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  • 1.
    Andersen, Marie Louise M.
    et al.
    Danmark.
    Vaziri-Sani, Fariba
    Högskolan Kristianstad, Forskningsmiljön Man & Biosphere Health (MABH). Lunds universitet.
    Delli, Ahmed
    Skåne University Hospital .
    Pörksen, Sven
    Danmark.
    Jacobssen, Emma
    Skåne University Hospital .
    Thomsen, Jane
    Danmark.
    Svensson, Jannet
    Danmark.
    Petersen, Jacob Steen
    Danmark.
    Hansen, Lars
    Danmark.
    Lernmark, Ake
    Skåne University Hospital .
    Mortensen, Henrik B
    Danmark.
    Nielsen, Lotte B
    Danmark.
    Association between autoantibodies to the Arginine variant of the Zinc transporter 8 (ZnT8) and stimulated C-peptide levels in Danish children and adolescents with newly diagnosed type 1 diabetes2012Inngår i: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 13, nr 6, 454-462 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    The zinc transporter 8 (ZnT8) was recently identified as a common autoantigen in type 1 diabetes (T1D) and inclusion of ZnT8 autoantibodies (ZnT8Ab) was found to increase the diagnostic specificity of T1D.

    Objectives

    The main aims were to determine whether ZnT8Ab vary during follow-up 1 year after diagnosis, and to relate the reactivity of three types of ZnT8Ab to the residual stimulated C-peptide levels during the first year after diagnosis. Subjects A total of 129 newly diagnosed T1D patients <15 years was followed prospectively 1, 3, 6, and 12 months after diagnosis.

    Methods

    Hemoglobin A1c, meal-stimulated C-peptide, ZnT8Ab, and other pancreatic autoantibodies were measured at each visit. Patients were genotyped for the rs13266634 variant at the SLC30A8 gene and HLA-DQ alleles. Results The levels of all ZnT8Ab [ZnT8Arg (arginine), ZnT8Trp (tryptophan), ZnT8Gln (glutamine)] tended to decrease during disease progression. A twofold higher level of ZnT8Arg and ZnT8Gln was associated with 4.6%/5.2% (p = 0.02), 5.3%/8.2% (p = 0.02) and 8.9%/9.7% (p = 0.004) higher concentrations of stimulated C-peptide 3, 6, and 12 months after diagnosis. The TT genotype carriers of the SLC30A8 gene had 45.8% (p = 0.01) and 60.1% (p = 0.002) lower stimulated C-peptide 6 and 12 months after diagnosis compared to the CC and the CT genotype carriers in a recessive model.

    Conclusions

    The levels of the Arg variant of the ZnT8 autoantibodies are associated with higher levels of stimulated C-peptide after diagnosis of T1D and during follow-up. Carriers of the TT genotype of the SLC30A8 gene predict lower stimulated C-peptide levels 12 months after diagnosis.

  • 2.
    Andersson, C
    et al.
    Lund University.
    Larsson, K
    Deparment of Paediatrics, Kristianstad hospital.
    Vaziri-Sani, Fariba
    Lund University.
    Lynch, K
    Lund University.
    Carlsson, A
    Lund University.
    Cedervall, E
    Ängelholm hospital.
    Jönsson, B
    Ystad hospital.
    Neiderud, J
    Helsingborg hospital.
    Månsson, M
    Lund University.
    Nilsson, A
    Lund University.
    Lernmark, Å
    Lund University.
    Elding Larsson, H
    Lund Univeristy.
    Ivarsson, SA
    Lund University.
    The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes2011Inngår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 44, nr 5, 394-405 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative.

    Methods: A total of 686 patients diagnosed in 1996–2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes.

    Results: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%—a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1*X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA.

    Conclusions: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1*X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials.

  • 3.
    Andersson, C
    et al.
    Lund Univeristy.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Delli, AJ
    Lund University.
    Lindblad, B
    The Queen Silvia Children's Hospital .
    Carlsson, A
    Lund University.
    Forsander, G
    The Queen Silvia Children's Hospital .
    Ludvigsson, J
    Linköping University.
    Marcus, C
    Karolinska Institute.
    Samuelsson, U
    Linköping Univeristy Hospital.
    Ivarsson, SA
    Lund University.
    Lernmark, Å
    Lund University.
    Elding Larsson, H
    Lund Univeristy.
    Triple specificity of ZnT8 autoantibodies in relation to HLA and other islet autoantibodies in childhood and adolescent type 1 diabetes2013Inngår i: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 14, nr 2, 97-105 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective

    To establish the diagnostic sensitivity of and the relationships between autoantibodies to all three Zinc transporter 8 (Zinc transporter 8 autoantibody to either one, two, or all three amino acid variants at position 325, ZnT8A) variants to human leukocyte antigen (HLA)-DQ and to autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A), and insulin (IAA).

