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Biomedical subjects

P M Danze

Publications and source records attributed to P M Danze.

At least 19 recordsLinked to original sources
PubMed2005

Polymorphisms of the receptor of advanced glycation endproducts (RAGE) and the development of nephropathy in type 1 diabetic patients.

OBJECTIVES: We investigated the association of the RAGE (Receptor for Advanced Glycation End products) exon3 gene polymorphisms with stages of nephropathy in type 1 diabetes. METHODS: The RAGE exon 3 genotype was assessed by Denaturing Gradient Gel Electrophoresis (DGGE) procedure in 487 type 1 diabetic patients with proliferative retinopathy subdivided into four groups according to their level of renal involvement and in 351 control subjects (GENEDIAB study). RESULTS: We reported here three main low frequency dimorphisms, previously submitted to data banks, Gly82Ser, Val89 CTC/CTG, and Arg77Cys. The genotype distribution of these polymorphisms was not statistically different in type 1 diabetic patients compared to healthy controls (p=0.37). Among the three described polymorphisms, only the RAGE Gly82Ser genotype frequency was significantly increased in the group with advanced nephropathy (11%) defined by a chronic renal failure compared to the three others groups: no nephropathy, 5%; incipient (microalbuminuria) 5%; established (macroalbuminuria), 2%) (P=0.04). The 82 Ser allele was identified as an independent risk marker for the stage of advanced nephropathy: adjusted odds ratio 3.17(95% CI 1,32-7,85, p=0.008). CONCLUSION: These data suggest that the 82 Ser allele of the RAGE gene is a risk allele for developing advanced nephropathy. This suggests that some RAGE gene polymorphisms may be associated with progression to diabetic advanced nephropathy in Caucasian type 1 diabetic patients.

Amino Acid Substitution↗
PubMed2002

CTLA-4 49 A/G dimorphism and type 1 diabetes susceptibility: a French case-control study and segregation analysis. Evidence of a maternal effect.

Several studies have demonstrated an association of cytotoxic T lymphocyte-associated molecule 4 (CTLA-4) (IDDM 12) alanine 17 with type 1 diabetes, but we wished to study the parental effect of CTLA-4 49 A/G dimorphism in diabetic families. The CTLA-4 exon 1 polymorphism (49 A/G), HLA-DRB1 and insulin gene (INS) variable number tandem repeats (VNTR) were analysed in 134 type 1 diabetic patients vs. 273 control subjects. The segregation analysis for transmission was carried out in 70 informative diabetic families using the transmission distortion test (TDT). All genotyping was performed by PCR-RFLP. CTLA-4 49 G allele frequency was not increased in diabetic patients compared to controls (41 vs. 38%, not significant). The distribution of GG, AG and AA CTLA-4 genotypes was similar in the two groups (13, 57 and 30% vs. 11, 54 and 35%, respectively) and was independent of HLA-DRB1 or INS VNTR polymorphism. The CTLA-4 49 G allele showed weak distorted transmission to the diabetic offspring, whereas random transmission was observed in unaffected offspring. This distortion is attributable to a maternal effect (71% compared to the 50% expected ratio; tdt = 4.8; P < 0.03). The combined transmission of maternal CTLA-4 G with HLA-DRB1*03 (90%; tdt = 6.4; P < 0.01) and VNTR class I (80%; tdt = 5.4; P < 0.02) enhanced the susceptibility effect of each marker separately. We noted a slight CTLA-4 49 G and HLA-DRB1*04 distortion of transmission shared in paternal and maternal diabetic meiosis. In non-diabetic offspring, the CTLA-4 49 A allele confers a protective effect in the presence of maternal HLA-DRB1*03 and paternal HLA-DRB1*04 alleles. Despite the absence of a positive association of the CTLA-4 49 G allele with type 1 diabetes, our segregation analysis supports the hypothesis of a modulation by CTLA-4 49 G/A dimorphism of the susceptibility conferred by maternal HLA-DRB1*03 inheritance. This potential parental effect needs to be confirmed in a larger data set.

