hkr.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Publications (10 of 34) Show all publications
Warvsten, A., Björnfors, M., Arvidsson, M., Vaziri-Sani, F., Jönsson, I., Olsson, G. E., . . . Nilsson, A.-L. (2017). Islet autoantibodies present in association with Ljungan virus infection in bank voles (Myodes glareolus) in northern Sweden. Journal of Medical Virology, 89(1), 24-31
Open this publication in new window or tab >>Islet autoantibodies present in association with Ljungan virus infection in bank voles (Myodes glareolus) in northern Sweden
Show others...
2017 (English)In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 89, no 1, p. 24-31Article in journal (Refereed) Published
Abstract [en]

Bank voles are known reservoirs for Puumala hantavirus and probably also for Ljungan virus (LV), a suggested candidate parechovirus in type 1 diabetes etiology and pathogenesis. The aim of this study was to determine whether wild bank voles had been exposed to LV and if exposure associated to autoantibodies against insulin (IAA), glutamic acid decarboxylase 65 (GADA) or islet autoantigen-2 (IA-2A). Serum samples from bank voles (Myodes glareolus) captured in early summer or early winter of 1997 and 1998, respectively, were analyzed in radiobinding assays for antibodies against Ljungan virus (LVA) and Puumala virus (PUUVA) as well as for IAA, GADA and IA-2A. LVA was found in 25% (189/752), IAA in 2.5% (18/723), GADA in 2.6% (15/615) and IA-2A in 2.5% (11/461) of available bank vole samples. LVA correlated with both IAA (p = 0.007) and GADA (p < 0.001) but not with IA-2A (p = 0.999). There were no correlations with PUUVA, detected in 17% of the bank voles. Compared to LVA negative bank voles, LVA positive animals had higher levels of both IAA (p = 0.002) and GADA (p < 0.001) but not of IA-2A (p = 0.205). Levels of LVA as well as IAA and GADA were higher in samples from bank voles captured in early summer.

IN CONCLUSION: LVA was detected in bank voles and correlated with both IAA and GADA but not with IA-2A. These observations suggest that exposure to LV may be associated with islet autoimmunity. It remains to be determined if islet autoantibody positive bank voles may develop diabetes in the wild. This article is protected by copyright. All rights reserved.

Keywords
Diabetes-related autoantibodies; type 1 diabetes; zoonotic viruses
National Category
Clinical Medicine
Identifiers
urn:nbn:se:hkr:diva-15863 (URN)10.1002/jmv.24597 (DOI)000387165200005 ()27283793 (PubMedID)
Available from: 2016-08-31 Created: 2016-08-31 Last updated: 2017-11-21Bibliographically approved
Vaziri-Sani, F., Brundin, C. & Agardh, D. (2017). Osteoprotegerin autoantibodies do not predict low bone mineral density in middle-aged women. Bone Reports, 7, 132-136
Open this publication in new window or tab >>Osteoprotegerin autoantibodies do not predict low bone mineral density in middle-aged women
2017 (English)In: Bone Reports, ISSN 2352-1872, Vol. 7, p. 132-136Article in journal (Refereed) Published
Abstract [en]

Purpose

Autoantibodies against osteoprotegerin (OPG) have been associated with osteoporosis. The aim was to develop an immunoassay for OPG autoantibodies and test their diagnostic usefulness of identifying women general population with low bone mineral density.

Methods

Included were 698 women at mean age 55.1 years (range 50.4–60.6) randomly selected from the general population. Measurement of wrist bone mineral density (g/cm2) was performed of the non-dominant wrist by dual-energy X-ray absorptiometry (DXA). A T-score < − 2.5 was defined as having a low bone mineral density. Measurements of OPG autoantibodies were carried by radiobinding assays. Cut-off levels for a positive value were determined from the deviation from normality in the distribution of 398 healthy blood donors representing the 99.7th percentile.

