| 1. |
- Jonsdottir, Berglind, et al.
(författare)
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Childhood thyroid autoimmunity and relation to islet autoantibodies in children at risk for type 1 diabetes in the diabetes prediction in skåne (DiPiS) study
- 2018
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 51:5, s. 228-237
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim was to determine prevalence and age at seroconversion of thyroid autoimmunity in relation to islet autoantibodies, gender and HLA-DQ genotypes in children with increased risk for type 1 diabetes followed from birth. Methods: In 10-year-old children (n = 1874), blood samples were analysed for autoantibodies against thyroid peroxidase (TPOAb), thyroglobulin (TGAb), glutamic acid decarboxylase 65 (GADA), Zink transporter 8 (ZnT8R/W/QA), insulinoma-associated protein-2 (IA-2A), insulin (IAA) and HLA-DQ genotypes. Prospectively collected samples from 2 years of age were next analysed for TPOAb, and TGAb and, finally, in confirming samples at 11–16 years of age along with TSH and FT4. Frequencies were tested with Chi-square or Fischer’s exact tests, autoantibody levels with Wilcoxon and correlations between autoantibody levels with Spearman’s rank correlation test. Results: The prevalence of thyroid autoimmunity was 6.9%, overrepresented in girls (p <.001) also having higher TPOAb levels at 10 years (p =.049). TPOAb was associated with GADA (p =.002), ZnT8R/W/QA (p =.001) and IA-2A (p =.001) while TGAb were associated with ZnT8R/W/QA (p =.021). In boys only, TPOAb were associated with GADA (p =.002), IA-2A (p =.001), ZnT8R/W/QA (p =.001) and IAA (p =.009), and TGAb with GADA (p =.013), IA-2A (p =.005) and ZnT8R/W/QA (p =.003). Levels of IA-2A correlated to both TPOAb (p =.021) and to TGAb (p =.011). In boys only, levels of GADA and TGAb correlated (p =.009 as did levels of IA-2A and TPOAb (p =.013). The frequency and levels of thyroid autoantibodies increased with age. At follow-up, 22.3% had abnormal thyroid function or were treated with thyroxine. Conclusions: Thyroid autoimmunity and high TPOAb levels were more common in girls. In contrast, in boys only, there was a strong association with as well as correlation between levels of thyroid and islet autoantibodies. It is concluded that while girls may develop autoimmune thyroid disease (AITD) independent of islet autoantibodies, the risk for thyroid disease in boys may be linked to concomitant islet autoimmunity.
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| 2. |
- Laine, Antti-Pekka, et al.
(författare)
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Two insulin gene single nucleotide polymorphisms associated with type 1 diabetes risk in the Finnish and Swedish populations
- 2007
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Ingår i: Disease Markers. - : Hindawi Limited. - 0278-0240 .- 1875-8630. ; 23:3, s. 139-45
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Tidskriftsartikel (refereegranskat)abstract
- We have developed high-throughput tests for the detection of the insulin gene region SNPs -23HphI and -2221MspI. The potential of these markers to enhance the efficiency of type 1 diabetes risk screening was then evaluated by analyzing them in Finnish and Swedish populations. Blood spots on filter paper were analyzed using PCR followed by sequence-specific hybridization and time-resolved fluorometry reading. Distribution of the genotypes at both positions differed significantly among the affected children compared to the controls. The risk genotypes (CC, AA) were significantly more common in Finland than in Sweden, both among patients and controls. The VNTR genotype homozygous for the protective class III alleles showed a significantly stronger protective effect than the heterozygote (p=0.02). Analyzing both SNPs enabled the detection of VNTR class III subclasses IIIA and IIIB. The observed significance between effects of the protective genotypes was due to the strong protective effect of the IIIA/IIIA genotype. IIIA/IIIA was the only genotype with significant discrepancy between protective effects compared to the other class III genotypes. These observations suggest that heterogeneity between the protective IDDM2 lineages could exist, and analyzing both -23HphI and -2221MspI would thus potentially enhance the sensitivity and specificity of type 1 diabetes risk estimation.
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| 3. |
- Wester, Axel, et al.
(författare)
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An Increased Diagnostic Sensitivity of Truncated GAD65 Autoantibodies in Type 1 Diabetes May Be Related to HLA-DQ8
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 66:3, s. 735-740
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Tidskriftsartikel (refereegranskat)abstract
- N-terminally truncated (96-585) GAD65 (tGAD65) autoantibodies may better delineate type 1 diabetes than full-length GAD65 (fGAD65) autoantibodies. We aimed to compare the diagnostic sensitivity and specificity between fGAD65 and tGAD65 autoantibodies for type 1 diabetes in relation to HLA-DQ. Sera from children and adolescents with newly diagnosed type 1 diabetes (n = 654) and healthy control subjects (n = 605) were analyzed in radiobinding assays for fGAD65 (fGADA), tGAD65 (tGADA), and commercial (125)I-GAD65 (RSRGADA) autoantibodies. The diagnostic sensitivity and specificity in the receiver operating characteristic curve did not differ between fGADA and tGADA. At the optimal cutoff, the diagnostic sensitivity for fGADA was lower than tGADA at similar diagnostic specificities. In 619 patients, 64% were positive for RSRGADA compared with 68% for fGADA and 74% for tGADA. Using non-DQ2/non-DQ8 patients as reference, the risk of being diagnosed with fGADA and tGADA was increased in patients with DQ2/2 and DQ2/8. Notably, logistic regression analysis suggested that DQ8/8 patients had an increased risk to be diagnosed with tGADA (P = 0.003) compared with fGADA (P = 0.09). tGADA had a higher diagnostic sensitivity for type 1 diabetes than both fGADA and RSRGADA. As DQ8/8 patients represent 10-11% of patients with newly diagnosed type 1 diabetes <18 years of age, tGADA analysis should prove useful for disease classification.
