study, we examined mutations in the NeuroD/BETA2 gene for association with either type 1 or 2 diabetes. Three variants were identified in patients with type 2 diabetes: Ala45Thr (allelic frequency 0.36, 95% CI 0.31-0.41), Pro197His (0.01), and Ser259Ser (0.01). Ala45Thr and Pro197His were not associated with type 2 diabetes, but the transmission disequilibrium test showed unequal transmission of the A45 allele to offspring with type 1 diabetes (chi2 = 5.90, P < 0.02, odds ratio 1.55, 95% CI 0.91-2.63). This association could not be explained by linkage disequilibrium between the Ala45 allele and IDDM7 (D2S152), which is also located on chromosome 2q32. When tested in vitro, the biological activity of Thr45 (117+/-36% vs. Ala45) and His197 (90+/-28% vs. Pro197) on the regulation of the human insulin gene promoter appeared normal. In conclusion, mutations in the NeuroD/BETA2 gene are not a common cause of late-onset type 2 diabetes among Danes. However, in the type 1 diabetic Danish population, the Ala45Thr variant of NeuroD/BETA2 may represent a susceptibility marker independent of IDDM7 on chromosome 2q32.

Age of Onset↗
PubMed1999

[Markers for risk of IDDM in children of Danish patients with IDDM. A population-based, historical prospective study].

To assess the offspring IDDM recurrence risk in a Danish population-based study and to investigate parental and offspring related biological variables that might influence this risk, we identified 2726 IDDM probands and their 2826 offspring from a background population of 1.725 million people (33% of the Danish population). Proband current age was 20-60 years and age at IDDM onset was 30 years or less. Offspring data were obtained by a questionnaire. The cumulative IDDM risk up to age 30 years was found significantly decreased in maternal offspring compared to paternal offspring (2.3 +/- 0.6% and 5.7 +/- 0.9%, RR = 2.40, 95% CI 1.30-4.47; Mantel Cox: p = 0.004) only if parents were diagnosed with IDDM before offspring birth. However, due to a low number of diabetic offspring of probands diagnosed with IDDM after offspring birth, this observation need to be confirmed in a larger population. Using the Cox proportional hazards model we found that among several biological variables tested separately on offspring of male and female probands, all diagnosed with IDDM before pregnancy, paternal age at IDDM onset was the only statistically significant predictor of IDDM risk in offspring. Our findings may be important for counselling families in which one parent has IDDM.

Adolescent↗
PubMed1999

No linkage of P187S polymorphism in NAD(P)H: quinone oxidoreductase (NQO1/DIA4) and type 1 diabetes in the Danish population. DIEGG and DSGD. Danish IDDM Epidemiology and Genetics Group and The Danish Study Group of Diabetes in Childhood.

Recent genome screening studies have identified novel regions of possible interest for susceptibility to type 1 diabetes. One of these is a 30-35 cM region mapping to 16q22-q24 (D16S515-D16S520), where also the gene encoding NAD(P)H: quinone oxidoreductase (NQO1) maps. Data has suggested association of a polymorphism (P187S) in the NQO1 gene and type 1 diabetes. NQO1 is involved in protection against oxidative stress, which is likely to be involved in beta-cell destruction. By use of the transmission disequilibrium test (TDT), we analyzed the P187S polymorphism for association to type 1 diabetes in a population-based sample of 247 Danish nuclear type 1 diabetic families. Random transmission patterns were observed to all affected offspring (p(tdt) = 0.82), to index cases (P(tdt) = 0.77), as well as to unaffected offspring (P(tdt) = 0.93). Hence, the NQO1 polymorphism is not likely to be an etiological mutation underlying the reported linkage of the 16q22-q24 region.

Chromosomes, Human, Pair 16↗
PubMed1999

Cytokine gene polymorphism in human disease: on-line databases.

The pathologies of many infectious, autoimmune and malignant diseases are influenced by the profiles of cytokine production in pro-inflammatory (TH1) and anti-inflammatory (TH2) T cells. Interindividual differences in cytokine profiles appear to be due, at least in part, to allelic polymorphism within regulatory regions of cytokine gene. Many studies have examined the relationship between cytokine gene polymorphism, cytokine gene expression in vitro, and the susceptibility to and clinical severity of diseases. A review of the findings of these studies is presented. An on-line version featuring appropriate updates is accessible from the World Wide Web site, http://www.pam.bris.ac.uk/services/GAI/cytokine4.htm.

