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1.
J Endocrinol Invest ; 43(9): 1345, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32495300

RESUMO

The article "EStradiol and PRogesterone in In vitro ferTilization (ESPRIT): a multicenter study evaluating third­ versus second­generation estradiol and progesterone immunoassays.

2.
J Endocrinol Invest ; 43(9): 1239-1248, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32170594

RESUMO

PURPOSE: To assess estradiol (E2) and progesterone levels during ovarian stimulation determined by third-generation (Gen III) and second-generation (Gen II) Elecsys® immunoassays. METHODS: E2 and progesterone concentrations were measured using Elecsys® Gen III and Gen II immunoassays, and progesterone concentrations on the day of ovulation triggering were determined by LC-MS/MS. This was a retrospective, non-interventional study conducted at European tertiary referral infertility clinics in women aged 18-45 years, with a body mass index 18-35 kg/m2, regular menses, and both ovaries. RESULTS: Serum samples were obtained from 230 women classified by oocyte retrieval as poor (33.0%; 0-3 oocytes), normal (40.9%; 4-15 oocytes), or high (26.1%; > 15 oocytes) responders. E2 and progesterone levels increased during ovarian stimulation, with greatest increases observed in high responders. Elecsys® Gen III and Gen II assay results were highly correlated for E2 (Pearson's r = 0.99) and progesterone (r = 0.89); Gen III results were lower than Gen II for both E2 and progesterone. On the day of triggering, Gen III E2 and progesterone levels showed a difference of - 15.0% and - 27.9%, respectively. Progesterone levels (on day of triggering) measured by LC-MS/MS correlated better with Gen III (0.98) than Gen II (0.90). Mean relative differences for Gen III and Gen II assays versus LC-MS/MS were 14.6% and 62.8%, respectively. CONCLUSION: E2 and progesterone levels determined with Elecsys® Gen II and III assays were highly correlated; results were lower for Gen III versus Gen II. Differences observed for progesterone on the day of triggering may be clinically relevant.


Assuntos
Análise Química do Sangue/métodos , Estradiol/sangue , Fertilização in vitro , Indução da Ovulação , Progesterona/sangue , Adolescente , Adulto , Cromatografia Líquida , Estradiol/análise , Feminino , Humanos , Imunoensaio/métodos , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Progesterona/análise , Estudos Retrospectivos , Espectrometria de Massas em Tandem , Adulto Jovem
3.
Eur J Immunogenet ; 29(4): 321-30, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12121278

RESUMO

Genes of the HLA-DR, DQ region confer strong susceptibility to type 1 diabetes mellitus (IDDM). A possible mechanism of susceptibility is a difference in the amounts of transcripts of predisposing and neutral or protective haplotypes. In this study we developed an assay to compare the amounts of mRNA of two distinct HLA-DQA1 alleles in peripheral blood lymphocytes (PBLs) of heterozygous individuals, using a quantitative RT-PCR with an internal standard covering all HLA-DQA1 specifities. We also developed an algorithm to calculate the amounts of mRNA for two distinct alleles in heterozygous individuals based on the comparison to the same internal standard. In total, 37 HLA-DQA1 heterozygous individuals were analysed, including patients with IDDM (n = 14) and healthy controls (n = 23). Intra-individually, we observed different amounts of mRNA for different HLA-DQA1 alleles in the order: HLA-DQA1*03 > *01 > *0201 > *05. This order was observed in all individuals. We also observed a variation in the ratio of these unbalanced amounts of mRNA in individuals with the same HLA-DQA1 allele combinations. In all allele combinations the average ratio was increased in patients with IDDM compared to the control samples. HLA-DQA1*03 positive and DQA1*03, *05 heterozygous patients had the highest average ratios. Nevertheless, based on limited sample numbers, these differences did not reach significance. We therefore conclude that variations between HLA-DQA1 alleles are not limited to the nucleotide sequence but are also found at the level of amounts of mRNA.


