Genetic variation of the heparan sulfate proteoglycan gene (perlecan gene). Association with urinary albumin excretion in IDDM patients.
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Albuminuria↗
Biomedical subjects
F Pociot
Publications and source records attributed to F Pociot.
Evidence of a non-MHC susceptibility locus in type I diabetes linked to HLA on chromosome 6.
Linkage studies have led to the identification of several chromosome regions that may contain susceptibility loci to type I diabetes (IDDM), in addition to the HLA and INS loci. These include two on chromosome 6q, denoted IDDM5 and IDDM8, that are not linked to HLA. In a previous study, we noticed that the evidence for linkage to IDDM susceptibility around the HLA locus extended over a total distance of 100 cM, which suggested to us that another susceptibility locus could reside near HLA. We developed a statistical method to test this hypothesis in a panel of 523 multiplex families from France, the United States, and Denmark (a total of 667 affected sib pairs, 536 with both parents genotyped), and here present evidence (P = .00003) of a susceptibility locus for IDDM located 32 cM from HLA in males but not linked to HLA in females and distinct from IDDM5 and IDDM8. A new statistical method to test for the presence of a second susceptibility locus linked to a known first susceptibility locus (here HLA) is presented. In addition, we analyzed our current family panel with markers for IDDM5 and IDDM8 on chromosome 6 and found suggestions of linkage for both of these loci (P = .002 and .004, respectively, on the complete family panel). When cumulated with previously published results, with overlapping families removed, the affected-sib-pair tests had a significance of P = .0001 for IDDM5 and P = .00004 for IDDM8.
Adult↗
Genetic markers for glutamic acid decarboxylase do not predict insulin-dependent diabetes mellitus in pairs of affected siblings. The Danish Study Group of Diabetes in Childhood.
Reliable genetic and immunological markers are important in the prediction of insulin-dependent diabetes mellitus (IDDM). Since glutamic acid decarboxylase (GAD) is a candidate primary autoantigen, we examined the possible linkage between IDDM and the genes encoding GAD65 (GAD2, 10p11-12) and GAD67 (GAD1, 2q31) in 58 Danish IDDM affected sib pairs. The allelic inheritance of 10 polymorphic dinucleotide repeat sequences spanning the chromosomal regions of the two GAD genes, were examined by affected sib pair analysis (ASP). In addition a restriction fragment length polymorphism (RFLP) was identified in the gene encoding GAD65 using the restriction enzyme PvuII. The GAD gene markers were analyzed in relation to the presence of specific HLA types and GAD autoantibodies. No evidence of linkage was found between IDDM and either of the genes encoding GAD. This was also the case when subgroups carrying specific HLA susceptibility alleles were analyzed. Nor did we observe any association between these GAD genetic markers and the presence of GAD autoantibodies. Considering the high prevalence of GAD autoantibodies in IDDM, a putative genetic association between GAD and IDDM would be expected to affect most diabetic individuals. Therefore, our data indicate that the association between GAD and IDDM is not genetically determined, and that microsatellites used in this study do not contribute to the prediction of IDDM.
Adolescent↗
IDDM2-VNTR-encoded susceptibility to type 1 diabetes: dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus.
IDDM2-encoded predisposition to type 1 diabetes has recently been mapped to the minisatellite or variable number of tandem repeat (VNTR) locus upstream of the insulin and insulin-like growth factor II genes on human chromosome 11p15.5. In a UK case-control study (n = 228 sporadic diabetics; n = 441 healthy controls), we show here that the genotype homozygous for VNTR class I alleles is predisposing to disease (RR = 2.68), and VNTR class III alleles are dominantly protective (RR = 0.37). In 722 diabetic families from the UK (n = 356), USA (n = 173), Denmark (n = 55) and Sardinia (n = 138), we have analysed the transmission of class I alleles to diabetic offspring from class I/III heterozygous parents. We confirm that in families from the USA, class I alleles are transmitted preferentially from fathers. However, in family data sets from the UK, Denmark and Sardinia, the reverse is true and maternal transmission is stronger. Furthermore, in the UK family data set, the difference between maternal and paternal transmissions is significant (P < 0.05). It is therefore unlikely that 'maternal imprinting' alone explains the parent-of-origin effects in IDDM2-encoded predisposition to type 1 diabetes, at least not in the UK. There is a relationship between VNTR class (allele length) and insulin gene expression, though some results from different studies are conflicting. In the human adult cadaveric pancreas, we confirm our preliminary results that class III alleles are associated with lower levels of insulin mRNA in vivo. Similar results have been obtained independently in human foetal pancreas samples. It is difficult to explain how these marginally lower levels of insulin expression could account for the observed VNTR class III-encoded protective effect. Perhaps the site of action of IDDM2, mediated by VNTR allelic variation, is not the pancreas but some other organ such as the thymus.