Results

Forty-five of the 698 (6.6%) women were IgG-OPG positive compared with 2 of 398 (0.5%) controls (p < 0.0001) and 35 of the 698 (5.0%) women had a T-score < − 2.5. There was no difference in bone mineral density between IgG-OPG positive (median 0.439 (range 0.315–0.547) g/cm2) women and IgG-OPG negative (median 0.435 (range 0.176–0.652) g/cm2) women (p = 0.3956). Furthermore, there was neither a correlation between IgG-OPG levels and bone mineral density (rs = 0.1896; p = 0.2068) nor T-score (rs = 0.1889; p = 0.2086). Diagnostic sensitivity and specificity of IgG-OPG for low bone mineral density were 5.7% and 92.9%, and positive and negative predictive values were 7.4% and 90.8%, respectively.

Conclusion

Elevated OPG autoantibody levels do not predict low bone mineral density in middle-aged women selected from the general population.

Keywords
Autoantibody;
National Category
Natural Sciences
Identifiers
urn:nbn:se:hkr:diva-17548 (URN)10.1016/j.bonr.2017.10.004 (DOI)
Available from: 2017-10-31 Created: 2017-10-31 Last updated: 2017-11-29Bibliographically approved
Kanatsuna, N., Delli, A., Andersson, C., Nilsson, A.-L., Vaziri-Sani, F., Larsson, K., . . . Lernmark, Å. (2015). Doubly reactive INS-IGF2 autoantibodies in children with newly diagnosed autoimmune (type 1) diabetes. Scandinavian Journal of Immunology, 82(4), 361-369
Open this publication in new window or tab >>Doubly reactive INS-IGF2 autoantibodies in children with newly diagnosed autoimmune (type 1) diabetes
Show others...
2015 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 82, no 4, p. 361-369Article in journal (Refereed) Published
Abstract [en]

The splice variant INS-IGF2 entails the preproinsulin signal peptide, the insulin B-chain, eight amino acids of the C-peptide and 138 unique amino acids from an ORF in the IGF2 gene. The aim of this study was to determine whether levels of specific INS-IGF2 autoantibodies (INS-IGF2A) were related to age at diagnosis, islet autoantibodies, HLA-DQ or both, in patients and controls with newly diagnosed type 1 diabetes. Patients (n = 676), 0-18 years of age, diagnosed with type 1 diabetes in 1996-2005 and controls (n = 363) were analysed for specific INS-IGF2A after displacement with both cold insulin and INS-IGF2 to correct for non-specific binding and identify double reactive sera. GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, ZnT8QA and HLA-DQ genotypes were also determined. The median level of specific INS-IGF2A was higher in patients than in controls (P < 0.001). Irrespective of age at diagnosis, 19% (126/676) of the patients had INS-IGF2A when the cut-off was the 95th percentile of the controls (P < 0.001). The risk of INS-IGF2A was increased among HLA-DQ2/8 (OR = 1.509; 95th CI 1.011, 2.252; P = 0.045) but not in 2/2, 2/X, 8/8, 8/X or X/X (X is neither 2 nor 8) patients. The association with HLA-DQ2/8 suggests that this autoantigen may be presented on HLA-DQ trans-heterodimers, rather than cis-heterodimers. Autoantibodies reactive with both insulin and INS-IGF2A at diagnosis support the notion that INS-IGF2 autoimmunity contributes to type 1 diabetes.