Assuntos
Diabetes Mellitus Tipo 1/genética , Antígenos HLA-DQ/genética , RNA Mensageiro , Diabetes Mellitus Tipo 1/imunologia , Cadeias alfa de HLA-DQ , Heterozigoto , Humanos , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
4.
Clin Endocrinol (Oxf) ; 54(3): 335-8, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11298085

RESUMO

OBJECTIVE: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare systemic autoimmune disorder of monogenic and autosomal-recessive inheritance. To date, 29 APECED causing mutations have been identified in the responsible gene AIRE-1, coding for a regulator of transcription. The aim of this study was to examine whether mutations in AIRE-1, in their heterozygous form, predispose to the more common isolated autoimmune endocrinopathies Addison's disease, type 1 diabetes mellitus, Graves' disease and Hashimoto's thyroiditis. DESIGN: Patients with isolated autoimmune endocrine disorders as well as healthy controls were analysed for two of the most common AIRE-1 mutations, mutation R257X in exon 6 and a 13-bp deletion in exon 8. Mutations were detected by polymerase chain reaction based techniques. PATIENTS: In total, 726 individuals were investigated for mutation R257X. Subjects comprised patients with Addison's disease, IDDM, Graves' disease and Hashimoto's thyroiditis. With regard to the 13 bp deletion we could screen 91 patients with Addison's disease. In addition, six patients with the APECED syndrome including one family were analysed for both mutations. RESULTS: Out of the 12 alleles in APECED patients six contained either mutation R257X or the 13 bp deletion, confirming that these mutations prevail in Europe. R257X was found in one subject with Hashimoto's thyroiditis in its heterozygous form. The 13 bp deletion was not detected in any subject with Addison's disease. CONCLUSIONS: The two studied AIRE-1 mutations are so rare in the general population that they can not contribute to susceptibility for the more common isolated autoimmune disorders.


Assuntos
Doença de Addison/genética , Diabetes Mellitus Tipo 1/genética , Doença de Graves/genética , Poliendocrinopatias Autoimunes/genética , Tireoidite Autoimune/genética , Fatores de Transcrição/genética , Análise Mutacional de DNA , Predisposição Genética para Doença , Testes Genéticos , Humanos , Proteína AIRE
5.
J Clin Endocrinol Metab ; 86(2): 653-5, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11158025

RESUMO

Several studies have demonstrated an association of CTLA4 (IDDM12) alanine-17 with type 1 diabetes, but CTLA4 variants have not yet been investigated in type 2 diabetes. The CTLA4 exon 1 polymorphism (49 A/G) was analyzed in 300 Caucasian patients with type 2 diabetes and 466 healthy controls. All patients were negative for glutamate decarboxylase and islet cell antibodies. CTLA4 alleles were defined by PCR, single-strand conformational polymorphism, and restriction length fragment polymorphism analysis using BBV:I. The distribution of alleles as well as the genotypic and phenotypic frequencies were similar among patients and controls [AA, 42 vs. 39%; AG, 47 vs. 46%; GG, 11 vs. 15%, P = not significant (n.s.); A/G, 65/35% vs. 62/38%, P = n.s.; alanine/threonine 92/58% vs. 85/61%, P = n.s.]. However, detailed analysis of clinical and biochemical parameters revealed a tendency of GG (alanine/alanine) toward younger age at disease manifestation (46.8 +/- 0.8 vs. 49.5 +/- 0.8 yr, mean +/- SEM), lower body mass index (21.4 +/- 0.5 vs. 24.4 +/- 0.5 kg/m(2), P = 0.042), and basal C-peptide level (0.33 +/- 0.07 vs. 0.53 +/- 0.07nmol/L), as well as earlier start of insulin treatment (5.8 +/- 1.2 vs. 8.7 +/- 0.6 yr) and higher portion of patients on insulin (71 vs. 61%). Patients with the AA genotype were significantly less likely to develop microangiopathic lesions (P < 0.0005). No differences were found for hypertension or family history of type 2 diabetes. In conclusion, CTLA4 alanine-17 does not represent a major risk factor for type 2 diabetes. Additional studies on larger groups and different ethnic groups are warranted to clarify the association of the GG genotype with faster ss-cell failure and the lower rate of microvascular complications in AA carriers.