Adenine↗
PubMed1999

HLA class II polymorphism in a Gabonese Banzabi population.

The HLA class II typing of 167 unrelated Gabonese individuals from the Banzabi ethnic group was assessed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The most frequent alleles at each locus were DRB1*1501-3 (0.31), DQA1*0102 (0.50), DQB1*0602 (0.42) and DPB1*0402 (0.29). The estimation of the haplotype frequencies as well as the observation of the segregation of several haplotypes using additional HLA typing of relatives, revealed that the three-locus haplotype DRB1*1501-3-DQA1*0102-DQB1*0602 was found at the highest frequency (0.31) among these individuals. This haplotype is not typically African and has already been described in Caucasians, but its presence at high frequency is exclusive to populations originating from Central Africa, and can thus be designated as a particular genetic marker of these populations.

Adolescent↗
PubMed1999

Human RAGE GLY82SER dimorphism and HLA class II DRB1-DQA1-DQB1 haplotypes in type 1 diabetes.

Advanced glycation end products (AGEs) are believed to play an important role in the development of diabetic complications. AGEs increase in diabetes and modulate cellular functions through binding to a specific cell surface receptor (RAGE). The RAGE gene maps to chromosome 6p in the HLA class III area and is telomeric to the class II region at 250 kb from DRA. A recent report described the characterization of a major RAGE gene variant as a biallelic single base polymorphism (G/A 557) in the exon 3 sequence leading to a change of a glycine to a serine at position 82. Using DGGE and PCR-RFLP, we have investigated the distribution of this dimorphism in conjunction with HLA class II genes in large populations of type 1 diabetic patients and healthy subjects. Although no association of this RAGE gene polymorphism with disease susceptibility was found, we report a strong linkage disequilibrium between the variant carrying the serine amino acid at position 82 and two HLA-DR2 and HLA-DR4 specificities. In particular, we describe two major extensive HLA class II haplotypes associated with this serine variant and identified as DRB1*0401-DQA1*0301-DQB1*0301 in the diabetic group and DRB1*1501-DQA1*0102-DQB1*0602 in control individuals. These data were partially confirmed by family transmission analysis.

Diabetes Mellitus, Type 1↗
PubMed1997

Gestational diabetes mellitus and HLA class II (-DQ, -DR) association: The Digest Study.

Gestational diabetes mellitus (GDM) and impaired glucose tolerance during pregnancy (IGT) are associated with an increased risk of perinatal morbidity and then further development of diabetes among 30-50% of affected women. This is a real public health problem that deserves investigation of phenotypic and genotypic predisposing markers. However, the involvement of genetic background in GDM and IGT remains unclear. In particular, association with HLA class II polymorphism has been poorly studied and has produced conflicting results. In attempt to clarify these discrepancies, we investigated HLA class II polymorphism in 95 GDM and 95 IGT women from the north of France using DNA amplification followed by restriction enzyme digestion (PCR-RFLP). Ninety-five pregnant women with normal glucose tolerance (NGT) were chosen as a control reference group. The distribution of HLA class II polymorphism was not found to be significantly different between GDM, IGT and NGT samples. In particular, we did not find any significant variation of DRB1*03 and DRB1*04 allele frequencies between these three groups. These data provide further evidence that insulin-dependent diabetes mellitus (IDDM) HLA class II susceptibility alleles cannot serve as genetic markers for susceptibility to glucose intolerance during pregnancy. However, GDM and IGT were not equivalent to the NGT control group and presented particular HLA patterns. In particular, we observed an increase of the DRB1*0701-DQA1*0201-DQB1*02 haplotype in GDM women (P = 0.02; Pc not significant) and an increase of DRB1*0101-DQA1*0101-DQB1*0501 and DRB1*1302-DQA1*0102-DQB1*0604 haplotypes in the IGT group (P = 0.02 and 8 x 10(-3), respectively; Pc not significant). In contrast, we found a decrease in the DRB1*1101 allele in IGT samples (P = 0.03; Pc not significant) and a decrease of DRB1*1103-*1104 alleles in the GDM group (P = 9 x 10(-3); Pc not significant). Although these findings are only descriptive, it points out the genetic heterogeneity of glucose intolerance during pregnancy.