    Methods

    We analyzed 3165 patients with type 1 diabetes (T1D) in the Better Diabetes Diagnosis study for HLA-DQ genotypes and all six autoantibodies (ZnT8RA, arginine 325 Zinc transporter 8 autoantibody; ZnT8WA, tryptophan 325 Zinc transporter 8 autoantibody; ZnT8QA, glutamine 325 Zinc transporter 8 autoantibody; GADA, IA-2A, and IAA).

    Results

    ZnT8A was found in 65% of the patients and as many as 108 of 3165 (3.4%) had 1–3 ZnT8A alone. None had ZnT8QA alone. Together with GADA (56%), IA-2A (73%), and IAA (33%), 93% of the T1D patients were autoantibody positive. All three ZnT8A were less frequent in children below 2 yr of age (p < 0.0001). All three ZnT8A were associated with DQA1-B1*X-0604 (DQ6.4) and DQA1-B1*03-0302 (DQ8). ZnT8WA and ZnT8QA were negatively associated with DQA1-B1*05-02 (DQ2).

    Conclusions

    Analysis of ZnT8A increased the diagnostic sensitivity of islet autoantibodies for T1D as only 7% remained islet autoantibody negative. The association between DQ6.4 and all three ZnT8A may be related to ZnT8 antigen presentation by the DQ6.4 heterodimer.

  • 4.
    Brorsson, Caroline
    et al.
    Danmark.
    Vaziri-Sani, Fariba
    Lund University.
    Bergholdt, Regine
    Danmark.
    Eising, Stefanie
    Danmark.
    Nilsson, Anita
    Lund University.
    Svensson, Jannet
    Danmark.
    Lernmark, Ake
    Lund University.
    Pociot, Flemming
    Danmark.
    Correlations between islet autoantibody specificity and the SLC30A8 genotype with HLA-DQB1 and metabolic control in new onset type 1 diabetes2011Inngår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 44, nr 2, 107-114 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We hypothesised that the correlation between autoantibody specificity for the ZnT8 Arg325Trp isoforms and the type 2 diabetes-associated rs13266634 may affect beta-cell function at type 1 diabetes (T ID) onset. To study this, we tested 482 newly diagnosed diabetic probands and 478 healthy siblings from the Danish population-based T1D registry for autoantibodies to ZnT8 (ZnT8A) in addition to GAD65 and IA-2. The prevalence and titres of autoantibodies were correlated with genotypes for rs13266634 and HLA-DQB1, age at diagnosis (AAD) and insulin dose-adjusted HbA1c (IDAA1c), as a proxy for residual beta-cell function. We replicated the correlation between rs13266634 genotypes and specificity for the ZnT8-Argenine (ZnT8R) and ZnT8-Tryptophan (ZnT8W) isoforms previously reported. ZnT8A overlapped substantially with autoantibodies to glutamate decarboxylase 65 (GADA) and IA-2 (IA-2A) and correlated significantly with IA-2A prevalence (p < 2e-16). No effect on IDAA1c was demonstrated for ZnT8A or rs13266634. We found a correlation between ZnT8R positivity and HLA-DQB1*0302 genotypes (p = 0.016), which has not been shown previously. Furthermore, significantly lower ZnT8R and GADA prevalence and titres was found among probands with AAD < 5 years (prevalence: p = 0.004 and p = 0.0001; titres: p = 0.002 and p = 0.001, respectively). The same trend was observed for IA-2A and ZnT8W; however, the difference was non-significant. Our study confirms ZnT8 as a major target for autoantibodies at disease onset in our Danish T1D cohort of children and adolescents, and we have further characterised the relationship between autoantibody specificity for the ZnT8 Arg325Trp epitopes and rs13266634 in relation to established autoantibodies, AAD, measures of beta-cell function and HLA-DQB1 genotypes in T1D.