Assuntos
Antígenos de Diferenciação/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Imunoconjugados , Polimorfismo Genético , Abatacepte , Substituição de Aminoácidos , Antígenos CD , Peptídeo C/sangue , Antígeno CTLA-4 , Códon , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/imunologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/imunologia , Neuropatias Diabéticas/genética , Neuropatias Diabéticas/imunologia , Retinopatia Diabética/genética , Retinopatia Diabética/imunologia , Feminino , Alemanha , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ , Cadeias beta de HLA-DQ , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Valores de Referência , População Branca
6.
Immunogenetics ; 51(11): 898-904, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11003383

RESUMO

Long terminal repeats (LTRs) are common retrovirus-related sequences spread throughout the human genome. We previously reported the human-specific integration of one LTR (DQLTR3) located 15 kb upstream of HLA DQB1. To elucidate the contribution of retroviral sequences to the variability and phylogenetic background of HLA DQB1 we investigated another LTR (DQLTR13), located 1.3 kb upstream of HLA DQB1, in German families, great apes, and Old World monkeys. Within German families, DQLTR13 presence was strongly linked to HLA DQB1*0302, *0303, and *0402 haplotypes. All other haplotypes had a low frequency or were devoid of DQLTR13. Phylogenetic analysis of DQLTR13 and adjacent nucleotide sequences in humans and non-human primates revealed a high degree of similarity and recent origin of HLA DQB1*0302, *0303, and *0402. Nevertheless, two lineages leading to DQB1*0301 and *0302 were generated by an ancient split of a DQB1*0301, *0302 progenitor. A third lineage consisting of DQB1*05/*06-related sequences may have evolved from the DQB1*0302 lineage, and a DQB1*0201-related sequence shared common ancestry with DQB1*0301. Among the human haplotypes, HLA DQB1*0201 and *0301 are linked to two different DQA1 alleles. Based on the small genetic distance of DQLTR13 as well as the adjacent sequences on these haplotypes, we suggest that a recent recombination is responsible for these associations. In the analysis of nonhuman primate species, we detected DQLTR13 in two lowland gorillas, dating the integration at at least 8 million years ago. We therefore conclude that noncoding sequences up to 1.3 kb upstream of DQB1 provide novel insight into the generation of MHC gene diversity.


Assuntos
Cercopithecidae/genética , Retrovirus Endógenos/genética , Variação Genética , Antígenos HLA-DQ/genética , Hominidae/genética , Sequências Repetidas Terminais , População Branca/genética , Animais , Sequência de Bases , Cercopithecidae/classificação , DNA Complementar , Retrovirus Endógenos/classificação , Heterogeneidade Genética , Antígenos HLA-DQ/classificação , Cadeias beta de HLA-DQ , Haplótipos , Hominidae/classificação , Humanos , Complexo Principal de Histocompatibilidade , Dados de Sequência Molecular , Homologia de Sequência do Ácido Nucleico , População Branca/classificação
7.
Diabetes ; 49(3): 504-7, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10868975

RESUMO

Vitamin D has been shown to exert manifold immunomodulatory effects. Because type 1 diabetes is regarded to be immune-mediated and vitamin D prevents the development of diabetes in the NOD mouse, we investigated the role of the vitamin D receptor (VDR) gene as a candidate for type 1 diabetes susceptibility. A total of 152 Caucasian families with at least one affected offspring were genotyped for four VDR restriction-site polymorphisms (FokI, BsmI, ApaI, and TaqI). Whereas the BsmI, ApaI, and TaqI polymorphisms are in strong linkage disequilibrium with each other, no significant linkage disequilibrium with the FokI site was observed. Extended transmission disequilibrium testing (ETDT) was used to detect preferential transmission of allelic combinations to affected offspring. We found significant haplotype-wise ETDT results for the BsmI/ApaI/TaqI (chi2 = 18.886, df = 7, P = 0.0086), the BsmI/TaqI (chi2 = 8.373, df = 3, P = 0.0389), and theApaI/TaqI (chi2 = 17.182, df = 3, P = 0.0006) haplotypes. The "At" and "Bt" alleles confer an increased risk, whereas "AT" and "at" are protective. The combination with the strongest susceptibility was the "BAt" haplotype (64% transmitted, P = 0.0106). Analysis of the FokI site does not provide more information on susceptibility (FokI/BsmI/ApaI/TaqI [chi2 = 24.702, df = 15, P = 0.0541]). These findings suggest a linkage of VDR itself or a nearby gene with type 1 diabetes susceptibility in Germans, confirming respective observations previously made in Indian Asians.