Alleles↗
PubMed1996

Are HLA-DR or TAP genes genetic markers of severity in ulcerative colitis?

The pathogeny of ulcerative colitis (UC) is not yet elucidated, but some arguments suggest the implication of genetic factors. Among the candidate genes, those encoding for HLA class II genotypes have been extensively studied in UC; however, discordant data may be imputable to heterogeneity, characterized by immunological markers such as atypical ANCA (p-ANCA), or to inclusion of more or less intractable UC. The aim of our study is to evaluate the interest of HLA class II and TAP genetic markers to identify different clinical forms of UC, according to p-ANCA status. Unrelated patients with a history of UC (n = 91) and healthy control subjects with no personal or family history of inflammatory bowel diseases (IBD) (n = 200) were included. HLA-DRB1*03 was less frequent in UC patients than in healthy controls (8% vs 28%, PC < 0.03). No association was found with any TAP genotypes. Moreover, there was no association with the HLA-DR2 specificity, either in the entire group of UC patients (38% vs 28%) or in the p-ANCA-positive subgroup of patients (30%). The most consistent finding in the present study is that some genetic markers may characterize intractability in UC patients. HLA-DR2 was associated with poor prognosis, regardless of p-ANCA status. In HLA-DR2 and non-HLA-DR2 groups, colectomy was done in 55% and 27% of patients, respectively, (PC < 0.05). Furthermore, in non-HLA-DR2 patients, p-ANCA could be of interest to characterize those with more severe prognosis. Our results confirm the interest of genetic studies to define UC genetic susceptibility, taking into account intractability of the disease. They do not support the hypothesis that p-ANCA is a subclinical marker of genetic susceptibility to UC.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

[HLA DRB1 polymorphism in rhizomelic pseudo-polyarthritis and Horton disease].

Some studies have suggested that distribution of HLA DRB1 alleles in polymyalgia rheumatica (PMR) resembles that found in giant cell arteritis (GCA). However these data are controversial. OBJECTIVE--To evaluate in French native patients whether PMR immunogenetically resembles GCA in determining HLA DRB1 alleles. PATIENTS AND METHODS--Fourty-five patients were included in the study. Twenty-one patients with PMR alone (Bird's criteria) and 24 with GCA (ACR criteria). In 11 patients, GCA was associated with PMR. HLA DRB1 genotype was determined by PCR-RFLP analysis. Statistical analysis was performed by the chi 2 test and determination of the odds ratio (OR). Two hundred and thirty-three unselected normal healthy subjects served as controls. RESULTS--A significant increased prevalence of HLA DR1 was observed in patient with PMR alone and an absence of DR7 (0% vs 10.3%, p = 0.02, OR = 0.1). An increased incidence of DR4 and particularly *0401 allele was only found in patients with GCA (OR = 2.4). No patient with isolated PMR had DR7 genotype compared with 25% in GCA (p < 0.001, OR = 0.03). A comparative study between isolated PMR versus GCA showed a significant increased in DR1 and DR3 alleles in isolated PMR and a significant increased prevalence of DR4 and DRB1 *0701 allele in GCA. CONCLUSION--The present study emphasizes the absence of similarity in HLA DRB1 allele distribution between PMR and GCA. The association of DR7 in patient with GCA seems characteristic in French native patients.

Aged↗
PubMed1995

Lack of correlation between HLA class II alleles and immune responses to Pf155/ring-infected erythrocyte surface antigen (RESA) from Plasmodium falciparum in Madagascar.

