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K Badenhoop

Publications and source records attributed to K Badenhoop.

At least 55 records · Page 3Linked to original sources
PubMed1998

Interferon-gamma gene microsatellite polymorphisms in patients with Graves' disease.

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.

Alleles↗
PubMed1998

Graves' hyperthyroidism after postpartum thyroiditis.

Two Caucasian patients are described who had destructive postpartum thyroiditis (PPT) before the subsequent onset of Graves' hyperthyroidism (GH). HLA class II DQ typing in these two subjects identified putative susceptibility alleles previously detected in GH and PPT. Although PPT destructive thyroiditis preceding the development of GH is relatively uncommon, the occurrence of both these syndromes in the same patient suggests the possibility of an etiological role for thyroid antigen release and genetic susceptibility as pathogenic factors in the development of Graves' disease.

Abortion, Therapeutic↗
PubMed1998

Adrenal insufficiency after recurrent post-partum thyroiditis (post-partum Schmidt syndrome): a case report.

Polyglandular autoimmune syndrome (PGAS) type 2 (Schmidt syndrome) is characterized by the association of primary adrenocortical insufficiency with autoimmune thyroid disease, and/or insulin-dependent diabetes mellitus (IDDM). In this report we describe the occurrence of two episodes of post-partum thyroiditis (PPT) after a first and second pregnancy as well the development acutely of adrenal insufficiency after a second pregnancy. A family history of autoimmune thyroid disease and IDDM as well as positive antiadrenal and antithyroid antibodies and HLA typing is evidence for an underlying polyendocrine autoimmune syndrome. This case report provides further evidence that the immune system that is suppressed in pregnancy to tolerate the fetal allograft can rebound post-partum to unmask polyendocrine autoimmune disorders such as adrenalitis and PPT in susceptible women.

Adrenal Glands↗
PubMed1998

CTLA4 codon 17 dimorphism in patients with rheumatoid arthritis.

The genetic susceptibility to rheumatoid arthritis is conferred by genes in the human leukocyte antigen (HLA) region on chromosome 6, but additional genes may be involved to determine disease susceptibility. We have studied the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in rheumatoid arthritis. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, SSCP and RFLP in 258 Caucasian rheumatoid arthritis patients and 456 controls. Rheumatoid arthritis patients were characterized by a decreased frequency of homozygotes for the Thr-17 substitution (32% versus 39%) and an overrepresentation of patients heterozygous for the Thr/Ala substitution (54% versus 46%). Gene frequencies for the Ala/Thr substitution differed only marginally from controls. In contrast, analyses of the CTLA4 exon 1 polymorphism with respect to HLA-DRB1*04 revealed significantly more patients with Ala in the homozygous (19% versus 15% controls) or heterozygous state (54% versus 39% controls) and less homozygous for Thr (27% versus 46% controls), with a particular increase of Ala/Ala genotypes among rheumatoid arthritis patients carrying the HLA-DRB1*0401 subtype. Among HLA-DRB1*04 negative rheumatoid arthritis patients, we observed no difference between the allele frequencies of the Ala-17 or Thr-17 substitution.

Abatacept↗
PubMed1998

CTLA-4 promoter variants in patients with Graves' disease and Hashimoto's thyroiditis.

Graves' disease (GD) and Hashimoto's thyroiditis (HT) are T-cell mediated organ-specific autoimmune disorders with a genetic predisposition. The cytotoxic T-lymphocyte antigen 4 (CTLA-4) molecule is the predominant receptor for B7 on activated T cells and represents a negative regulator for T-cell function. Since the CTLA-4-guanine at position 49 of exon 1 is associated with susceptibility to GD as well as to HT and IDDM, we investigated a recently detected cytosine/thymine substitution at position -318 within the CTLA-4 promoter region in patients with GD and HT. 125 patients with GD were significantly more often homozygous for cytosine (86% vs. 73% in controls, P=0.006) and less frequently heterozygous for cytosine and thymine (14% vs. 27%, P=0.008). In 64 patients with HT, the distribution was similar but not significant (81% homozygous for cytosine and 16% heterozygous). When correlating the promoter and the exon 1 polymorphism we found the strongest linkage between thymine (promoter) and adenine (exon 1). In conclusion, a promoter variant of the CTLA-4 gene represents an additional risk marker for GD and HT, but their predisposition is linked to the exon 1 alleles.