Assuntos
Alelos , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença/genética , Receptores de Calcitriol/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Frequência do Gene , Ligação Genética , Genótipo , Alemanha , Haplótipos , Humanos , Lactente , Masculino , População Branca/genética
8.
Tissue Antigens ; 55(3): 271-4, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10777104

RESUMO

HLA-DR4 is a primary disease association marker in type 1 diabetes mellitus (IDDM). We therefore analyzed the transmission of 228 DR4+ haplotypes in 183 families with an IDDM proband (95 from Germany and 88 from Belgium). In a separate case-control data set, we investigated the HLA-DRB1*04 and DQ allele distribution in 245 IDDM patients and 177 controls from Germany, all DR4 positive. HLA-DRB1 *0401 and *0402 linked to DQB1 *0302 were significantly more often transmitted to patients in the studied families (81% and 89%) in contrast to DRB1 *0401-DQB1 *0301 (33%). The case-control study of HLA-DQB1 *0302+ individuals revealed -DRB1 *0405 to be more frequent in patients with IDDM and HLA-DRB1 *0403 and -DRB1 *0404 to be less frequent. HLA-DQA1 *0102-DQB1 *0602 and -DQA1 *0501-DQB1 *0301 in trans complementation with DRB1 *0401-DQB1 *0302 were also significantly less frequent in IDDM patients (P<3x 10(-7) and P<0.02). In conclusion, HLA-DRB1 *0403 and -DQB1*0301 alleles in cis as well as protective DQ haplotypes in trans, confer dominant protection against IDDM in a German / Belgian population.


Assuntos
Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença/genética , Antígenos HLA-DR/genética , Adolescente , Adulto , Bélgica , Estudos de Casos e Controles , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/imunologia , Suscetibilidade a Doenças , Feminino , Alemanha , Antígenos HLA-DQ , Cadeias alfa de HLA-DQ , Cadeias beta de HLA-DQ , Cadeias HLA-DRB1 , Humanos , Lactente , Masculino
9.
Autoimmunity ; 31(1): 67-72, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10593571

RESUMO

Vitamin D has been shown to modulate the immune system thereby preventing the development of diabetes in NOD mice. Since the vitamin D binding protein (DBP) is the main transporter for vitamin D and DBP has immunomodulatory properties itself, we investigated three polymorphic sites within the DBP gene as candidates for type 1 diabetes susceptibility for the first time. 152 Caucasian families with at least one affected offspring were genotyped for intron 8 [(TAAA)n repeat] and exon 11 (HaeIII, StyI) polymorphisms. Transmission disequilibrium testing was used to detect preferential transmission to affected offspring. We found no significant transmission disequilibrium for DBP alleles. The strongest deviation from expected values was observed for the "10" allele (relative risk = 0.57, transmitted 13 of 36 times (corrected p = 0.249)). Although we cannot exclude an association of the studied DBP alleles with type 1 diabetes at present, these data do not suggest their contribution to this disease in Germans.


Assuntos
Alelos , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença/genética , Desequilíbrio de Ligação/genética , Proteína de Ligação a Vitamina D/genética , Cromossomos Humanos Par 1/genética , Família , Feminino , Alemanha , Haplótipos , Humanos , Masculino , Reação em Cadeia da Polimerase , Polimorfismo Genético , População Branca/genética
10.
Exp Clin Endocrinol Diabetes ; 107(8): 568-9, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10612489

RESUMO

Cystic fibrosis (CF) is one of the most common recessively inherited disorders in Caucasian populations and is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. A three base deletion known as deltaF508 occurs on about 70%, of CF chromosomes and accounts for the high prevalence of the disease. Since type 2 diabetes mellitus occurs more frequently in relatives of patients with CF than in the normal population, we addressed the hypothesis whether heterozygosity for deltaF508 might be a genetic risk factor for type 2 diabetes. We screened 301 patients with type 2 diabetes mellitus which had been treated for at least three years from diagnosis by diet or oral antihyperglycemic agents. Healthy controls (n = 282) had no family history for diabetes. The genotype distribution did not differ significantly between patients with type 2 diabetes (2% heterozygotes) and controls (3% heterozygotes). According to these results, we conclude, that the deltaF508 mutation in its heterozygous form does not represent a major genetic risk factor for type 2 diabetes mellitus.