Cytokines↗
PubMed1999

A population-based survey of frequencies of self-reported spontaneous and induced abortions in Danish women with Type 1 diabetes mellitus. Danish IDDM Epidemiology and Genetics Group.

AIMS: Whether pregnant women with Type 1 diabetes mellitus (Type 1 DM) have an increased risk of abortions is controversial. The aim of the present Danish population-based study of 33% of the Danish population was to describe the pattern of self-reported miscarriage and stillbirths from 1304 women with Type 1 DM. METHODS: Data were obtained by questionnaire. The current age of the women was 20-65 years and their age at diabetes onset was 30 years or less. RESULTS: The frequency of spontaneous abortions (SA) and induced abortions (IA) reported from women diagnosed with Type 1 DM prior to pregnancy was 17.5% (95% CI 15.5-19.9%) and 18.0%. (95% CI 16.0-20.0%), respectively. No significant differences in abortion frequencies before or after 1980 were reported. Previous findings of a decreasing stillbirth-rate in diabetic pregnancies during the last decades were supported. CONCLUSIONS: The reported SA frequency of 17.5% (95% CI 15.5-19.9%) in pregnant women with Type 1 DM is higher than previously reported SA rates of 10-12% in Danish nondiabetic women and the SA rate is more than twice the SA rate found in a previous Danish study from a highly specialized obstetrical centre for diabetic women. These data suggest an urgent need for further improvement in the general management of Danish pregnant women with Type 1 DM.

Abortion, Induced↗
PubMed1999

The predisposition to type 1 diabetes linked to the human leukocyte antigen complex includes at least one non-class II gene.

The human leukocyte antigen (HLA) complex, encompassing 3.5 Mb of DNA from the centromeric HLA-DPB2 locus to the telomeric HLA-F locus on chromosome 6p21, encodes a major part of the genetic predisposition to develop type 1 diabetes, designated "IDDM1." A primary role for allelic variation of the class II HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci has been established. However, studies of animals and humans have indicated that other, unmapped, major histocompatibility complex (MHC)-linked genes are participating in IDDM1. The strong linkage disequilibrium between genes in this complex makes mapping a difficult task. In the present paper, we report on the approach we have devised to circumvent the confounding effects of disequilibrium between class II alleles and alleles at other MHC loci. We have scanned 12 Mb of the MHC and flanking chromosome regions with microsatellite polymorphisms and analyzed the transmission of these marker alleles to diabetic probands from parents who were homozygous for the alleles of the HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes. Our analysis, using three independent family sets, suggests the presence of an additional type I diabetes gene (or genes). This approach is useful for the analysis of other loci linked to common diseases, to verify if a candidate polymorphism can explain all of the association of a region or if the association is due to two or more loci in linkage disequilibrium with each other.

Alleles↗
PubMed1999

Onset of type 1 diabetes: a dynamical instability.

Type 1 diabetes is a disease characterized by progressive loss of beta-cell function due to an autoimmune reaction affecting the islets of Langerhans. It is now generally accepted that cytokines are implicated in the pathogenesis of autoimmune diseases. Animal studies have shown that interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma affect type 1 diabetes development profoundly. It has been suggested that beta-cells are destroyed by cytokine-induced free radical formation before cytotoxic T-helper (Th)-lymphocytes and/or autoantibody-mediated cytolysis. This hypothesis is known as the "Copenhagen model." We introduce a mathematical model encompassing the various processes within this framework. The model is expressed in rate equations describing the changes in numbers of beta-cells, macrophages, and Th-lymphocytes. Being concerned with the earliest events, we explore the conditions necessary to maintain self-sustained beta-cell elimination based on the feedback between immune cells and insulin-producing cells. The motivation for this type of analysis becomes clear when we consider the multifactorial and complicated nature of the disease. Indeed, recent research has provided detailed information about the different factors that contribute to the development of the disease, stressing the importance of incorporating these findings into a more general picture. A mathematical formalism allows for a more comprehensive description of the biological problem and can reveal nonintuitive properties of the dynamics. Despite the rather complicated structure of the equations, our main conclusion is simple: onset of type 1 diabetes is due to a collective, dynamical instability, rather than being caused by a single etiological factor.

Animals↗