  • 5.
    Henmyr, Viktor
    et al.
    Högskolan Kristianstad, Sektionen för lärande och miljö, Avdelningen för Naturvetenskap. Högskolan Kristianstad, Forskningsmiljön Biomedicin.
    Vandeplas, Griet
    University Hospital Ghent.
    Halldén, Christer
    Högskolan Kristianstad, Sektionen för lärande och miljö, Avdelningen för Naturvetenskap. Högskolan Kristianstad, Forskningsmiljön Biomedicin.
    Säll, Torbjörn
    Lund University.
    Olze, Heidi
    Charité Berlin.
    Bachert, Claus
    Karolinska Institutet.
    Cardell, Lars Olaf
    Karolinska Institutet.
    Replication study of genetic variants associated with chronic rhinosinusitis and nasal polyposis2014Inngår i: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 133, nr 1, 273-275 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 6.
    Ingemansson, Sofie
    et al.
    Lund University.
    Vaziri-Sani, Fariba
    Lund University.
    Lindblad, Ulf
    University of Gothenburg.
    Gudbjornsdottir, Soffia
    The Nordic Research Academy for Global Health.
    Törn, Carina
    Lund University.
    Long-term sustained autoimmune response to beta cell specific zinc transporter (ZnT8, W, R, Q) in young adult patients with preserved beta cell function at diagnosis of diabetes2013Inngår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 46, nr 1, 50-61 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to examine whether autoantibodies to: ZnT8-Tryptophan (ZnT8WA), ZnT8-Arginine (ZnT8RA) or ZnT8-Glutamine (ZnT8QA) correlated with C-peptide or other autoantibodies and to assess diagnostic sensitivity of ZnT8WRQA. Specimens from 270 newly diagnosed diabetic subjects (age 15-34 years) and after 5 years duration of disease were examined. Four linear regression models were used to dissect the importance of different factors from diagnosis for the respective difference of (logZnT8WA), (logZnT8RA) and (logZnT8QA); A) unadjusted model for: initial C-peptide, age, BMI, gender, clinical classification, ICA, GADA, IA-2A, (ZnT8WA/ZnT8RA/ZnT8QA); B) C-peptide corrected for clinical factors; C) C-peptide corrected for autoantibodies; D) C-peptide corrected for all factors. The least decrease of ZnT8WA was observed in patients with high initial C-peptide in all models A) p = 0.054; B) p = 0.021; C) p = 0.047 and D) p = 0.017. A less statistically significant decrease of ZnT8RA was observed in patients with high initial C-peptide in A) p = 0.038 and C) p = 0.047, but this finding was not confirmed in B or D. The decrease of ZnT8QA levels was not related to C-peptide in any model but correlated to age D) p = 0.049. Furthermore, patients with unclassifiable diabetes showed the least decrease in D) p = 0.035. ZnT8WA, ZnT8RA or ZnT8QA were identified as a single autoantibody in 3.8% (10/266) of patients, thereby increasing diagnostic sensitivity from 79.3% (211/266) to 83.1% (221/266). In conclusion, high initial C-peptide was the most important factor even after adjusting for other factors in patients positive for ZnT8WA or ZnT8RA to remain autoantibody positive 5 years after diagnosis.

  • 7. Kanatsuna, Norio
    et al.
    Taneera, Jalal
    Vaziri-Sani, Fariba
    Lund University.
    Wierup, Nils
    Larsson, Helena Elding
    Delli, Ahmed
    Skarstrand, Hanna
    Balhuizen, Alexander
    Bennet, Hedvig
    Steiner, Donald F.
    Torn, Carina
    Fex, Malin
    Lernmark, Ake
    Autoimmunity against INS-IGF2 Protein Expressed in Human Pancreatic Islets2013Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, nr 40, 29013-29023 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Insulin is a major autoantigen in islet autoimmunity and progression to type 1 diabetes. It has been suggested that the insulin B-chain may be critical to insulin autoimmunity in type 1 diabetes. INS-IGF2 consists of the preproinsulin signal peptide, the insulin B-chain, and eight amino acids of the C-peptide in addition to 138 amino acids from the IGF2 gene. We aimed to determine the expression of INS-IGF2 in human pancreatic islets and autoantibodies in newly diagnosed children with type 1 diabetes and controls. INS-IGF2, expressed primarily in beta cells, showed higher levels of expression in islets from normal compared with donors with either type 2 diabetes (p = 0.006) or high HbA1c levels (p < 0.001). INS-IGF2 autoantibody levels were increased in newly diagnosed patients with type 1 diabetes (n = 304) compared with healthy controls (n = 355; p < 0.001). Displacement with cold insulin and INS-IGF2 revealed that more patients than controls had doubly reactive insulin-INS-IGF2 autoantibodies. These data suggest that INS-IGF2, which contains the preproinsulin signal peptide, the B-chain, and eight amino acids of the C-peptide may be an autoantigen in type 1 diabetes. INS-IGF2 and insulin may share autoantibody-binding sites, thus complicating the notion that insulin is the primary autoantigen in type 1 diabetes.