Assuntos
Fibrose Cística/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Mutação , Índice de Massa Corporal , Fibrose Cística/complicações , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
11.
Exp Clin Endocrinol Diabetes ; 107 Suppl 3: S89-92, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10522814

RESUMO

Type 1 Diabetes mellitus (IDDM) results from an immune-mediated destruction of the pancreatic b-cells. The genetic predisposition is mainly confered by variations within MHC class II region on chromosome 6p as well as the CTLA4 gene located on chromosome 2q33. We analysed the transmission of HLA DQA1, DQB1, DRB1*04 alleles as well as an endogenous retroviral element (DQLTR3) in 130 families with a type 1 diabetic offspring in order to evaluate their role in genetic susceptibility to IDDM. Also the combined transmission of HLA and CTLA4 haplotypes was investigated. MHC class II alleles were typed using sequence-specific primer analysis. The presence or absence of DQLTR3 was defined by a nested PCR approach and CTLA4 microsatellite polymorphisms were detected with fluorescence-labeled primer on an automated sequencing system. By transmission distortion test we confirm the linkage of HLA DQA1*0501 DQB1*0201 (DR3 DQ2) as well as DQA1*0301 DQB1*0302 (DR4 DQ8) with IDDM. Whereas the combination with CTLA4 risk markers leads to the highest transmission rate on DR3 positive haplotypes, the predisposing CTLA4 variant does not modulate the risk on DR4 haplotypes. However, the absence of DQLTR3 on DR3, but its presence on DR4 haplotypes significantly increases the genetic risk for type 1 diabetes. Therefore predisposing MHC class II haplotypes are defined by distinct loci which differentially control genetic susceptibility. The combined transmission of protective CTLA4 and HLA DR3 as well as DR4 haplotypes confirms the dominant role of HLA class II polymorphisms in defining disease susceptibility to type 1 diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Imunoconjugados , Abatacepte , Antígenos CD , Antígenos de Diferenciação/genética , Antígeno CTLA-4 , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Ligação Genética , Predisposição Genética para Doença/genética , Variação Genética , Alemanha , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Antígeno HLA-DR3/genética , Haplótipos , Humanos , Masculino
12.
Tissue Antigens ; 54(3): 291-4, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10519369

RESUMO

The HLA-DMA and HLA-DMB genes are located in the HLA-D region between DQ and DP. Four variants of DMA (DMA*0101-0104) and five of the DMB (DMB*0101-0105) have so far been identified. HLA-DM molecules are required in the process of peptide loading to HLA class II antigens, both regulating the dissociation of class II-associated invariant chain peptides (CLIP) and the subsequent binding of exogenous peptides to HLA class II molecules. In order to investigate the immunogenetic heterogeneity within the HLA-D susceptibility region, we analysed the distribution of DMA alleles in 125 patients with type 1 diabetes mellitus and 90 healthy controls, and of DMB alleles in 102 patients and 89 healthy controls. Patients and controls were all from central Germany. The polymerase chain reaction (PCR) amplified products were purified and separated on a 10% polyacrylamide gel electrophoresis. Among the four recognized DMA alleles, DMA*0102 was significantly less frequent (12% vs. 28.9%, P<0.01) in patients with type 1 diabetes mellitus. DMB*0101 (70.6% vs. 97.8%, P<5.5x10(-3)) was also reduced in frequency compared to controls. Comparing patients and controls positive for the type 1 diabetes high-risk markers we found a significant association between DMA*0102 and DQA*0501 (9.5% vs. 39.1%, P<0.02), as well as DMB*0101 and DQA*0501 (62.5% vs. 96.2%, P<0.03). In conclusion, DMA*0102 and DMB*0101 contribute to genetic protection to type 1 diabetes mellitus in individuals with high-risk DQA markers in the German population.


