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Yaron Tomer

Publications and source records attributed to Yaron Tomer.

31 records · Page 2Linked to original sources
PubMed2003

The etiology of autoimmune diabetes and thyroiditis: evidence for common genetic susceptibility.

Type 1 diabetes (T1D) and the autoimmune thyroid diseases (AITD) are the most common autoimmune endocrine diseases. Both are organ-specific T-cell mediated diseases. Abundant epidemiological data support a strong genetic basis for both T1D and AITD. Furthermore, both diseases commonly occur in the same individuals and in the same families. Indeed, studies suggest that the etiology of T1D and AITD may involve common genetic factors. Two immune regulatory genes, HLA and CTLA-4 contribute to the susceptibility to both diseases. Additionally, two tissue-specific genes, the insulin VNTR in T1D and Thyroglobulin in AITD play a major role in their pathogenesis. Therefore, it is likely that both immune regulatory and target tissue genes contribute to these and other autoimmune diseases.

Antigens, CD↗
PubMed2003

The impact of costimulatory molecule gene polymorphisms on clinical outcomes in liver transplantation.

CTLA-4 and CD28 deliver opposing signals for T-cell proliferation. We examined single nucleotide polymorphisms (SNPs) CTLA-4 -318C/T and CD28 IVS3 +17T/C for associations with acute rejection in liver transplant recipients. These and two other polymorphisms in CTLA-4 [microsatellite polymorphism +642(AT)n and SNP +49 A/G] were also analyzed for influence on graft survival. Two hundred and eleven liver transplant recipient genotypes were determined by direct sequencing or restriction fragment length polymorphism analysis of PCR-amplified genomic DNA. Mean graft survival for patients with the GG genotype of CTLA-4 +49 A/G was 58.5 +/- 6.0 months compared with 70.3 +/- 4.0 months and 73.8 +/- 2.8 months for the AA and AG genotypes, respectively (p = 0.0055). This is in support of previous studies suggesting decreased CTLA-4 function and increased incidence of autoimmune disease for this genotype. The 92-, 94-, and 100-bp alleles of CTLA-4 +642(AT)n occurred more often in African-American transplant recipients and were associated with decreased graft survival (p = 0.0001 and 0.007, respectively) but the independence of these variables could not be established. No associations with acute rejection or graft survival were found for CTLA-4 -318C/T or CD28 IVS3 +17T/C. The described associations between CTLA-4 gene polymorphisms and transplant outcomes provide the foundation for further investigations leading to genetic risk stratification for transplant recipients.

Alleles↗
PubMed2003

Searching for the autoimmune thyroid disease susceptibility genes: from gene mapping to gene function.

The autoimmune thyroid diseases (AITD) are complex diseases that are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility, in combination with external factors (e.g., dietary iodine), is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been used to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked with AITD, and in some of these loci putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD) and Hashimoto's thyroiditis (HT), and some are common to both diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g., human leukocyte antigen, cytotoxic T lymphocyte antigen-4) and thyroid-specific genes (e.g., TSH receptor, thyroglobulin). Most likely these loci interact, and their interactions may influence disease phenotype and severity. It is hoped that in the near future additional AITD susceptibility genes will be identified and the mechanisms by which they induce AITD will be unraveled.

Antigens, CD↗
PubMed2002

CTLA-4 and autoimmune thyroid disease: lack of influence of the A49G signal peptide polymorphism on functional recombinant human CTLA-4.