Abatacept↗
PubMed1997

Polymorphisms of TAP1 and TAP2 genes in German patients with type 1 diabetes mellitus.

Type 1 diabetes mellitus (IDDM) is an autoimmune disorder in which the alleles HLA DQA1*0501-DQB1*0201 and DQA1*0301-DQB1*0302 confer strong susceptibility. The genes for transporters associated with antigen processing (TAP1 and TAP2) are located near HLA DQ and display only a limited degree of polymorphism. Since polymorphisms of TAP might influence susceptibility to IDDM possibly by selection of different antigen peptides, we investigated sequence variants of TAP1 and TAP2 genes in 120 German patients with IDDM and 218 random healthy German controls by polymerase chain reaction (PCR) followed by sequence-specific oligonucleotide analysis (SSO), single-strand conformation polymorphism (SSCP) analysis and amplification refractory mutation system (ARMS). TAP1*02011 (16% vs. 4% in controls, P = 0.001, RR = 5.0) and TAP2*0101 (96% vs. 69% in controls, P < 0.0001, RR = 10.6) showed a positive association with IDDM. However, these associations disappeared when patients and controls were matched for predisposing HLA DQA1 or DQB1 alleles as well as for DRB1*0401. In conclusion, our findings indicate that the observed association of TAP variants with IDDM in German patients is due to linkage disequilibrium with HLA DQ alleles/DRB1*04 subtypes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Polymorphisms of TAP1 and TAP2 genes in Graves' disease.

Graves' disease is an autoimmune disorder in which HLA DQA1*0501 and DQB1*0201 confer predisposition. The genes for transporters associated with antigen processing (TAP1 and TAP2) locate near to HLA DQ coding regions and display only a limited degree of polymorphism. Since polymorphisms of TAP might influence susceptibility to Graves' disease by a possibly different selection of antigenic peptides, we investigated sequence variants of TAP1 and TAP2 genes in 235 patients with Graves' disease and 218 random healthy controls by polymerase chain reaction (PCR) followed by sequence specific oligonucleotide analysis (SSO), single strand conformational polymorphism (SSCP) analysis and amplification refractory mutation system (ARMS). TAP1*0301 (Val-333/Asp-637: 71% vs. 55% in controls, p < 0.008, RR = 2.05) and TAP2*0101 (Val-379/Ala-565/Thr-665/stop-687: 83% vs. 69% in controls, p < 0.03, RR = 2.20) showed a positive association with Graves' disease whereas TAP1*0401 a negative (Ile-333/Gly-637: 4% vs. 13% in controls, p < 0.01, RR = 0.25). After selection of patients and controls for HLA DQA1*0501 a similar association was found for TAP1*0301 (72% vs. 50% in controls, p < 0.02, RR = 2.63) and TAP1*0401 (4% vs. 16% in controls, p < 0.04, RR = 0.22), when matching for HLA DQB1*0201 as well as for TAP1*0401 (3% vs. 16% in controls, p < 0.05, RR = 0.18). Our findings indicate that the positive association of TAP1*0301 and the negative of TAP1*0401 with Graves' disease cannot only be explained by linkage disequilibrium between TAP alleles and HLA DQ. Therefore, these TAP alleles contribute to genetic susceptibility in Graves' disease as additional permissive and protective factors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Polymorphisms of tumor necrosis factor receptor 2 are not associated with insulin-dependent diabetes mellitus or Graves' disease.