Assuntos
Alelos , Diabetes Mellitus Tipo 1/genética , Antígenos HLA-D/genética , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos B/genética , Frequência do Gene , Marcadores Genéticos/genética , Predisposição Genética para Doença , Alemanha , Antígenos de Histocompatibilidade Classe II/genética , Humanos
13.
Tissue Antigens ; 53(6): 551-8, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10395105

RESUMO

Long terminal repeats (LTRs) of the human endogenous retrovirus K (HERV-K) family have been found at several sites within the human genome, of which one is located in the vicinity of HLA-DQB1. Since this DQLTR3 is only present on some haplotypes, we performed a linkage analysis in 130 Caucasian families. In order to date the integration event we also investigated the presence of this DQLTR3 in apes and Old World monkeys. Additionally, we sequenced the adjacent region of DQLTR3-positive and -negative haplotypes in humans, apes and old world monkeys to elucidate their evolution. Linkage analysis revealed a differential integration of DQLTR3 on specific HLA-DQ haploypes: there was a high frequency of this LTR on haplotypes containing HLA-DQB1*0302 (0.96) and a moderate frequency on HLA-DQB1*0402 (0.78), HLA-DQB1*0303 (0.44), HLA-DQB1*0502 (0.38) and HLA-DQB1*0301 (0.35). HLA-DQB1*0201 (0.18), HLA-DQB1*0503 (0.15), HLA-DQB1*0603 (0.15), HLA-DQB1*0602 (0.04), HLA-DQB1*0501 (0.03) and HLA-DQB1*0604 were rarely positive or devoid of DQLTR3. In apes and Old World primates there was no DQLTR3 rendering it a human specific insertion. Sequence analysis of the adjacent region showed two different motifs in humans corresponding to either presence or absence of DQLTR3. Two different motifs were observed within three sequences of Macaca mulatta: One motif is closely related to the sequence from Macaca nemestrina and Macaca fascicularis whereas the other sequence is more closely related with that of Papio papio and Cercopithecus aethiops. Therefore the analysis of retroviral elements as well as intronic sequences of MHC-DQB1 could help to clarify the evolution of this gene region as well the phylogenic relationship between humans, apes and Old World monkeys.


Assuntos
Antígenos HLA-DQ/genética , Íntrons/imunologia , Sequências Repetidas Terminais/imunologia , Animais , Sequência de Bases , Cercopithecidae , Segregação de Cromossomos/genética , Retrovirus Endógenos/genética , Evolução Molecular , Cadeias beta de HLA-DQ , Hominidae , Humanos , Dados de Sequência Molecular , Polimorfismo Genético/genética , Alinhamento de Sequência , Homologia de Sequência do Ácido Nucleico , Especificidade da Espécie , População Branca
14.
Z Arztl Fortbild Qualitatssich ; 93 Suppl 1: 11-5, 1999 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-10355043

RESUMO

Graves' disease is exceptional as a disorder of stimulatory autoimmunity in comparison with all other endocrine autoimmunopathies. Research into its pathogenesis has so far focussed on the genetics next to characterisation of antibody-antigen as well as T-lymphocyte interactions. A multigenic predisposition similar to other autoimmune diseases has been proposed. Such polygenic disorders are frequent in the population and require special genetic epidemiological tools to dissect the many gene loci, where polymorphisms are readily detectable by several molecular typing assays. This review presents these tools and methods as well as the currently identified main susceptibility loci in the Human Leukocyte Antigen (HLA DQA1*0501), cytotoxic T-lymphocyte antigen 4 (CTLA4-ala17) as well as interferon-gamma (IFN-gamma *2) regions. Most of these predisposing alleles are shared risk factors in several endocrine autoimmune diseases. Further research is required to identify those gene variants that determine the individual course of thyroid stimulation or destruction.