  • 8.
    Karpman, D
    et al.
    Lunds universitet.
    Manea, M
    Lunds universitet.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Stahl, A L
    Lunds universitet.
    Kristoffersson, A C
    Lunds universitet.
    Platelet activation in hemolytic uremic syndrome2006Inngår i: Seminars in Thrombosis and Hemostasis, ISSN 0094-6176, E-ISSN 1098-9064, Vol. 32, nr 2, 128-145 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Platelet consumption in platelet-fibrin aggregates leading to thrombocytopenia and small vessel obstruction are major features of the hemolytic uremic syndrome (HUS). Although thrombocytopenia has been correlated to poor prognosis, the mechanisms by which thrombocytopenia develops in HUS have not been completely elucidated. However, plausible explanations have been platelet contact with thrombogenic surfaces and/or direct contact with an aggregating agent. This article summarizes several mechanisms of platelet activation, interactions with leukocytes, chemokine release, complement activation, and antimicrobial defense. Specific mechanisms are outlined by which platelets may be activated, leading to thrombocytopenia during HUS. In diarrhea-associated HUS Shiga toxin has been shown to injure the endothelium, thus exposing the subendothelium, releasing tissue factor, and rendering the vessel wall prothrombotic. Shiga toxin also binds to and activates platelets. The toxin may activate endothelial cells and platelets simultaneously. In atypical HUS the alternative complement pathway is activated because of mutations in complement regulatory proteins. Mutated factor H does not bind to endothelium and platelets efficiently, enabling complement activation on these cells. In thrombotic thrombocytopenic purpura, intravascular platelet clotting Occurs due to dysfunction of the von Willebrand factor (VWF)-cleaving protease ADAMTS13. Thrombi are formed by binding of platelets to ultralarge VWF multimers.

  • 9.
    Kjellerås, Jennifer
    et al.
    Lunds universitet.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Agardh, Daniel
    Lunds universitet.
    Improved efficacy by using the pTnT-rhtTG plasmid for the detection of celiac disease specific tissue transglutaminase autoantibodies in radioligand binding assays2011Inngår i: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 71, nr 8, 701-704 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Tissue transglutaminase (tTG) autoantibodies are serological markers for celiac disease. The aim was to study the efficacy of the pTnT-rhtTG plasmid and subsequent diagnostic accuracy of tTG autoantibodies for childhood celiac disease using radioligand binding assays.

    Methods: Coupled in vitro transcription and translation of tTG were performed by pTnT-rhtTG as well as by the pGEMt Easy-rhtTG vectors using the TNT SP6 Coupled Reticulocyte Lysate System in the presence of [(35)S] methionine. Sera from 190 celiac disease children and 74 controls were measured for tTG autoantibodies in two separate radioligand binding assays using anti-human IgA agarose and protein A sepharose beads for the detection of IgA-tTG and IgG-tTG, respectively.

    Results: Median incorporation of [(35)S] methionine into the pTnT-rhtTG was 26% compared to 16% for the pGEMt Easy-rhtTG plasmid (p = 0.0016). Using pTnT-rhtTG (as compared to pGEMt Easy-rhtTG), sensitivities were IgA-tTG = 96.3% (95.7%) and IgG-tTG = 95.8% (97.3%) and specificities were IgA-tTG = 91.9% (90.5%) and IgG-tTG = 94.6% (98.4%). According to receiver operator characteristics for the pTnT (pGEMt Easy) assays, area under the curves were IgA-tTG = 98.4% (98.4%) and IgG-tTG = 97.7% (97.2%), respectively.

    Conclusion: The pTnT-rhtTG plasmid increased the efficacy of tTG antigen usage without reducing the diagnostic accuracy of IgA-tTG and IgG-tTG for childhood celiac disease. The pTnT-rhtTG plasmid is therefore recommended over the pGEMt Easy-rhtTG for the assessment of IgA-tTG and IgG-tTG using radioligand binding assays.

  • 10. Nielsen, Lotte B.
    et al.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Poerksen, Sven
    Andersen, Marie-Louise M.
    Svensson, Jannet
    Bergholdt, Regine
    Pociot, Flemming
    Hougaard, Philip
    de Beaufort, Carine
    Castano, Luis
    Mortensen, Henrik B.
    Lernmark, Ake
    Hansen, Lars
    Relationship between ZnT8Ab, the SLC30A8 gene and disease progression in children with newly diagnosed type 1 diabetes2011Inngår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 44, nr 8, 616-623 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Autoantibodies against the newly established autoantigen in type 1 diabetes, zinc transporter 8, ZnT8, are presented as two types, ZnT8RAb and ZnT8WAb. The rs13266634 variant of the SLC30A8 gene has recently been found to determine the type of ZnT8Ab. The aim of this study was to explore the impact of this genetic variant and the ZnT8Ab on the residual beta-cell function during disease progression the first year after disease diagnosis in children with newly diagnosed type 1 diabetes. This cohort consists of 257 children aged < 16 years, all patients were newly diagnosed with type 1 diabetes. A Boost-test was carried out at 1, 6, and 12 months to characterize the residual beta-cell function. Carriers of the CC and CT genotype groups of the rs13266634 SNP of the SLC30A8 gene had higher stimulated C-peptide levels the first year after onset compared with those of the TT genotype group (29%, p = 0.034). CC genotype carriers were highly associated with the presence of ZnT8RAb subtype during disease progression (compared with TT, p < 0.0001). On the other hand, the TT genotype was associated with the presence of ZnT8WAb subtype during disease progression (compared with CC, p < 0.0001). The C allele of the SLC30A8 gene is associated with preserved beta-cell function in type 1 diabetes patients. The genetic determination of the rs13266634 variant on the ZnT8Ab specificity is sustained the first 12 months after the diagnosis of type 1 diabetes in a pediatric cohort.