A single nucleotide A49G polymorphism (SNP) of CTLA-4 has been linked and associated with the autoimmune thyroid diseases (AITD) and thyroid autoantibody secretion. We have explored the functional mechanisms of CTLA-4 by means of recombinant human CTLA-4 expressed on transfected Jurkat T cells. Analysis of CTLA-4 transcripts with quantitative real-time PCR demonstrated similar baseline and PHA-stimulated levels for both the A49 and G49 alleles, which were markedly enhanced by anti-CTLA-4 engagement. Both alleles also coded for proteins which were expressed on the cell membrane, as measured by FACS analysis using anti-CTLA-4 (G: 34.4+/-11.9% cells, A: 27.6+/-8.6% cells) (p=ns). Baseline and PHA-stimulated IL-2 production were also similar among control and CTLA-4 clones expressing both alleles. After anti-CTLA-4 engagement, IL-2 production was markedly inhibited in a dose- and time-dependent manner but this also appeared to be similar in the A and G allele expressing cells (95.7+/-1.2% inhibition and 94.9+/-1.1% inhibition, respectively). In conclusion, both the extrinsic and intrinsic actions of human CTLA-4 were not affected by the signal peptide A49G polymorphism. Therefore, the linkage of the CTLA-4 A49G SNP to AITD is most likely secondary to linkage disequilibrium.

Abatacept↗
PubMed2002

A C/T single nucleotide polymorphism at the tyrosine kinase domain of the insulin receptor gene is associated with polycystic ovary syndrome.

OBJECTIVE: To examine whether the insulin receptor (INSR) gene contributes to genetic susceptibility to the polycystic ovary syndrome (PCOS). DESIGN: Case-control study. SETTING: Academic endocrinology clinic. PATIENT(S): Ninety-nine women with PCOS as defined by the National Institutes of Health consensus and polycystic ovaries on ultrasonography, and 136 healthy controls. MAIN OUTCOME MEASURE: Frequency of genotypes of a single nucleotide polymorphism of the INSR gene in patients and controls. RESULT(S): After stratification of participants by body mass index, the frequency of the uncommon T allele of the INSR single nucleotide polymorphism was significantly increased in lean patients with PCOS (body mass index < or =27 kg/m2) compared with lean controls (relative risk, 2.1). CONCLUSION(S): The INSR gene is a susceptibility gene for PCOS among lean patients with PCOS. It remains to be determined whether the exon 17 C/T single nucleotide polymorphism is the susceptibility single nucleotide polymorphism for PCOS or whether it is in linkage disequilibrium with another INSR gene polymorphism.

Adolescent↗
PubMed2002

Genetic dissection of familial autoimmune thyroid diseases using whole genome screening.

The autoimmune thyroid diseases (AITDs) are multifactorial disease which are caused by genetic susceptibility and environmental triggers. Various epidemiological and genetic techniques can be employed to study the genetic contribution to disease development. Most epidemiologic data support an important genetic contribution to the development of AITD. The genetic susceptibility to AITD involves several genes with varying effects. Some AITD susceptibility genes are most likely immune modifying genes which increase the susceptibility to autoimmunity in general (e.g. HLA, CTLA-4) while others may be thyroid-specific (e.g. thyroglobulin). These genes probably act in concert to increase the autoimmune reactions in susceptible individuals and direct them towards the thyroid.

Abatacept↗
PubMed2002

The influence of human leucocyte antigen (HLA) genes on autoimmune thyroid disease (AITD): results of studies in HLA-DR3 positive AITD families.