Keywords
Insulin antibodies, mellitus, risk, assay, antibodies, beta, specificity, prevalence, appearance, epitope
National Category
Clinical Medicine
Identifiers
urn:nbn:se:hkr:diva-15865 (URN)10.1111/sji.12325 (DOI)000361142600008 ()26073034 (PubMedID)
Available from: 2016-08-31 Created: 2016-08-31 Last updated: 2017-11-21Bibliographically approved
Skärstrand, H., Vaziri-Sani, F., Delli, A. J., Törn, C., Elding Larsson, H., Ivarsson, S., . . . Lernmark, A. (2015). Neuropeptide Y is a minor autoantigen in newly diagnosed type 1 diabetes patients. Pediatric Diabetes, 16(8), 621-628
Open this publication in new window or tab >>Neuropeptide Y is a minor autoantigen in newly diagnosed type 1 diabetes patients
Show others...
2015 (English)In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 16, no 8, p. 621-628Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Autoantibodies (A) against Neuropeptide Y (NPY), was reported in 9% newly diagnosed type 1 diabetes (T1D) patients. A single nucleotide polymorphism (SNP) at rs16139 (T1128C) within the NPY-gene identified an amino acid substitution from leucine (L) to proline (P) (L7P) associated with both glucose tolerance and type 2 diabetes. We aimed to determine: (i) the influence of autoantibodies to leucine neuropeptide Y (NPY-LA) and autoantibodies to proline neuropeptide Y (NPY-PA) on the diagnostic sensitivity of type 1 diabetes (T1D), (ii) the association of NPYA with major islet autoantibodies, and (iii) the association of NPYA with HLA-DQ genotypes in newly diagnosed T1D patients.

METHODS: Serum from the HLA-DQ typed T1D patients (n = 673; median age 10 yr) from Skåne, Sweden, were analyzed for autoantibodies against NPY-L and NPY-P in a radioligand binding assay, and against glutamic acid decarboxylase 65 (GAD65), insulin, insulinoma associated protein-2 (IA-2), and zinc transporter 8 (ZnT8) in addition to islet cell antibodies (ICA). A total of 1006 subjects (median age 9 yr) were used as controls.

RESULTS: A total of 9.2% (n = 62) of the T1D patients were positive for NPY-LA (p < 0.001) and 7.6% (n = 51) for NPY-PA (p < 0.001) compared to 1.1% (n = 11) in controls. The NPY-LA and NPY-PA appeared together (κ = 0.63; p < 0.001) and the median levels correlated (R² = 0.603; p < 0.001). T1D patients diagnosed after 10 yr of age were at an increased risk for NPYA at diagnosis [odds ratio (OR = 2.46; 95% CI 1.46-4.16; p = 0.001)] adjusted for age at diagnosis, gender, autoantibody positivity, and HLA.

CONCLUSIONS: NPY is a minor autoantigen in children with newly diagnosed T1D. Therefore, NPY autoantibodies may be investigated in T1D autoimmunity.

Keywords
HLA genotype; autoimmunity; minor autoantibodies; radioligand binding assay
National Category
Clinical Medicine
Identifiers
urn:nbn:se:hkr:diva-15869 (URN)10.1111/pedi.12222 (DOI)000363929400009 ()25258030 (PubMedID)
Available from: 2016-08-31 Created: 2016-08-31 Last updated: 2017-11-21Bibliographically approved
Araujo de Pina Cabral, D., Dantas, J., Skärstrand, H., Barone, B., Carvalho, F., Tortora, R., . . . Rodacki, M. (2015). Prospective evaluation of glutamine and phospholipids levels in first degree relatives of patients with Type 1 Diabetes from a multiethnic population. Diabetology and Metabolic Syndrome, 7(52)
Open this publication in new window or tab >>Prospective evaluation of glutamine and phospholipids levels in first degree relatives of patients with Type 1 Diabetes from a multiethnic population
Show others...
2015 (English)In: Diabetology and Metabolic Syndrome, ISSN 1758-5996, E-ISSN 1758-5996, Vol. 7, no 52Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: A dysregulation in the metabolism of lipids may be an early marker of autoimmunity in Type 1 Diabetes (T1D). It would be of general importance to identify metabolic patterns that would predict the risk for T1D later in life. The aim of this study was to perform a prospective evaluation of glutamine and phospholipids levels in Brazilian first degree relatives (FDR) of patients with T1D in a mean interval of 5 years.