  • 11.
    Nilsson, Anna-Lena
    et al.
    Östersund Hospital.
    Vaziri-Sani, Fariba
    Lund University.
    Andersson, Cecilia
    Lund University.
    Larsson, Karin
    Kristianstad Hospital.
    Carlsson, Anneli
    Lund University.
    Cedervall, Elisabeth
    Ängelholm Hospital.
    Jönsson, Björn
    Ystad Hospital.
    Neiderud, Jan
    Helsingborg Hospital.
    Elding Larsson, Helena
    Lund University.
    Ivarsson, Sten-Anders
    Lund University.
    Lernmark, Ake
    Lund University.
    Relationship between Ljungan virus antibodies, HLA-DQ8, and insulin autoantibodies in newly diagnosed type 1 diabetes children2013Inngår i: Viral immunology, ISSN 0882-8245, E-ISSN 1557-8976, Vol. 26, nr 3, 207-215 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Environmental factors, including viral infections, may explain an increasing and fluctuating incidence of childhood type 1 diabetes (T1D). Ljungan virus (LV) isolated from bank voles have been implicated, but it is unclear whether LV contributes to islet autoimmunity, progression to clinical onset, or both, of T1D. The aim was to test whether LV antibodies (LVAb) were related to HLA-DQ and islet autoantibodies in newly diagnosed T1D patients (n = 676) and controls (n = 309). Patients, 0-18 years of age, diagnosed with T1D in 1996-2005 were analyzed for LVAb, HLA-DQ genotypes, and all seven known islet autoantibodies (GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, and ZnT8QA). LVAb at 75th percentile, defined as cut off, was 90 (range 6-3936) U/mL and 4th quartile LVAb were found in 25% (170/676) of which 64% were < 10 (n = 108, p < 0.0001), and 27% were < 5 (n = 45; p < 0.0001) years old. The 4th quartile LVAb in children < 10 years of age correlated to HLA DQ2/8, 8/8, and 8/X (p < 0.0001). Furthermore, in the group with 4th quartile LVAb, 55% were IAA positive (p = 0.01) and correlation was found between 4th quartile LVAb and IAA in children < 10 years of age (p = 0.035). It is concluded that 1) LVAb were common among the young T1D patients and LVAb levels were higher in the younger age groups; 2) 4th quartile LVAb correlated with IAA; and 3) there was a correlation between 4th quartile LVAb and HLA-DQ8, particularly in the young patients. The presence of LVAb supports the notion that prior exposure to LV may be associated with T1D.

  • 12.
    Nilsson, Daniel
    et al.
    Högskolan Kristianstad, Sektionen för lärande och miljö, Avdelningen för Naturvetenskap. Högskolan Kristianstad, Forskningsmiljön Biomedicin.
    Henmyr, Viktor
    Högskolan Kristianstad, Sektionen för lärande och miljö, Avdelningen för Naturvetenskap. Högskolan Kristianstad, Forskningsmiljön Biomedicin.
    Halldén, Christer
    Högskolan Kristianstad, Sektionen för lärande och miljö, Avdelningen för Naturvetenskap. Högskolan Kristianstad, Forskningsmiljön Biomedicin.
    Säll, T.
    Department of Biology, Lund University.
    Kull, I.
    Department of Clinical Science and Education, Karolinska Institutet.
    Wickman, M.
    Institute of Environmental Medicine Karolinska Institutet.
    Melén, E.
    Institute of Environmental Medicine Karolinska Institutet.
    Cardell, L. O.
    Division of ENT Diseases, CLINTEC, Karolinska Institutet.
    Replication of genomewide associations with allergic sensitization and allergic rhinitis2014Inngår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 69, nr 11, 1506-1514 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Three genomewide metastudies have recently reported associations with self-reported allergic rhinitis and allergic sensitization. The three studies together identified a set of 37 loci but showed low concordance. This study investigates the reproducibility of the detected single nucleotide polymorphism (SNP) associations in an extensively characterized longitudinal cohort, BAMSE.

    METHODS: Phenotypic evaluation of allergic rhinitis (AR) and allergic sensitization was performed on 2153 children from BAMSE at 8 and 16 years of age. Allele frequencies of 39 SNPs were investigated for association with the exact allergic phenotypes of the metastudies. Odds ratios and false discovery rates were calculated, and the impact of asthma was evaluated. The cases were also evaluated for age at onset effects (≤ or >8 years of age).

    RESULTS: Association tests of the 39 SNPs identified 12 SNPs with P-values < 0.05 and Q-values < 0.10. Two of the four loci (TLR6-TLR1 and HLA-DQA1-HLA-DQB1) identified in all three original studies were also identified in this study. Three SNPs located in the TLR6-TLR1 locus had the lowest P-values and Q-values < 0.1 when using a well-defined AR phenotype. Two loci showed significant age at onset effects, but the effect of asthma on the associations was very limited.