Assuntos
Doença de Graves/genética , Marcadores Genéticos/genética , Humanos , Fatores de Risco
15.
J Clin Endocrinol Metab ; 84(4): 1404-8, 1999 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10199786

RESUMO

Major genetic susceptibility to type 1 diabetes mellitus maps to the human leukocyte antigen (HLA) region on chromosome 6p. During evolution, endogenous retroviral long terminal repeats (LTR) have been integrated at several sites within this region. We analyzed the presence of a solitary HERV-K LTR in the HLA DQ region (DQ-LTR3) and its linkage to DRB1, DQA1, and DQB1 haplotypes derived from 246 German and Belgian families with a patient suffering from type 1 diabetes mellitus. Segregation analysis of 984 HLA DQA1/B1 haplotypes showed that DQ-LTR3 is linked to distinct DQA1 and DQB1 haplotypes but is absent in others. The presence of DQ-LTR3 on HLA DQB1*0302 haplotypes was preferentially transmitted to patients from heterozygous parents (82%; P < 10(-6)), in contrast to only 2 of 7 DQB1*0302 haplotypes without DQ-LTR3. Also, the extended HLA DRB1*0401, DQB1*0302 DQ-LTR3-positive haplotypes were preferentially transmitted (84%; P < 10(-6)) compared with 1 of 6 DR-DQ matched DQ-LTR3 negative haplotypes. DQ-LTR3 is missing on most DQB1*0201 haplotypes, and those LTR3 negative haplotypes were also preferentially transmitted to patients (80%; P < 10(-6)), whereas DQB1*0201 DQ-LTR3-positive haplotypes were less often transmitted to patients (36%). Other DQA1/B1 haplotypes did not differ for DQ-LTR3 between transmitted and nontransmitted haplotypes. Thus, the presence of DQLTR3 on HLA DQB1*0302 and its absence on DQB1*0201 haplotypes are independent genetic risk markers for type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1/genética , Retrovirus Endógenos/genética , Predisposição Genética para Doença , Antígenos HLA-DQ/genética , Haplótipos , Sequências Repetidas Terminais , Feminino , Heterozigoto , Humanos , Masculino
16.
Hum Immunol ; 60(1): 63-8, 1999 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9952028

RESUMO

Human endogenous retrovirus (HERV) long terminal repeat (LTR) elements contain regulatory sequences that can influence the expression of adjacent cellular genes, which may contribute to breakdowns of the immune function leading to autoimmune disease. Rheumatoid arthritis (RA) is associated with particular HLA-DR/DQ haplotypes that modulate the pathogenesis of this autoimmune disease. We have therefore studied a solitary LTR element (DQ-LTR3) of the HERV-K family at the HLA-DQB1 locus for a possible disease association among 228 RA patients and 311 unrelated blood donors. The DQ-LTR3 was significantly more frequent among patients (76% vs 33%, OR = 5.07,p < 0.0001), with the majority of patients being heterozygous for the DQ-LTR3 (61% vs 22%, p < 0.0001). HLA-DRB1*04 positive patients did still differ for the presence of the DQ-LTR3 (88% vs 70%, OR = 3.03, p < 0.001), with an increase of both DQ-LTR3 homozygous and heterozygous patients, when compared to DRB1*04 positive controls (p = 0.0015). HLA-DR/DQ genotype analysis among HLA-DRB1*04 positive individuals revealed significantly more DQ-LTR3 homozygotes among HLA-DRB1*04-DQBI*03 homozygous patients (72% vs 27%, P = 0.015), and the number of DQ-LTR3 homozygous (23% vs 19%) and heterozygous (66% vs 53%) individuals was also increased among HLA-DRB1*04 heterozygous patients (p = 0.034). The presence of the DQ-LTR3 element increased both the relative risk and the positive predictive value for either DRB1*04-DQB1*03 positive/negative individuals when compared to the presence of HLA-DRB1*04-DQB1*03 alone. In conclusion, these data suggest that this DQ-LTR3 enhances susceptibility to RA.