FINDINGS: Brazilian FDR (n = 30) of patients with T1D were evaluated and blood was sampled to measure the levels of glutamine and phospholipids in the fasting serum by quantitative colorimetric method. The tests were repeated after a mean interval of 5 years and compared to a control group (n = 20). The FDR presented lower levels of phospholipids than controls (p = 0.028), but not of glutamine (p = 0.075). Phospholipids levels decreased over time (p = 0.028) in FDR and were associated with Glutamic acid decarboxylase autoantibody (GADA) titers (p = 0.045), autoantibody positivity (p = 0.008) and PTPN22 polymorphisms (p = 0.014).

CONCLUSIONS: In this Brazilian multiethnic population, there was a significant decrease in phospholipids levels in FDR in patients with T1D during a 5-year prospective follow-up, as well as a significant association between these metabolite, GADA and PTPN22 polymorphisms. For Glutamine no difference was found. These findings suggest that a dysregulation in the metabolism of lipids may precede the onset of the autoimmunity in T1D.

Keywords
Metabolic, Diabetes, Non-whites, Antibodies, Multiethnic
National Category
Clinical Medicine
Identifiers
urn:nbn:se:hkr:diva-15864 (URN)10.1186/s13098-015-0048-x (DOI)000360000400001 ()26082806 (PubMedID)
Available from: 2016-08-31 Created: 2016-08-31 Last updated: 2017-11-21Bibliographically approved
Nilsson, A.-L., Vaziri-Sani, F., Broberg, P., Elfaitouri, A., Pipkorn, R., Blomberg, J., . . . Lernmark, Å. (2015). Serological evaluation of possible exposure to Ljungan virus and related parechovirus in autoimmune (type 1) diabetes in children. Journal of Medical Virology, 87(7), 1130-1140
Open this publication in new window or tab >>Serological evaluation of possible exposure to Ljungan virus and related parechovirus in autoimmune (type 1) diabetes in children
Show others...
2015 (English)In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 87, no 7, p. 1130-1140Article in journal (Refereed) Published
Abstract [en]

Exposure to Ljungan virus (LV) is implicated in the risk of autoimmune (type 1) diabetes but possible contribution by other parechoviruses is not ruled out. The aim was to compare children diagnosed with type 1 diabetes in 2005-2011 (n = 69) with healthy controls (n = 294), all from the Jämtland County in Sweden, using an exploratory suspension multiplex immunoassay for IgM and IgG against 26 peptides of LV, human parechoviruses (HPeV), Aichi virus and poliovirus in relation to a radiobinding assay (RBA) for antibodies against LV and InfluenzaA/H1N1pdm09. Islet autoantibodies and HLA-DQ genotypes were also determined. 1) All five LV-peptide antibodies correlated to each other (P < 0.001) in the suspension multiplex IgM- and IgG-antibody assay; 2) The LV-VP1_31-60-IgG correlated with insulin autoantibodies alone (P = 0.007) and in combination with HLA-DQ8 overall (P = 0.022) as well as with HLA-DQ 8/8 and 8/X subjects (P = 0.013); 3) RBA detected LV antibodies correlated with young age at diagnosis (P < 0.001) and with insulin autoantibodies (P < 0.001) especially in young HLA-DQ8 subjects (P = 0.004); 4) LV-peptide-VP1_31-60-IgG correlated to RBA LV antibodies (P = 0.009); 5) HPeV3-peptide-IgM and -IgG showed inter-peptide correlations (P < 0.001) but only HPeV3-VP1_1-30-IgG (P < 0.001) and VP1_95-124-IgG (P = 0.009) were related to RBA LV antibodies without relation to insulin autoantibody positivity (P = 0.072 and P = 0.486, respectively). Both exploratory suspension multiplex IgG to LV-peptide VP1_31-60 and RBA detected LV antibodies correlated with insulin autoantibodies and HLA-DQ8 suggesting possible role in type 1 diabetes. It remains to be determined if cross-reactivity or concomitant exposure to LV and HPeV3 contributes to the seroprevalence.