    CONCLUSION: The TLR6-TLR1 locus is likely to have a central role in the development of allergic disease. The association between genetic variation in the SSTR1-MIPOL1 and TSLP-SLC25A46 loci and age at onset is the first report of age at onset effects in allergic rhinitis.

  • 13.
    Shulman, L M
    et al.
    Israel.
    Hampe, C S
    USA.
    Ben-Haroush, A
    Israel.
    Perepliotchikov, Y
    Israel.
    Vaziri-Sani, Fariba
    Lund University.
    Israel, S
    Israel.
    Miller, K
    Israel.
    Bin, H
    Israel.
    Kaplan, B
    Israel.
    Laron, Z
    Israel.
    Antibodies to islet cell autoantigens, rotaviruses and/or enteroviruses in cord blood and healthy mothers in relation to the 2010-2011 winter viral seasons in Israel: a pilot study2014Inngår i: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 31, nr 6, 681-685 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims

    To determine whether antivirus and/or islet cell antibodies can be detected in healthy pregnant mothers without diabetes and/or their offspring at birth in two winter viral seasons.

    Methods

    Maternal and cord blood sera from 107 healthy pregnant women were tested for islet cell autoantibodies using radioligand binding assays and for anti-rotavirus and anti-CoxB3 antibody using an enzyme-linked immunosorbent assay.

    Results

    Glutamic acid decarboxylase (GAD)65 autoantibodies and rotavirus antibodies, present in both maternal and cord blood sera, correlated with an odds ratio of 6.89 (95% CI: 1.01-46.78). For five, 22 and 17 pregnancies, antibodies to GAD65, rotavirus and CoxB3, respectively, were detected in cord blood only and not in the corresponding maternal serum. In 10 pregnancies, rotavirus antibody titres in the cord blood exceeded those in the corresponding maternal serum by 2.5-5-fold. Increased antibody titres after the 20(th) week of gestation suggested CoxB3 infection in one of the 20 pregnancies and rotavirus in another.

    Conclusion

    The concurrent presence of GAD65 antibodies in cord blood and their mothers may indicate autoimmune damage to islet cells during gestation, possibly caused by cross-placental transmission of viral infections and/or antivirus antibodies. Cord blood antibody titres that exceed those of the corresponding maternal sample by >2.5-fold, or antibody-positive cord blood samples with antibody-negative maternal samples, may imply an active in utero immune response by the fetus. What's new? <list list-type="bulleted" id="dme12404-list-0001"> It has been hypothesized that viral infections initiate islet cell autoimmunity. Previous research suggests an association of viral infection in utero and islet autoimmunity. We found a significant correlation between glutamic acid decarboxylase 65 autoantibodies and anti-rotavirus in healthy mothers at delivery and in cord blood. The presence of antibodies in cord blood with antibody-negative mothers suggests an independent fetal immune response. Our findings support the hypothesis that viral infections during pregnancy damage fetal islet cells, triggering islet autoimmunity.

  • 14.
    Skärstrand, H
    et al.
    Lund University.
    Dahlin, L. B.
    Lund University.
    Lernmark, Ake
    Lund University.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Neuropeptide Y autoantibodies in patients with long-term type 1 and type 2 diabetes and neuropathy2013Inngår i: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 27, nr 6, 609-617 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: The neurotransmitter Neuropeptide Y (NPY) was previously reported as a minor autoantigen in newly diagnosed type 1 diabetes (T1D) patients. The single nucleotide polymorphism at rs16139 (T1128C, L7P) in the NPY gene was associated with an increased risk for the development of type 2 diabetes (T2D). We aimed to develop a radiobinding assay for NPY-L (Leucine) and NPY-P (Proline) autoantibodies (A) to study the levels and the association with other islet autoantibodies and neuropathy. Methods: Autoantibodies against NPY-L, NPY-P, ZnT8, GAD65 and IA-2 were studied in T1D (n = 48) and T2D (n = 26) patients with duration up to 42 and 31 years. A subgroup of T1D (n = 32) patients re-examined, 5-8 years after first visit, was tested for peripheral (Z-score) and autonomic neuropathy (E/I ratio). Results: NPY-LA and NPY-PA were detected in 23% and 19% in T1D (p<0.001), and 12% and 23% in T2D patients (p<0.001) compared to 2.5% controls (n = 398). The levels of NPYA declined during follow-up in the T1D patients (p < 0.001). The neuropathy was not related to the NPYA or the other islet autoantibodies. Conclusions: Regardless of the absence of an association between NPYA and neuropathy, NPY may contribute to the pathogenesis of T1D and T2D as a minor autoantigen.