Adolescent↗
Linkage of type I diabetes to 15q26 (IDDM3) in the Danish population.
Affected sib pair and linkage disequilibrium analysis, intrafamilial and case-control association studies were performed on 81 Danish multiplex insulin-dependent diabetes mellitus (IDDM) families (382 individuals) and 82 healthy Danish controls. The results confirm the linkage of D15S107 to IDDM in these Danish IDDM families (P = 0.010). When these data are combined with those of previous studies, an even stronger case for linkage can be made (P = 0.0005). Our analyses show that the D15S107*130 allele provides increased susceptibility (P = 0.02, relative risk = 3.55) and that the D15S107 locus contributes up to 16% of the familial clustering of IDDM. The analysis of affected sib pairs suggests that HLA and D15S107 may possibly act independently of each other. Taken together with our previous findings, our results suggest that three causes of susceptibilities can be discerned in the IDDM patient population: (1) a major susceptibility caused by the HLA-DRB1 alleles; (2) a minor susceptibility caused by the joint action of HLA and other non-HLA gene(s); and (3) a minor susceptibility caused by non-HLA gene(s).
Alleles↗
An association between type 1 diabetes and the interleukin-1 receptor type 1 gene. The DiMe Study Group. Childhood Diabetes in Finland.
The polygenic susceptibility to type 1 diabetes is well established and recent studies have demonstrated linkage of a further locus on chromosome 2q to disease. We have studied a polymorphism of the interleukin-1 receptor type 1 gene (IL1R1) on chromosome 2q in type 1 diabetic and control subjects from Finland, the United Kingdom, South India: three populations in which the risk of disease varies from very high to very low. In the medium-risk U.K. population we find a very strong association of IL1R1 with type 1 diabetes (p = 0.0002) but we find no overall association in either the high-risk Finnish or low-risk South-Indian populations. However, we do find heterogeneity of risk at IL1R1 amongst Finnish diabetic subjects according to the possession of HLA-DR associated susceptibility (p = 0.0001); there is an association with IL1R1 in only those Finnish diabetic subjects who do not possess high-risk HLA-DR4 or DR3 haplotypes (p = 0.006), as recently demonstrated for the insulin gene region in this population. We find no such heterogeneity of risk in either the U.K. or South-Indian populations. This study further demonstrates the genetic heterogeneity of disease susceptibility between and within populations and also supports the hypothesis of an interaction of the IL1R1 locus with genes within the HLA and insulin gene regions in the susceptibility to type 1 diabetes.
Adolescent↗
Linkage and association of the HLA gene complex with IDDM in 81 Danish families: strong linkage between DR beta 1Lys71+ and IDDM.
Many studies have shown an association of IDDM with polymorphisms in the HLA region on chromosome 6p21. Previously our case-control study in the Belgian population showed significant association between IDDM and certain HLA class II alleles, in particular Lys71+, encoding DRB1 alleles. In the present study, 81 Danish multiplex IDDM families and 82 healthy Danish controls were examined for polymorphisms in the HLA-DRB genes and 54 of the 81 families for polymorphisms in HLA-B, -DQA1, -DQB1, -TNFA, and -TNFB genes. The results confirm our previous studies in the Belgian population and show that DRB1Lya71+/+ homozygotes have a relative risk (RR) of 103.5. Linkage between IDDM and DRB1 alleles that encode Lys71+ was shown by affected zib pair analysis which showed strong linkage (p < 1 x 10(-6). By family based association studies, the DRB1Lys71+ was identified as the allale which increased susceptibility to develop IDDM most in the HLA region (haplotype relative risk = 8.38). Haplotype analysis confirmed the increased risk contributed by DRB1Lys71+ alleles and in addition showed that DRB1Lys71- provides protection against IDDM even in the presence of DQB1Aep47-. These results indicate that DRB1Lys71+ screening is a powerful test compared to full HLA typing to determine the risk for a random person to develop IDDM in the Danish population, with an even higher probability than shown previously for the Belgians.
Alleles↗
Cytokines and the endocrine system. II. Roles in substrate metabolism, modulation of thyroidal and pancreatic endocrine cell functions and autoimmune endocrine diseases.
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Animals↗
Strain-dependent differences in sensitivity of rat beta-cells to interleukin 1 beta in vitro and in vivo: association with islet nitric oxide synthesis.