OBJECTIVE: Population-based, case-control studies have consistently shown association of Graves' disease (GD) with human leucocyte antigen (HLA)-DR3 in Caucasian populations. HLA association studies in Hashimoto's thyroiditis (HT) have also suggested an association with DR3, as well as with other HLA alleles. In contrast, HLA linkage studies in autoimmune thyroid disease (AITD) have been largely negative. The aim of the present study was to investigate the role of HLA in AITD and to explain the observed associations, but lack of linkage, by examining only AITD families with the associated allele, DR3. PATIENTS: We studied 99 probands (60 with GD and 39 with HT) from 99 multiplex, multigenerational Caucasian AITD families, and 135 age- and sex-matched Caucasian controls in association studies. In addition, a dataset of 34 Caucasian AITD families (out of the 99 families) with HLA-DR3 positive probands were analysed in linkage studies. DESIGN: HLA typing was performed using the technique of group-specific polymerase chain reaction-amplification with restriction enzyme digestion. Whole genome screening was performed using the ABI microsatellite panels. For fine mapping of the HLA region, we used the following markers: D6S276, D6S464, D6S439, D6S273, tumour necrosis factor alpha and D6S1610. LOD scores were calculated using the LIPED and GeneHunter programs. RESULTS: Case-control association analyses using the probands from our 99 Caucasian families showed an association of GD with DRB1*03 [P = 0.00032, relative risk (RR) = 3.4]. Linkage analysis for the HLA region in the 34 DR3 positive AITD families showed negative LOD scores throughout the region. The two-point LOD score at marker D6S273 (the closest to HLA-DRB1) was -3.0, and the multipoint LOD score was -7.6, demonstrating strong evidence against linkage to the HLA region in the subset of DR3 positive families. Whole genome screening in the subset of 34 DR3 positive families revealed one locus showing evidence for linkage to AITD: D3S1580 on chromosome 3q27 with a maximum two-point LOD score of 2.1. CONCLUSIONS: The HLA locus did not cosegregate with disease in DR3 positive families, suggesting that HLA genes are not major genes for AITD expression even within DR3 positive families; Hence, although HLA-DR3 was associated with GD in the probands, it was most likely a modulating gene and not causative; and, as the DR3 positive families showed evidence for linkage with D3S1580, it may imply that the DR3 gene modulated the effect of a susceptibility gene within the D3S1580 locus.

Case-Control Studies↗
PubMed2002

A germline single nucleotide polymorphism at the intracellular domain of the human thyrotropin receptor does not have a major effect on the development of Graves' disease.

Graves' disease (GD) is caused by an interplay of genetic factors and environmental triggers. The major antigen in GD is the thyrotropin receptor (TSHR) on the surface of the thyroid epithelial cell. Population-based case-control studies have largely shown no association of GD with the D36H (Asp to His) and P52T (Pro to Thr) single nucleotide polymorphisms (SNPs) in the N-terminal region of the extracellular domain of the TSHR gene in Caucasian populations. Recently, a D727E (Asp to Glu) SNP in the intracellular C-terminal domain of the TSHR was reported to be associated with GD in a Russian population. In the present study we assessed whether the codon 727 SNP is associated with GD in a Caucasian population. We found no significant differences in codon 727 SNP frequencies between GD patients and controls. In addition, our results did not show an effect of the SNP on the GD phenotype and on disease severity. Further analysis showed no evidence that the TSHR 727 SNP modulated the risk for GD conferred by HLA (DR3) and/or CTLA-4 (SNP 49 G allele) genes. A meta-analysis combining our data and those of 2 previous studies showed a very weak association between the D727E SNP and GD (p = 0.03, relative risk = 1.6). Therefore, we concluded that the TSHR gene is not a major gene for GD in our population.

Gene Expression↗
PubMed2002

A C/T single-nucleotide polymorphism in the region of the CD40 gene is associated with Graves' disease.

Graves' disease (GD) develops as a result of an interaction between susceptibility genes and environmental factors. We have previously mapped a susceptibility locus for GD on chromosome 20q11 (GD-2), which has recently been independently replicated. Among the genes mapped to 20q11 was the CD40 gene, an important costimulatory molecule and a good positional candidate gene for GD. We investigated whether the CD40 gene was the GD susceptibility gene on 20q11. Linkage analysis in a subset of Caucasian families showed a maximum multipoint logarithm of odds (LOD) score of 3.3 at the CD40 locus. We then sequenced all 9 exons of the CD40 gene in 8 probands and 10 controls and identified a new C/T single-nucleotide polymorphism (SNP) in the Kozak sequence of the CD40 gene at position -1. Case control association analysis of the CD40 C/T(-1) SNP in 154 Caucasian patients with GD and 118 Caucasian controls showed an association between the CC genotype and GD (p = 0.048, relative risk [RR] = 1.6). Furthermore, the association was stronger when only the probands from the linked families (n = 20) were used (p = 0.009, RR = 4.8). Transmission disequilibrium test (TDT) analysis also showed preferential transmission of the C allele of the CD40 C/T(-1) SNP to affected individuals (p = 0.02). In conclusion, our results suggested that the CD40 gene was a new susceptibility gene for GD within certain families because it was both linked and associated with GD.