To investigate the relationships between predominant HLA class II alleles and immune responses to the Plasmodium falciparum ring-infected erythrocyte surface antigen (Pf155/RESA), 50 individuals from the highlands of Madagascar were followed-up from 1988 to 1991. The T cell reactivity and antibody responses to synthetic peptides (EENV)4, (EENVEHDA)4, and (DDEHVEEPTVA)3, representing major T and B epitopes of Pf155/RESA antigen, were assessed with an average of five determinations per individual over the four-year follow-up period. The T cell reactivity was investigated by lymphocyte proliferation and assays for interferon-gamma and interleukin-2 release. Antipeptide antibodies were measured using the Falcon assay screening test-enzyme-linked immunosorbent assay. The cumulative prevalence rates of cellular (range for the three peptides = 64-68%) and antibody responders (range = 70-74%) were similar for each peptide. The HLA class II typing was performed using polymerase chain reaction-restriction fragment length polymorphisms. The prevalent alleles or groups of alleles (frequency > 20%) were similar in responders and nonresponders, both for cellular and antibody responses to each peptide. These were HLA-DR 5 group and HLA-DQA1 *0601, *0101-0102-0104, HLA-DQB1 *0301, and HLA-DPB1 *0101-2601 alleles. Allelic distribution was similar in individuals presenting with (74%) or without (26%) a malaria attack during a 20-week follow-up conducted when malaria was hyperendemic (P > 0.05, by Fisher's exact test). Despite repeated immunologic measures that better identify the responders, no relationship was found between HLA class II alleles and the cellular or antibody responses to Pf155/RESA epitopes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Hydrodynamic characterization and DNA-binding properties of the liganded and unliganded forms of the retinoic-acid receptor alpha from human HL-60 cells.

The hydrodynamic parameters of the retinoic-acid receptor from human myeloblastic leukemia HL-60 cells were accurately investigated. The ligand-bound retinoic-acid receptor (RAR) has a Stokes radius of 3.5 nm when analyzed by size-exclusion chromatography. A 53-kDa protein was detected by Western blot analysis using a polyclonal antibody directed against the F domain of hRAR alpha, in the fractions containing the 3.5-nm complex. Fractionation of a crude nuclear extract from HL-60 cells, untreated with retinoic acid, yielded antibody-revealed material with Stokes radii ranging from 3.5 nm to 6 nm. From the hydrodynamic data, a molecular mass of 52 kDa was calculated for the liganded receptor, whereas no precise value could be deduced for the unliganded receptor form, since it dissociates rapidly into the 3.5-nm form. Gel-retardation experiments showed that the 3.5-nm form of hRAR alpha bound specifically to DNA, whereas binding of the unliganded receptor form was sharply reduced. These findings suggest that the unliganded inactive receptor form dissociates upon ligand binding and acquires a ligand-dependent DNA-binding activity.

Amino Acid Sequence↗
PubMed1993

[Rheumatoid polyarthritis in the elderly--rhizomelic pseudopolyarthritis: what differences?].

The authors have conducted a comparative retrospective study between polymyalgia rheumatic (N = 26) and rheumatoid arthritis in the elderly (N = 44), including HLA DRB1 genotype determination by PCR-RFLP analysis. No clinical nor biological differences were significant between the 2 groups of patients. However 70% of RA patients had one ore more susceptibility alleles (shared epitope hypothesis) and 50% in polymyalgia rheumatica.

Aged↗
PubMed1993

[Systemic manifestations of rheumatoid arthritis: prognostic value of the HLA DRB1 0405 allele].

The aim of the present study was to determine HLA DRB1* genotype by PCR-RFLP analysis in patients with rheumatoid arthritis (N = 122) associated with extra-articular manifestations (N = 24). A significant increased of DRB1* 0405 was found in RA patients with extra-cellular involvement (odd-ratio = 8.33, confidence interval = 1.44 - 56.7). In patients with RA, HLA DRB1*0405 allele might constitute a susceptibility marker of extra-articular involvement such as vasulitis or cardio-pulmonary manifestations.

Alleles↗
PubMed1988

Association of the glucocorticoid receptor binding subunit with the 90K nonsteroid-binding component is stabilized by both steroidal and nonsteroidal antiglucocorticoids in intact cells.