Insulin-dependent diabetes mellitus (IDDM) and Graves' disease (GD) are autoimmune endocrinopathies and associated with distinct HLA-DR and -DQ alleles as well as several tumor necrosis factor alpha (TNF-alpha) and beta (TNF-beta) alleles. TNF-alpha and TNF-beta interact with TNF receptor (TNF-R), of which two subtypes have been described: TNF-R1 and TNF-R2. We investigated TNF-R2 alleles in 90 patients with IDDM, 101 with GD and 70 healthy controls. Genomic DNA was amplified with specific flanking primers for the untranslated 3' region of TNF-R2. SSCP analysis revealed two alleles by different fragment patterns: TNF-R2*1 and TNF-R2*2. Patients with IDDM or Graves' disease and controls did not differ significantly: TNF-R2*1/*1:IDDM(8%)/GD(2%)/KO(4%); TNF-R2*2/*2:IDDM(34%)/GD(48%)/KO(42%), heterozygosity TNF-R2*1/*2:IDDM(58%)/GD(50%)/KO(54%) (IDDM vs KO: P=0.46, chi2=1.57; GD vs KO: P=0.59, chi2=1.05). In conclusion, the studied polymorphism of TNF-R2 was associated with neither IDDM nor GD in a German population.

Alleles↗
PubMed1997

Highly polymorphic promoter regions of HLA DQA1 and DQB1 genes do not help to further define disease susceptibility in insulin-dependent diabetes mellitus.

HLA DQA1, HLA DQB1 genes confer susceptibility to insulin-dependent (type 1) diabetes mellitus (IDDM). Since variants of their upstream regulatory regions are linked to the exons, we investigated their promoter polymorphisms (QAP and QBP) by a combination of PCR-based typing protocols in 136 IDDM patients, 167 controls and 6 families with an IDDM proband to identify possible additional susceptibility markers. Of major interest for IDDM susceptibility are the promoter "splits" of HLA DQA1*0301 (QAP3.1 and QAP3.2) and HLA DQB1*0302 (QBP3.2 and QBP3.3). QAP 3.1 (96% in patients vs 98% in controls) and QBP3.2 (100% vs 99%) were found to be the most frequent promoter variants for HLA DQA1*0301 and DQB1*0302, respectively, whereas QAP3.2 and QBP3.3 were very rare. Furthermore the promoter "splits" were equally distributed on the respective exon alleles in all groups and cosegregated in families as expected. In conclusion, HLA DQ-mediated susceptibility and protection in IDDM is not restricted to the exon but extends to the promoter region without further defining the genetic risk.

Diabetes Mellitus, Type 1↗
PubMed1997

CTLA4 alanine-17 confers genetic susceptibility to Graves' disease and to type 1 diabetes mellitus.

The genetic susceptibility to Graves' disease and type 1 (insulin-dependent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other genes are presumed to determine disease susceptibility. Among those candidate genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in Graves' disease and IDDM. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, single strand conformation polymorphism, and restriction fragment length polymorphism analysis in 305 patients with Graves' disease, 293 patients with IDDM, and 325 controls. Patients with Graves' disease had significantly more Ala alleles than controls, both as homozygotes (21% vs. 13%) and as heterozygotes (53% vs. 46%), and less Thr as homozygotes (26% vs. 42%; P < 2 x 10(-4). The phenotypic frequency of Ala-positive patients (73%) was significantly higher than of controls (58%; P = 10(-4); relative risk = 2). Patients with IDDM also had significantly more Ala alleles as homozygotes (19%) or heterozygotes (50%; P = 0.01). In conclusion, an alanine at codon 17 of CTLA4 is associated with genetic susceptibility to Graves' disease as well as to IDDM.

Abatacept↗
PubMed1997

Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto's thyroiditis and Addison's disease.