  • 15.
    Skärstrand, H
    et al.
    Lund University.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Andersson, C.
    Lund University.
    Elding Larsson, H
    Lund Univeristy.
    Ivarsson, SA
    Lund University.
    Lernmark, Åke
    Lund University.
    NPY minor autoantibodies in newly diagnosed type 1 diabetes patients2013Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, 19-19 s.Artikkel i tidsskrift (Annet vitenskapelig)
  • 16.
    Sorensen, J. S.
    et al.
    Danmark.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Maziarz, M.
    USA.
    Kristensen, K.
    Danmark.
    Ellerman, A.
    Danmark.
    Breslow, N.
    USA.
    Lernmark, A.
    Lund University.
    Pociot, F.
    Danmark.
    Brorsson, C.
    Danmark.
    Birkebaek, N. H.
    Danmark.
    Islet autoantibodies and residual beta cell function in type 1 diabetes children followed for 3-6 years2012Inngår i: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 96, nr 2, 204-210 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: To test if islet autoantibodies at diagnosis of type 1 diabetes (T1DM) and after 3-6 years with T1D predict residual beta-cell function (RBF) after 3-6 years with T1D.

    Methods: T1D children (n = 260, median age at diagnosis 9.4, range 0.9-14.7 years) were tested for GAD65, IA-2, ZnT8R, ZnT8W and ZnT8Q autoantibodies (A) at diagnosis, and 3-6 years after diagnosis when also fasting and stimulated RBF were determined.

    Results: For every 1-year increase in age at diagnosis of TID, the odds of detectable C-peptide increased 1.21 (1.09, 1.34) times for fasting C-peptide and 1.28 (1.15, 1.42) times for stimulated C-peptide. Based on a linear model for subjects with no change in IA-2A levels, the odds of detectable C-peptide were 35% higher than for subjects whose IA-2A levels decreased by half (OR = 1.35 (1.09, 1.67), p = 0.006); similarly for ZnT8WA (OR = 1.39 (1.09, 1.77), p = 0.008) and ZnT8QA (OR = 1.55 (1.06, 2.26) p = 0.024). Such relationship was not detected for GADA or ZnT8RA. All OR adjusted for confounders.

    Conclusions: Age at diagnosis with T1D was the major predictor of detectable C-peptide 3-6 years post-diagnosis. Decreases in IA-2A, and possibly ZnT8A, levels between diagnosis and post-diagnosis were associated with a reduction in RBF post-diagnosis.

  • 17.
    Vaziri-Sani, Fariba
    et al.
    Lunds universitet.
    Delli, Ahmed J.
    Lund University.
    Elding Larsson, H
    Lund Univeristy.
    Lindblad, Bengt
    Queen Silvia Childrens Hospital.
    Carlsson, Annelie
    Lund University.
    Forsander, Gun
    Queen Silvia Childrens Hospital.
    Ivarsson, Sten A.
    Lund University.
    Ludvigsson, Johnny
    Linköping University.
    Marcus, Claude
    Karolinska Institute.
    Lernmark, Ake
    Lund University.
    A novel triple mix radiobinding assay for the three ZnT8 (ZnT8-RWQ) autoantibody variants in children with newly diagnosed diabetes2011Inngår i: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 371, nr 1-2, 25-37 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and aims: Autoantibodies against the zinc transporter 8 (ZnT8A) are common in type 1 diabetes (T1D). ZnT8A analyses are complicated by the fact that there are three variants of the autoantigen at amino acid position 325 representing ZnT8-R (Arginine), ZnT8-W (Tryptophan) and ZnT8-Q (Glutamin). The aims of the study were: 1) to develop an autoantigen triple mix Radio-Binding Assay (RBA) for ZnT8A: 2) to identify the individual ZnT8-R,-W,-QA reactivity and 3) to validate the triple mix ZnT8A RBA in children with newly diagnosed T1D.

    Methods: Serum samples were obtained from 2664 (56% males, n = 1436) patients in the Swedish nationwide Better Diabetes Diagnosis (BDD) study representing patients with T1D (97%, n = 2582), T2D (1.7%, n = 46), MODY (1.0%, n = 28) and secondary diabetes (0.3%, n = 8). cDNA coding for the C-terminal end of each variant was prepared by site-directed mutagenesis and subcloned into a high efficiency in vitro transcription translation vector. The ZnT8 variants were labeled with 35S-methionine and used in a standard RBA separating free from autoantibody-bound autoantigen with Protein A-Sepharose.

    Results: ZnT8-TripleA was detected in 1678 (65%) patients with T1D, 4 (9%) T2D, 3 (11%) MODY and in none (0%) of the patients with secondary diabetes. Among the T1D patients ZnT8-RA was detected in 1351 (52%) patients, ZnT8-WA in 1209(47%) and ZnT8-QA in 790(31%) demonstrating that 1661 (64%) had one or several ZnT8A. The ZnT8-TripleA assay showed a false positive rate of 1.9% (n = 49). Only 1.2% (n = 32) of the T1D patients were false negative for ZnT8-TripleA compared to 0/46(0%) of the T2D patients. The precision (intra assay CV) and reproducibility (inter assay CV) of the ZnT8-TripleA assay did not differ from the RBA of the individual ZnT8 variants.