The interaction of various antiglucocorticoids with the glucocorticoid receptor from intact rat thymocytes was investigated. Reversible antiglucocorticoids (RU 486, cortexolone, progesterone) underwent more limited nuclear transfer than potent glucocorticoids (dexamethasone, triamcinolone acetonide, progesterone). This behavior was correlated with an impeded dissociation of cytosolic antiglucocorticoid receptor complexes preformed in intact cells, as assayed by high-performance size exclusion chromatography in physiological conditions (i.e., isotonic molybdate-free buffer). Antagonist-receptor complexes remained in a 7-8-nm form whatever the antiglucocorticoid tested (including dexamethasone mesylate and trifluoroperazine, a nonsteroidal antiglucocorticoid) and the incubation time at 37 degrees C, whereas agonist-receptor complexes were rapidly converted into 5-nm species. This stabilization was not detectable by conventional sucrose gradient centrifugation because of artifactual dissociation of untransformed complexes, a pitfall overcome by resorting to vertical tube centrifugation. Moreover, the low amount of nuclear antiglucocorticoid receptor complexes was also in the undissociated form, in contrast with nuclear agonist-receptor complexes. Immunological probes demonstrated that the 90-kDa non-steroid-binding component was associated with the antiglucocorticoid-stabilized receptor. Thus, whatever their chemical structure and their affinity for the receptor, antiglucocorticoids stabilize the oligomeric form of the glucocorticoid receptor in intact cells. Our data, demonstrating for the first time that all antiglucocorticoids probably act via a common mechanism, suggest a key role for subunit dissociation during in vivo receptor activation.

Animals↗
PubMed1988

Inhibition of glucocorticoid receptor transformation, subunit dissociation, and temperature-dependent inactivation by various N-substituted maleimides.

A series of N-substituted maleimides were synthesized, and their effect on the activation to the DNA binding state of the rat liver glucocorticoid receptor was studied. Unactivated (preincubated at 0 degrees C) cytosolic [3H]triamcinolone acetonide-receptor complexes were pretreated with various N-alkylmaleimides at 0 degrees C and then heated at 25 degrees C and assayed for DNA-cellulose binding. No inhibition of the DNA binding activity was observed with either N-ethylmaleimide or N-substituted maleimides bearing an ionizable substituent, like N-(omega-carboxyalkyl)maleimides and N-[2-(trimethylammonio) ethyl]maleimide. On the contrary, treatment with long-chain alkylmaleimides like N-heptylmaleimide resulted in significant inhibition. The highest inhibition was obtained with N-benzylmaleimide and, to a lesser extent, N-(ethylphenyl)-maleimide, whereas N-benzylsuccinimide was ineffective. Treatment of cytosol containing unactivated glucocorticoid complexes at 3 degrees C with N-benzymaleimide also prevents the temperature-mediated conversion of 8S receptor to 4S. Moreover, N-benzylmaleimide was able to inhibit the inactivation of the receptor steroid-binding activity caused by heat. N-Benzylmaleimide shares with molybdate ions the ability to inhibit glucocorticoid receptor activation, dissociation, and inactivation. However, their respective mechanisms of action are probably distinct, since their effects on receptor inactivation appear additive. It is suggested from the comparison of the various maleimides tested that the sulfhydryl groups essential for receptor activation and dissociation lie in a rather nonpolar environment including aromatic amino acid(s).

Animals↗
PubMed1987

Evidence for an increased glycation of IgG in diabetic patients.

The levels of non-enzymatically glycated total plasma proteins, albumin and IgG were determined in diabetic and non-diabetic patients using affinity chromatography on boronate-agarose gels. A significant increase in both glycated albumin and IgG, and in total glycated plasma proteins was demonstrated. A good correlation between glycated albumin and glycated hemoglobin was observed, while the correlation between glycated IgG and glycated albumin (or hemoglobin) was lower. This was found probably related to wide variations of glycated IgG for diabetics patients who have high glycated hemoglobin levels. These variations were inversely correlated with total serum IgG. Determination of fructosamine or 5-hydroxymethylfurfural content of IgG showed a significant increase in diabetics. Glycated IgG was found to contain approximately one mole of glucose. The main site of glycation was determined to be present in the Fab (more precisely the Fd) part of the IgG molecule.

Blood Glucose↗