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| 4. |
- Aglago, Elom K., et al.
(författare)
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A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
- 2023
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Ingår i: Cancer Research. - : American Association For Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 83:15, s. 2572-2583
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer.SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
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| 5. |
- Akhtar, Monira, et al.
(författare)
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Cell type and context-specific function of PLAG1 for IGF2 P3 promoter activity
- 2012
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Ingår i: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 41:6, s. 1959-1966
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Tidskriftsartikel (refereegranskat)abstract
- The fetal transcription factor PLAG1 is found to be overexpressed in cancers, and has been suggested to bind the insulin like growth factor 2 (IGF2) P3 promoter, and to activate the IGF2 gene. The expression of IGF2 has partly been linked to loss of CTCF-dependent chromatin insulator function at the H19 imprinting control region (ICR). We investigated the role of PLAG1 for IGF2 regulation in Hep3B and JEG-3 cell lines. Chromatin immunoprecipitation revealed cell type-specific binding of PLAG1 to the IGF2 P3 promoter, which was substantially insensitive to recombinant PLAG1 overexpression in the endogenous context. We hypothesized that the H19 chromatin insulator may be involved in the cell type-specific PLAG1 response. By using a GFP reporter gene/insulator assay plasmid construct with and without the H19 ICR and/or an SV40 enhancer, we confirm that the effect of the insulator is specifically associated with the activity of the IGF2 P3 promoter in the GFP reporter system, and furthermore, that the reporter insulator is functional in JEG-3 but not in Hep3B cells. FACS analysis was used to assess the function of PLAG1 in low endogenously expressing, but Zn-inducible stable PLAG1 expressing JEG-3 cell clones. Considerable increase in IGF2 expression upon PLAG1 induction with a partial insulator overriding activity was found using the reporter constructs. This is in contrast to the effect of the endogenous IGF2 gene which was insensitive to PLAG1 expression in JEG-3, while modestly induced the already highly expressed IGF2 gene in Hep3B cells. We suggest that the PLAG1 binding to the IGF2 P3 promoter and IGF2 expression is cell type-specific, and that the PLAG1 transcription factor acts as a transcriptional facilitator that partially overrides the insulation by the H19 ICR.
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| 6. |
- Andersson Svärd, Agnes, et al.
(författare)
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Decreased HLA-DQ expression on peripheral blood cells in children with varying number of beta cell autoantibodies
- 2020
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Ingår i: Journal of Translational Autoimmunity. - : Elsevier BV. - 2589-9090. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- The risk for type 1 diabetes is strongly associated with HLA-DQ and the appearance of beta cell autoantibodies against either insulin, glutamate decarboxylase (GAD65), insulinoma-associated protein-2 (IA-2), or zinc transporter 8 (ZnT8). Prolonged exposure to autoantibodies may be related to T cell exhaustion known to occur in chronic infections or autoimmune disorders. It was hypothesized that autoantibody exposure may affect HLA-DQ expression on peripheral blood cells and thereby contribute to T cell exhaustion thought to be associated with the pathogenesis of type 1 diabetes. The aim of this study was to determine whether autoantibody exposure as an expression of autoimmunity burden was related to peripheral blood cell HLA-DQ cell surface expression in either 1) a cross-sectional analysis or 2) cumulative as area under the trajectory of autoantibodies during long term follow-up in the Diabetes Prediction in Skåne (DiPiS) study. Children (n = 67), aged 10-15 years were analyzed for complete blood count, HLA-DQ cell surface median fluorescence intensity (MFI), autoantibody frequency, and HLA genotypes by Next Generation Sequencing. Decreased HLA-DQ cell surface MFI with an increasing number of autoantibodies was observed in CD16+, CD14+CD16-, CD4+ and CD8+ cells but not in CD19+ cells and neutrophils. HLA-DQ cell surface MFI was associated with HLA-DQ2/8 in CD4+ T cells, marginally in CD14+CD16- monocytes and CD8+ T cells. These associations appeared to be related to autoimmunity burden. The results suggest that HLA-DQ cell surface expression was related to HLA and autoimmunity burden.
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| 9. |
- Arvidsson, Daniel, 1974, et al.
(författare)
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Validity of the ActiReg system in assessing energy requirement in chronic obstructive pulmonary disease patients
- 2006
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Ingår i: Clin Nutr. ; 25:1, s. 68-74
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Malnutrition and weight loss are common in patients with chronic obstructive pulmonary disease (COPD) and effective nutritional support relies on accurate assessment of energy requirement. This could only be performed by measuring energy expenditure using objective methods. The aim of this study was to examine the validity of the ActiReg system in assessing energy requirement in non-hospitalized patients with severe COPD, using doubly labelled water (DLW) as criterion method. METHODS: Total energy expenditure (TEE) was assessed from 14 days DLW analysis in 13 patients. During the first 7 days TEE was simultaneously assessed using the ActiReg system, combining measured resting energy expenditure (REE) with physical activity monitoring. RESULTS: A difference of -88 (782) kJ d(-1) (P = 0.69) was observed between the ActiReg system and DLW. REE explained 52% of the variation in TEE from DLW. Adding physical activity energy expenditure from the ActiReg system (PAEE(AR) = TEE(AR)-REE) increased the explained variation in TEE from DLW with 16%. CONCLUSIONS: The ActiReg system is valid in assessing energy requirement in non-hospitalized patients with severe COPD. The unique feature of being able to discriminate within both the low intensity activity range and moderate-to-high intensity activity range makes the ActiReg system a valuable tool in clinical nutritional support.
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| 10. |
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