CD40 Antigens↗
PubMed2002

Thyroglobulin is a thyroid specific gene for the familial autoimmune thyroid diseases.

The autoimmune thyroid diseases (AITDs) develop as a result of a complex interaction between predisposing genes and non-genetic factors. We have completed a whole genome scan in 56 families which revealed 7 major AITD loci (LOD scores >2), and additional minor loci (LOD scores >1). One of the minor loci was on chromosome 8q24 giving a maximum LOD score (MLS) of 1.8 at marker D8S284. This locus contained the thyroglobulin (Tg) gene which was a strong candidate gene for AITD. Because of this we analyzed the Tg gene region in detail using an expanded dataset of 102 families. The new linkage analysis showed stronger evidence for linkage at the Tg gene locus with an MLS of 3.5 between markers D8S514 and D8S284 (NPL = 2.0). We then proceeded to analyze the Tg gene directly. We identified a new microsatellite inside intron 27 of the Tg gene (designated Tgms2). Tgms2 showed strong evidence for linkage with AITD (MLS = 2.9), further suggesting that the Tg gene was linked to AITD. Association studies comparing 224 Caucasian AITD patients to 134 Caucasian controls showed an association of Tgms2 with AITD (p = 0.05, relative risk [RR] = 1.4). The association was stronger when only the probands from the linked families (n = 32) were used (p = 0.004, RR = 2.3). Transmission disequilibrium test (TDT) analysis also showed an association of Tgms2 with AITD (p = 0.02). We concluded therefore that the Tg gene was a major AITD susceptibility gene because it was both linked and associated with AITD.

Case-Control Studies↗
PubMedDate not supplied

The contribution of immune regulatory and thyroid specific genes to the etiology of Graves' and Hashimoto's diseases.

The autoimmune thyroid diseases (AITD) are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine) are believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked with AITD, and in some of these loci putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD) and Hashimoto's thyroiditis (HT) and some are common to both diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4) and thyroid specific genes (e.g. TSHR, Tg). Most likely these loci interact and their interactions may influence disease phenotype and severity.

Antigens, CD↗
PubMedDate not supplied

The effects of alpha interferon on the development of autoimmune thyroiditis in the NOD H2h4 mouse.

Alpha interferon (alphaIFN) therapy is known to induce thyroid autoimmunity in up to 40% of patients. The mechanism is unknown, but Th1 switching has been hypothesized. The aim of our study was to examine whether alphaIFN accelerated the development of thyroiditis in genetically susceptible mice. We took advantage of NOD-H2h4, a genetically susceptible animal model, which develops thyroiditis when fed a high iodine diet. Six to eight week old male NOD H2h4 mice were injected with mouse alphaIFN (200 units) or with saline three times a week for 8 weeks. All mice drank iodinated water (0.15%). Mice were sacrificed after 8 weeks of injection. Their thyroids were examined for histology and blood was tested for antithyroglobulin antibody levels. T4 and glucose levels were also assessed. In the IFN-injected group, 6/13 (46.2%) developed thyroiditis and/or thyroid antibodies while in the saline-injected group, only 4/13 (30.8%) developed thyroiditis and/or thyroid antibodies (p = 0.4). The grade of thyroiditis was not different amongst the two groups. None of the mice developed clinical thyroiditis or diabetes mellitus. Our results showed that alphaIFN treatment did not accelerate thyroiditis in this mouse model. This may imply that alphaIFN induces thyroiditis in a non-genetically dependent manner, and this would not be detected in a genetically susceptible mouse model if the effect were small. Alternatively, it is possible that alphaIFN did not induce thyroiditis in mice because, unlike in humans, in mice alphaIFN does not induce Th1 switching.

Animals↗