    Conclusion: We conclude that the ZnT8-TripleA assay had low false positive and false negative rates. The ZnT8-TripleA assay would therefore be highly suitable not only to analyze patient with newly diagnosed diabetes but also for screening the general population since this assay demonstrated high sensitivity and very high specificity.

  • 18.
    Vaziri-Sani, Fariba
    et al.
    Lunds universitet.
    Holmberg, L
    Sjöholm, A G
    Kristoffersson, A C
    Manea, M
    Fremeaux-Bacchi, V
    Fehrman-Ekholm, I
    Raafat, R
    Karpman, D
    Phenotypic expression of factor H mutations in patients with atypical hemolytic uremic syndrome2006Inngår i: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 69, nr 6, 981-988 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We investigated the phenotypic expression of factor H mutations in two patients with atypical hemolytic uremic syndrome (HUS). Factor H in serum was assayed by rocket immunoelectrophoresis, immunoblotting, and double immunodiffusion and in tissue by immunohistochemistry. Functional activity was analyzed by hemolysis of sheep erythrocytes and binding to endothelial cells. A homozygous mutation in complement control protein (CCP) domain 10 of factor H was identified in an adult man who first developed membranoproliferative glomerulonephritis and later HUS. C3 levels were very low. The patient had undetectable factor H levels in serum and a weak factor H 150 kDa band. Double immunodiffusion showed partial antigenic identity with factor H in normal serum owing to the presence of factor H-like protein 1. Strong specific labeling for factor H was detected in glomerular endothelium, mesangium and in glomerular and tubular epithelium as well as in bone marrow cells. A heterozygous mutation in CCP 20 of factor H was found in a girl with HUS. C3 levels were moderately decreased at onset. Factor H levels were normal and a normal 150 kDa band was present. Double immunodiffusion showed antigenic identity with normal factor H. Factor H labeling was minimal in the renal cortex. Factor H dysfunction was demonstrated by increased sheep erythrocyte hemolysis and decreased binding to endothelial cells. In summary, two different factor H mutations associated with HUS were examined: in one, factor H accumulated in cells, and in the other, membrane binding was reduced.

  • 19.
    Vaziri-Sani, Fariba
    et al.
    Lunds universitet.
    Oak, Shilpa
    Radtke, Jared
    Lernmark, Ake
    Lynch, Kristian
    Agardh, Carl. -D.
    Cilio, Corrado M.
    Lethagen, Asa L.
    Ortqvist, Eva
    Landin-Olsson, Mona
    Torn, Carina
    Hampe, Christiane S.
    ZnT8 autoantibody titers in type 1 diabetes patients decline rapidly after clinical onset2010Inngår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 43, nr 8, 598-606 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Autoantibodies to the islet-specific zinc transporter isoform 8 (ZnT8) are detected in the majority of type 1 diabetes patients prior to and at clinical diagnosis. The presence of ZnT8Ab after diagnosis has not been investigated. This study analyzed the autoantibody response to ZnT8 in regard to age at onset and disease duration. Two new onset type 1 diabetes patient cohorts with different age distributions at onset (2-17 and 15-34 years of age at onset), a longitudinal subset of the younger type 1 diabetes patient cohort (n = 32), and a cohort of GAD65Ab-positive LADA patients (n = 47) was analyzed for the presence of autoantibodies directed to the two major isoforms, ZnT8-Arginine (ZnT8R) and ZnT8-Tryptophan (ZnT8W). The majority of type 1 diabetes patients tested positive for ZnT8Ab to both isoforms. ZnT8Ab titers were significantly higher in the younger type 1 diabetes patients as compared with the older cohort (ZnT8RAb at a median of 148 and 29 U/ml, respectively, p < 0.001) (ZnT8WAb at a median of 145 and 58 U/ml, respectively, p < 0.01). ZnT8RAb and ZnT8WAb titers were significantly lower in the LADA patients (ZnT8RAb at a median of 14 U/ml, ZnT8WAb at a median of 25 U/ml) as compared with either type 1 diabetes cohorts. In our longitudinal analysis of type 1 diabetes patients after clinical diagnosis, ZnT8Ab levels to both isoforms declined significantly during the initial year of disease (ZnT8RAb from a median of 320-162 U/ml, p = 0.0001; ZnT8WAb from a median of 128-46 U/ml, p = 0.0011). The antibody titers further declined during the following 4 years (p < 0.0001). We conclude that ZnT8Ab presents a useful marker for type 1 diabetes, especially in younger patients at disease diagnosis.

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