The aim of this study was to investigate whether strain-dependent differences in beta-cell sensitivity to interleukin (IL) 1 beta exist in vitro and in vivo and if so, whether these differences correlate to variations in IL-1 beta-induced islet inducible nitric oxide synthase (iNOS) mRNA expression and nitrite production in vitro and islet iNOS protein content in vivo. Isolated islets of Langerhans in vitro from Wistar-Kyoto/Møllegården (WK/Mol) rats were sensitive to the inhibitory effect of IL-1 beta on accumulated and acute insulin secretion, whereas islets from Brown Norway/Charles River (BN/CR) rats were resistant. Furthermore, IL-1 beta induced higher islet iNOS mRNA expression and nitric oxide production from WK/Mol islets compared with BN/CR islets. WK/Mol, WK/CR, BN/Mol, BN/CR, and Lewis-Scripps/Mol (LS/Mol) rats received one daily injection of recombinant human IL-1 beta (4.0 microg/kg) or vehicle for 5 days. All the strains investigated were susceptible to IL-1 beta-induced changes in body weight, food intake, temperature, and plasma glucagon and corticosterone. However, IL-1 beta induced hyperglycemia and impairment of beta-cell glucose responsiveness in WK/Mol and LS/Mol rats, but not in BN rats. Furthermore, IL-l beta-induced islet iNOS expression in vivo determined by immunostaining was greater in WK/Mol rats compared with WK/CR and BN/CR rats. No restriction fragment length polymorphisms, using 20 restriction enzymes, were identified in the iNOS gene in six rat strains including BioBreeding rats. In conclusion, the relative resistance of BN rat islets to IL-1 beta-induced inhibition of beta-cell function in vitro was associated with lower islet iNOS mRNA expression and nitrite production in this strain. Further, the resistance of BN rats to IL-1 beta-induced hyperglycemia was associated with a lower islet iNOS expression in vivo.
Animals↗
Insulin-dependent diabetes mellitus--a polygenic disorder?
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Animals↗
Characterization of polymorphisms of an interleukin 1 receptor type 1 gene (IL1RI) promotor region (P2) and their relation to insulin-dependent diabetes mellitus (IDDM). The Danish Study Group of Diabetes in Childhood.
We have identified two PstI polymorphisms of the interleukin 1 receptor type I gene (IL1RI). One of these (RFLP-A) showed significant association to IDDM (P = 0.027), whereas no difference between patients and control subjects was found for RFLP-B (p = 0.42). RFLP-A was physically mapped to the 5'UTR of the gene. We sequenced and analysed a 411 bp region of a putative promotor region (P2) around RFLP-A. RFLP-A was due to a C to T transition in exon 1B of the IL1RI gene. This single-base mutation did not affect any known transcription factor recognition sequence or the predicted secondary mRNA structure. In addition, we found two other single-base substitutions in more than one individual. Neither of these showed specific disease association or absolute linkage with the RFLP-A.
Alleles↗
Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus.
The IDDM2 locus encoding susceptibility to type 1 diabetes was mapped previously to a 4.1-kb region spanning the insulin gene and a minisatellite or variable number of tandem repeats (VNTR) locus on human chromosome 11p15.5. By 'cross-match' haplotype analysis and linkage disequilibrium mapping, we have mapped the mutation IDDM2 to within the VNTR itself. Other polymorphisms were systematically excluded as primary disease determinants. Transmission of IDDM2 may be influenced by parent-of-origin phenomena. Although we show that the insulin gene is expressed biallelically in the adult pancreas, we present preliminary evidence that the level of transcription in vivo is correlated with allelic variation within the VNTR. Allelic variation at VNTRs may play an important general role in human disease.
Adult↗
Functional analysis of a new polymorphism in the human TNF alpha gene promoter.
In this paper the functional relevance of a TNFA promoter polymorphism, a G/A polymorphic sequence at position -238, was tested by analysing its influence on TNF alpha production upon in vitro stimulation of monocytes from 78 healthy, unrelated individuals by lipopolysaccharide (LPS) or after allogenic stimulation in a panel of 32 healthy individuals. All TNFA-A positive individuals were either DR3 or DR7 positive, confirming the previously reported strong linkage disequilibrium of the TNFA-A allele with the two extended haplotypes (B18, F1C30, DR3) and (B57, SC61, DR7). No individuals homozygous for the TNFA-A allele were present in the panel. The mean level of TNF alpha production was not significantly different in TNFA-G/G homozygous and in TNFA-A/G heterozygous individuals after LPS stimulation of monocytes (P = 0.35) or after allogenic stimulation (P = 0.7). After LPS and allogenic stimulation DR3 positive individuals had a higher mean TNF production. This could not be further differentiated by typing for TNF -283.
Adolescent↗
An evaluation of tumor necrosis factor microsatellite alleles in genetic susceptibility to multiple sclerosis.