Endocrine autoimmune disorders share susceptibility and resistance factors of the human leukocyte antigen system on the short arm of chromosome 6, but other gene loci also contribute to predisposition and protection. Because the cytotoxic T lymphocyte antigen 4 (CTLA4) alanine-17 encoded by the CTLA4 gene on chromosome 2q33 confers susceptibility to Graves' disease, as well as to type 1 (insulin-dependent) diabetes mellitus, we investigated this dimorphism in the other endocrine autoimmune disorders: Hashimoto's thyroiditis and Addison's disease. We analyzed the CTLA4 exon 1 polymorphism (49 A/G) in 73 patients with Hashimoto's thyroiditis, 76 with Addison's disease, and 466 healthy controls. This dimorphism corresponds to an aminoacid exchange (Thr/Ala) in the leader peptide of the expressed protein. CTLA4 alleles were defined by PCR, single-strand conformational polymorphism analysis, and restriction fragment length polymorphism analysis using BbvI. Patients with Hashimoto's thyroiditis had significantly more Ala alleles than controls, both as homozygotes (22% vs. 15%) and heterozygotes (53% vs. 46%), and less Thr than controls as homozygotes (25% vs. 39%), P < 0.04. The phenotypic frequency for Ala was significantly higher in patients (75%), compared with controls (61%), P < 0.03. Patients with Addison's disease did not differ significantly from controls, but those carrying the suceptibility marker, human leukocyte antigen DQA1*0501, were significantly more CTLA4 Ala17 positive than controls with the same DQA1 allele (P < 0.05). In conclusion, an alanine at codon 17 of CTLA4 confers genetic susceptibility to Hashimoto's thyroiditis, whereas this applies only to the subgroup of DQA1*0501+ patients with Addison's disease.

Abatacept↗
PubMed1996

Endogenous retroviral long terminal repeats of the HLA-DQ region are associated with susceptibility to insulin-dependent diabetes mellitus.

HLA-DQ genes are the main inherited factors predisposing to IDDM. This gene region harbors long terminal repeat (DQ LTR) elements of the human endogenous retrovirus HER V-K, which we analyzed for a possible association with disease. We first investigated whether LTR segregate with DQ alleles in families. Members (n = 110) of 29 families with at least one diabetic child, unrelated patients with IDDM (n = 159), and healthy controls (n = 173) were analyzed. Genomic DNA was amplified for DQ LTR3 by a nested primer approach as well as for DQA1 and DQB1 second exons, to assign DQA1 and DQB1 alleles. DQ LTR segregated in 24 families along with DQ alleles. Of the 29 families, 20 index patients were positive for DQ LTR. The DQ LTR was in all patients on the haplotype carrying the DQA1 *0301 and DQB1 *0302 alleles. A majority of patients had DQ LTR (62%) compared with controls (38%) (p < 1.3 x 10(-5)), even after matching for the high-risk alleles DQA1 *0501, DQB1 *0201-DQA1 *0301, and DQB1 *0302 (79% of patients and 48% of controls; p < 0.02). Subtyping for DRB1 *04 alleles in all DQB1 *0302+ individuals showed 56% DRB1 *0401, DQB1 *0302 [LTR' patients vs. 29% controls with the same haplotype (p < 0.002)]. In conclusion, these data demonstrate the segregation of DQ LTR with DQA1, DQB1 alleles on HLA haplotypes. Furthermore their presence on DRB1 *0401-, DQA1 *0301-, and DQB1 *0302-positive haplotypes suggest that they contribute to DQ-related susceptibility for IDDM.

Diabetes Mellitus, Type 1↗
PubMed1996

Genetic markers in diagnosis and prediction of relapse in Graves' disease.

Hyperthyroidism of Graves' disease takes an unpredictable clinical course in the long-term follow-up. Whereas roughly 30-60% of patients relapse after their first antithyroid drug treatment, the likelihood of remission in the remaining group can not be foreseen. We have analysed-retrospectively-patients with Graves' disease that had been on antithyroid drug treatment for one year and were followed up thereafter. Patients were investigated for a variety of clinical parameters like ophthalmopathy status and relapse or remission as well as gene polymorphisms of the HLA and other regions. Of the 259 patients analysed so far, patients with ophthalmopathy did not differ from those without for HLA DQA1 and CTLA4 alleles tested. Also, the subgroup of patients with relapses after antithyroid drug treatment showed no different distribution of those alleles from the group with long-term remission. This study also confirms that the allele HLA DQA1* 0501 confers susceptibility to Graves' disease, furthermore, that the CTLA4-alanine 17 allele is an additional predisposing factor.

Abatacept↗