Assuntos
Artrite Reumatoide/genética , Retrovirus Endógenos/genética , Antígenos HLA-DQ/genética , Sequências Repetidas Terminais , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Predisposição Genética para Doença , Antígenos HLA-DQ/imunologia , Cadeias beta de HLA-DQ , Teste de Histocompatibilidade , Humanos , Pessoa de Meia-Idade
17.
Diabetes ; 48(1): 215-8, 1999 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9892247

RESUMO

Recently, human endogenous retrovirus type K (HERV-K [IDDMK(1,2)22]) was isolated from an IDDM patient's beta-cell supernatant and shown to be implicated in expression as a superantigen. Furthermore, HERV-K RNA was found in plasma samples from newly diagnosed patients but not in those from healthy control subjects. We had earlier identified the presence of a HERV-K long terminal repeat element of the HLA DQ gene (DQ-LTR) to be positively associated with IDDM, which led us to investigate whether DQ-LTR is related to transcription of the putative retroviral superantigen. Additionally, we sought immunological evidence to determine whether those retroviral antigens could evoke an antibody response. Patients with IDDM (n = 14), Hashimoto's thyroiditits (n = 5), and Graves' disease (n = 12), as well as healthy control subjects (n = 12), were investigated, as were four nuclear families of Graves' disease patients and two of IDDM patients. RNA was isolated from plasma and peripheral blood lymphocytes and subjected to reverse transcription-polymerase chain reaction for transcripts of the env region of the HERV-K (IDDMK(1,2)22) sequence. We identified env transcripts in both plasma and peripheral blood lymphocytes in all individuals studied: patients with recent-onset or long-standing IDDM, their relatives, and healthy control subjects, as well as patients with thyroid autoimmune disorders. Furthermore, we screened the sera of patients (n = 62) and control subjects (n = 35) for evidence of humoral immunity against HERV-K by Western blot specific for the ENV protein. Similar frequencies of antibody-positives were observed both in patients with IDDM (29%) and in healthy control subjects (26%). We conclude that neither the ubiquitous HERV-K transcripts nor the comparable percentage of ENV protein antibodies are associated with IDDM. An earlier, presymptomatic antibody response against HERV-K (IDDMK(1,22)22) ENV cannot be ruled out. However, the superantigen hypothesis of an endogenous retrovirus in beta-cell autoimmunity awaits confirmation.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/virologia , RNA Mensageiro/metabolismo , RNA Viral/metabolismo , Retroviridae/metabolismo , Proteínas do Envelope Viral/imunologia , Formação de Anticorpos/fisiologia , Western Blotting , Diabetes Mellitus Tipo 1/genética , Humanos , Valores de Referência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas do Envelope Viral/metabolismo
18.
Thyroid ; 8(11): 1013-7, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9848715

RESUMO

Although some of the susceptibility to Graves' disease is conferred by genes in the human leucocyte antigen (HLA) region on the short arm of chromosome 6, other genetic factors must also predispose. Among the cytokines involved in thyroid autoimmunity interferon-gamma (IFN-gamma) plays a key role in the pathogenesis of Graves' disease. We therefore analyzed the first intron of the IFN-gamma gene for a dinucleotide (CA) repeat polymorphism on chromosome 12q. Two hundred two Caucasian patients with Graves' disease and 214 Caucasian controls were analyzed by polymerase chain reaction (PCR) and subsequent polyacrylamide gel electrophoresis technique: eight different alleles designated as IFN-gamma*1 to IFN-gamma*8 could be differentiated. Among Graves' disease patients IFN-gamma*5 (12.9% vs. 6.8%, p < 0.04) was significantly more frequent whereas IFN-gamma*2 (2.5% vs. 9.8%, p < 0.002) was significantly less frequent. Patients positive for the genetic susceptibility marker HLA DQA1*0501 had significantly more IFN-gamma*3 alleles (13.6% vs. 2.6%, p < 0.009) and IFN-gamma*5 alleles (22.1% vs. 7.6%, p < 0.03) compared with DQA1*0501 positive controls. Also, among patients with endocrine ophthalmopathy IFN-gamma*3 (17.9% vs. 4.2%, p < 8 x 10(-6)) and IFN-gamma*5 (18.9% vs. 7.0%, p < 0.003) were significantly more frequent compared with controls. Although a significant association of IFN-gamma microsatellite polymorphism was observed, only a small proportion of Graves' disease patients have these markers. Thus, it is likely that the detected microsatellite polymorphisms play only a minor role in the susceptibility to Graves' disease.


Assuntos
Doença de Graves/genética , Interferon gama/genética , Repetições de Microssatélites/genética , Polimorfismo Genético/genética , Alelos , Frequência do Gene , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ , Humanos , Valores de Referência
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