Keywords
HLA-DQ; autoimmune disease; insulin autoantibodies; islet autoantibodies; picornavirus
National Category
Clinical Medicine
Identifiers
urn:nbn:se:hkr:diva-15866 (URN)10.1002/jmv.24127 (DOI)000354203900009 ()25873230 (PubMedID)
Available from: 2016-08-31 Created: 2016-08-31 Last updated: 2017-11-21Bibliographically approved
Skärstrand, H., Krupinska, E., Haataja, T. J., Vaziri-Sani, F., Lagerstedt, J. O. & Lernmark, Å. (2015). Zinc transporter 8 (ZnT8) autoantibody epitope specificity and affinity examined with recombinant ZnT8 variant proteins in specific ZnT8R and ZnT8W autoantibody-positive type 1 diabetes patients. Clinical and Experimental Immunology, 179(2), 220-229
Open this publication in new window or tab >>Zinc transporter 8 (ZnT8) autoantibody epitope specificity and affinity examined with recombinant ZnT8 variant proteins in specific ZnT8R and ZnT8W autoantibody-positive type 1 diabetes patients
Show others...
2015 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 179, no 2, p. 220-229Article in journal (Refereed) Published
Abstract [en]

Variant-specific zinc transporter 8 autoantibodies (ZnT8A) against either arginine (R) or tryptophan (W) at amino acid (aa) position 325 of the zinc transporter 8 (ZnT8) has been identified in type 1 diabetes (T1D) patients. Reciprocal cross-over tests revealed differences in half-maximal binding to indicate variable affinity of patient ZnT8 autoantibodies. Insufficient recombinant ZnT8 variant proteins have precluded detailed analyses of ZnT8 autoantibody affinity. The aims in the present study were to (i) generate recombinant ZnT8R- and ZnT8W-aa275-369 proteins; (ii) test the ZnT8R- and ZnT8W-aa275-369 proteins in reciprocal competitive radiobinding assays (RBA) against ZnT8R- and ZnT8W-aa268-369 labelled with (35) S-methionine; and (iii) determine the specificity and affinity of sera specific for either ZnT8 arginine (R) or ZnT8 tryptophan (W) autoantibodies in newly diagnosed T1D patients. The results demonstrate, first, that it was possible to produce recombinant human MBP-ZnT8-aa275-369 protein purified to homogeneity for RBA reciprocal competition experiments. Secondly, high-titre ZnT8WA sera diluted to half maximal binding showed significant specificity for respective variants of either ZnT8R or ZnT8W. Thirdly, ZnT8WA-positive sera showed high affinity for ZnT8W compared to ZnT8RA for ZnT8R. These data demonstrate that T1D patients may have single amino acid-specific autoantibodies directed against either ZnT8R or ZnT8W and that the autoantibody affinity to the respective variant may be different. Further studies are needed to assess the mechanisms by which variant-specific ZnT8A of variable affinity develop and their possible role in the pathogenic process leading to the clinical onset of T1D.

Keywords
ZnT8 autoantibodies; autoantibody affinity; autoimmune diabetes; epitope analysis; polymorphic residue
National Category
Clinical Medicine
Identifiers
urn:nbn:se:hkr:diva-15870 (URN)10.1111/cei.12448 (DOI)000347233800008 ()25178386 (PubMedID)
Available from: 2016-08-31 Created: 2016-08-31 Last updated: 2017-11-21Bibliographically approved
Shulman, L. M., Hampe, C. S., Ben-Haroush, A., Perepliotchikov, Y., Vaziri-Sani, F., Israel, S., . . . Laron, Z. (2014). 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 study. Diabetic Medicine, 31(6), 681-685
Open this publication in new window or tab >>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 study
Show others...
2014 (English)In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 31, no 6, p. 681-685Article in journal (Refereed) Published
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.