We have analyzed the distribution of tumor necrosis factor (TNF) a and -b microsatellite alleles in HLA-DQ and -DR typed Swedish patients with multiple sclerosis (MS) (n = 122) and ethnically matched control subjects (n = 178). We found significant differences in the frequencies of TNFa and TNFb alleles between patients and controls. TNFaII was significantly associated with MS. This was also the case for the combination of TNFaII with TNFb4. However, TNFaII (alone or in combination with TNFb4) did not show any disease association independent of DQA1*0102/ DQB1*0602/DR2, whereas the previously reported strong association with HLA-DQA1*0102/DQB1*0602/DR2 in Scandinavian populations was confirmed. Therefore the association of TNFaII (and TNFb4) is most likely secondary to the increase of DQA1*0102/DQB1*0602/DR2 in MS patients. The proportion of TNFa6 positive individuals was lower among DR2-negative MS patients than among DR2-negative controls (P = 0.08). Since the presence of the TNFa6 allele correlates with low TNF alpha production in response to lipopolysaccharide, it could be speculated that DR2-negative MS patients have an increased risk of being high TNF alpha producers in response to exogenous stimuli.
Alleles↗
Cytokines and the endocrine system. I. The immunoendocrine network.
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Acute-Phase Reaction↗
T cell proliferative responses to glutamic acid decarboxylase-65 in IDDM are negatively associated with HLA DR3/4.
Based on studies in spontaneously non-obese diabetic (NOD) mice, it has been suggested that the Mr 65,000 isoform of glutamic acid decarboxylase (GAD65) is of major importance in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). In humans, antibodies to GAD65 are present before and at onset of the disease and in vitro T cell reactivity to GAD has also been reported. To further characterize the T cell recognition of GAD65, we incubated peripheral blood mononuclear cells from 45 newly diagnosed IDDM patients with purified recombinant human islet GAD65 and correlated the proliferative response with HLA DR haplotype and the presence of GAD65 autoantibodies. Fifty healthy individuals were studied as controls. Of the patients, 49% showed proliferative responses to GAD65 in contrast to only 4% of the controls. T cell proliferation to GAD65 was significantly more frequent in patients not being HLA DR3/4 heterozygous (19/29, 66%) as compared to HLA DR3/4 heterozygous patients (3/16, 19%) (p < 0.01). The difference was most pronounced in females with 64% (9/14) of the HLA non-DR3/4 patients being positive compared to none (0/6) of the HLA DR3/4 patients (p < 0.05). The overall frequency of GAD65 autoantibodies was 71% (32/45) with a similar distribution between patients with HLA DR3/4 (10/16, 63%) and HLA non-DR 3/4 (22/29, 76%). There was no correlation between levels of the T and B cell responses to GAD65 (r = 0.24). In conclusion, we find a proliferative T cell response to GAD65 in approximately 50% of recent onset IDDM patients and unexpectedly find the majority of responders to be HLA non-DR 3/4 heterozygous patients. No difference was observed in B cell responsiveness between the two HLA groups.
Adolescent↗
[Familial aggregation of insulin-dependent diabetes mellitus in Denmark. A nation-wide population study].
This study aimed to assess the prevalence of familial aggregation of insulin-dependent diabetes mellitus (IDDM), among Danish families with a diabetic child and to compare epidemiological data for familial and sporadic cases of IDDM children. All IDDM patients aged 19 years or less treated at paediatric departments or departments of internal medicine were identified and asked to complete a questionnaire regarding diabetes onset and family history. Of 1574 probands identified, 1419 participated (90.2%). Additional cases of IDDM were found in 12.8% of the families. Among these families, in 6.8% the father and in 2.1% the mother were diabetics and in 5.0% at least one of the siblings were diabetics. In familial cases the proband was significantly younger at diabetes onset, the parents were younger at birth of the IDDM child and no differences in gender were observed in contrast to sporadic cases, where more males were found. Thus, heterogeneity in epidemiological characteristics was observed between familial and sporadic cases.
Adolescent↗
[Nicotinamide and prevention of insulin-dependent diabetes mellitus. Rationale, effects, toxicology and clinical experiences. ENDIT Group].
IDDM is caused by an immune-mediated destruction of the insulin-producing beta cells. Beta cells are destroyed by induction of oxygen-derived free radicals (FR) and nitric oxide (NO), which results in perturbation of the mitochondrial respiratory system and DNA strand breaks. As a result of beta cell destruction, islet cell antibodies (ICA) can be demonstrated in the circulation. These antibodies can be detected up to eight years prior to overt IDDM. Nicotinamide, a vitamin B3 derivative, interferes with the immune mediated beta-cell destruction by reducing the content of FR and NO and thereby reducing their deleterious effects. At the same time, nicotinamide increases the intracellular NAD pool, thus increasing the energy supply of the cell. Nicotinamide protects against chemically induced as well as spontaneous diabetes in animal models of the disease. Recently, open clinical studies have suggested that nicotinamide when administered to humans can prevent or delay clinical onset of IDDM. To test the possible preventive effect of nicotinamide in IDDM, a prospective, randomized, placebo-controlled study is needed. A multicentre study including 18 European countries, Israel and Canada is planned to start during 1993.
Animals↗