National Category
Immunology in the medical area Cell and Molecular Biology
Identifiers
urn:nbn:se:hkr:diva-12673 (URN)10.1111/dme.12404 (DOI)000335949000008 ()
Available from: 2014-08-21 Created: 2014-08-21 Last updated: 2018-01-11Bibliographically approved
Redondo, M. J., Muniz, J., Rodriguez, L. M., Lyer, D., Vaziri-Sani, F., Haymond, M. W., . . . Balasubramanyam, A. (2014). Association of TCF7L2 variation with single islet autoantibody expression in children with type 1 diabetes. BMJ open diabetes research & care, 2(1), 1-6
Open this publication in new window or tab >>Association of TCF7L2 variation with single islet autoantibody expression in children with type 1 diabetes
Show others...
2014 (English)In: BMJ open diabetes research & care, ISSN 2052-4897, Vol. 2, no 1, p. 1-6Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The transcription factor 7-like 2 (TCF7L2) gene has the strongest genetic association with type 2 diabetes. TCF7L2 also associates with latent autoimmune diabetes in adults, which often presents with a single islet autoantibody, but not with classical type 1 diabetes.

METHODS: We aimed to test if TCF7L2 is associated with single islet autoantibody expression in pediatric type 1 diabetes. We studied 71 prospectively recruited children who had newly diagnosed type 1 diabetes and evidence of islet autoimmunity, that is, expressed ≥1 islet autoantibody to insulin, glutamic acid decarboxylase 65, islet cell autoantigen 512, or zinc transporter 8. TCF7L2 rs7903146 alleles were identified. Data at diagnosis were cross-sectionally analyzed.

RESULTS: We found that 21.1% of the children with autoimmune type 1 diabetes expressed a single islet autoantibody. The distribution of TCF7L2 rs7903146 genotypes in children with a single autoantibody (n=15) was 40% CC, 26.7% CT and 33.3% TT, compared with children with ≥2 islet autoantibodies (50% CC, 42.9% CT and 7.1% TT, p=0.024). Furthermore, compared with children with ≥2 autoantibodies, single-autoantibody children had characteristics reflecting milder autoimmune destruction of β-cells. Restricting to lean children (body mass index<85th centile; n=36), 45.5% of those expressing a single autoantibody were rs7903146 TT homozygotes, compared with 0% of those with ≥2 autoantibodies (p<0.0001).

CONCLUSION: These results suggest that, in children with only mild islet autoimmunity, mechanisms associated with TCF7L2 genetic variation contribute to diabetogenesis, and this contribution is larger in the absence of obesity.

Keywords
Autoantibodies; LADA (Latent Autoimmune Diabetes in Adults); Pediatric Type 1 Diabetes; Transcription Factor
National Category
Clinical Medicine
Identifiers
urn:nbn:se:hkr:diva-15867 (URN)10.1136/bmjdrc-2013-000008 (DOI)25452857 (PubMedID)
Available from: 2016-08-31 Created: 2016-08-31 Last updated: 2017-01-12Bibliographically approved
Flannick, J., Thorleifsson, G., Beer, N. L., Jacobs, S. B. R., Grarup, N., Burtt, N. P., . . . Altshuler, D. (2014). Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nature Genetics, 46(4), 357-363
Open this publication in new window or tab >>Loss-of-function mutations in SLC30A8 protect against type 2 diabetes
Show others...
2014 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, no 4, p. 357-363Article in journal (Refereed) Published
Abstract [en]

Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets1-3, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of -150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) 4 and harbors a common variant (p. Trp325Arg) associated with T2D risk and glucose and proinsulin levels5-7. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 x 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p. Lys34Serfs* 50) demonstrated reduced glucose levels (-0.17 s. d., P = 4.6 x 10(-4)). The two most common proteintruncating variants (p. Arg138* and p. Lys34Serfs* 50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk(8,9), and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts(10-15). In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.

National Category
Medical Genetics
Identifiers
urn:nbn:se:hkr:diva-12655 (URN)10.1038/ng.2915 (DOI)000334510100011 ()24584071 (PubMedID)
Available from: 2014-06-13 Created: 2014-08-21 Last updated: 2018-01-11Bibliographically approved
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9953-2829

Search in DiVA

Show all publications