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Cavalli, Marco
Publications (10 of 13) Show all publications
Cavalli, M., Baltzer, N., Umer, H. M., Grau, J., Lemnian, I., Pan, G., . . . Wadelius, C. (2019). Allele specific chromatin signals, 3D interactions, and motif predictions for immune and B cell related diseases. Scientific Reports, 9, Article ID 2695.
Open this publication in new window or tab >>Allele specific chromatin signals, 3D interactions, and motif predictions for immune and B cell related diseases
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 2695Article in journal (Refereed) Published
Abstract [en]

Several Genome Wide Association Studies (GWAS) have reported variants associated to immune diseases. However, the identified variants are rarely the drivers of the associations and the molecular mechanisms behind the genetic contributions remain poorly understood. ChIP-seq data for TFs and histone modifications provide snapshots of protein-DNA interactions allowing the identification of heterozygous SNPs showing significant allele specific signals (AS-SNPs). AS-SNPs can change a TF binding site resulting in altered gene regulation and are primary candidates to explain associations observed in GWAS and expression studies. We identified 17,293 unique AS-SNPs across 7 lymphoblastoid cell lines. In this set of cell lines we interrogated 85% of common genetic variants in the population for potential regulatory effect and we identified 237 AS-SNPs associated to immune GWAS traits and 714 to gene expression in B cells. To elucidate possible regulatory mechanisms we integrated long-range 3D interactions data to identify putative target genes and motif predictions to identify TFs whose binding may be affected by AS-SNPs yielding a collection of 173 AS-SNPs associated to gene expression and 60 to B cell related traits. We present a systems strategy to find functional gene regulatory variants, the TFs that bind differentially between alleles and novel strategies to detect the regulated genes.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-379258 (URN)10.1038/s41598-019-39633-0 (DOI)000459571100059 ()30804403 (PubMedID)
Funder
Swedish Research Council, 78081Swedish National Infrastructure for Computing (SNIC)EXODIAB - Excellence of Diabetes Research in SwedenSwedish Diabetes AssociationErnfors FoundationSwedish Cancer Society, 160518German Research Foundation (DFG), GR-3526/1German Research Foundation (DFG), GR-3526/2
Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-10-07Bibliographically approved
Diamanti, K., Cavalli, M., Pan, G., Pereira, M. J., Kumar, C., Skrtic, S., . . . Wadelius, C. (2019). Intra- and inter-individual metabolic profiling highlights carnitine and lysophosphatidylcholine pathways as key molecular defects in type 2 diabetes. Scientific Reports, 9, Article ID 9653.
Open this publication in new window or tab >>Intra- and inter-individual metabolic profiling highlights carnitine and lysophosphatidylcholine pathways as key molecular defects in type 2 diabetes
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 9653Article in journal (Refereed) Published
Abstract [en]

Type 2 diabetes (T2D) mellitus is a complex metabolic disease commonly caused by insulin resistance in several tissues. We performed a matched two-dimensional metabolic screening in tissue samples from 43 multi-organ donors. The intra-individual analysis was assessed across five key metabolic tissues (serum, visceral adipose tissue, liver, pancreatic islets and skeletal muscle), and the inter-individual across three different groups reflecting T2D progression. We identified 92 metabolites differing significantly between non-diabetes and T2D subjects. In diabetes cases, carnitines were significantly higher in liver, while lysophosphatidylcholines were significantly lower in muscle and serum. We tracked the primary tissue of origin for multiple metabolites whose alterations were reflected in serum. An investigation of three major stages spanning from controls, to pre-diabetes and to overt T2D indicated that a subset of lysophosphatidylcholines was significantly lower in the muscle of pre-diabetes subjects. Moreover, glycodeoxycholic acid was significantly higher in liver of pre-diabetes subjects while additional increase in T2D was insignificant. We confirmed many previously reported findings and substantially expanded on them with altered markers for early and overt T2D. Overall, the analysis of this unique dataset can increase the understanding of the metabolic interplay between organs in the development of T2D.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-391017 (URN)10.1038/s41598-019-45906-5 (DOI)000474222900010 ()31273253 (PubMedID)
Funder
AstraZenecaSwedish Research Council FormaseSSENCE - An eScience CollaborationSwedish Diabetes AssociationErnfors Foundation
Available from: 2019-08-21 Created: 2019-08-21 Last updated: 2019-09-22Bibliographically approved
Hallberg, P., Smedje, H., Eriksson, N., Kohnke, H., Daniilidou, M., Öhman, I., . . . Wadelius, M. (2019). Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival. EBioMedicine, 40, 595-604
Open this publication in new window or tab >>Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 40, p. 595-604Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The incidence of narcolepsy rose sharply after the swine influenza A (H1N1) vaccination campaign with Pandemrix. Narcolepsy is an immune-related disorder with excessive daytime sleepiness. The most frequent form is strongly associated with HLA-DQB1*06:02, but only a minority of carriers develop narcolepsy. We aimed to identify genetic markers that predispose to Pandemrix-induced narcolepsy.

METHODS: We tested for genome-wide and candidate gene associations in 42 narcolepsy cases and 4981 controls. Genotyping was performed on Illumina arrays, HLA alleles were imputed using SNP2HLA, and single nucleotide polymorphisms were imputed using the haplotype reference consortium panel. The genome-wide significance threshold was p < 5 × 10-8, and the nominal threshold was p < 0.05. Results were replicated in 32 cases and 7125 controls. Chromatin data was used for functional annotation.

FINDINGS: Carrying HLA-DQB1*06:02 was significantly associated with narcolepsy, odds ratio (OR) 39.4 [95% confidence interval (CI) 11.3, 137], p = 7.9 × 10-9. After adjustment for HLA, GDNF-AS1 (rs62360233) was significantly associated, OR = 8.7 [95% CI 4.2, 17.5], p = 2.6 × 10-9, and this was replicated, OR = 3.4 [95% CI 1.2-9.6], p = 0.022. Functional analysis revealed variants in high LD with rs62360233 that might explain the detected association. The candidate immune-gene locus TRAJ (rs1154155) was nominally associated in both the discovery and replication cohorts, meta-analysis OR = 2.0 [95% CI 1.4, 2.8], p = 0.0002.

INTERPRETATION: We found a novel association between Pandemrix-induced narcolepsy and the non-coding RNA gene GDNF-AS1, which has been shown to regulate expression of the essential neurotrophic factor GDNF. Changes in regulation of GDNF have been associated with neurodegenerative diseases. This finding may increase the understanding of disease mechanisms underlying narcolepsy. Associations between Pandemrix-induced narcolepsy and immune-related genes were replicated.

Keywords
(MeSH), Autoimmune diseases, Drug-related side effects and adverse reactions, Genetic variation, Genome-wide association study, Glial cell line-derived neurotrophic factor, H1N1 subtype, Influenza A virus, Influenza vaccines, Narcolepsy, Pharmacogenetics, RNA, long noncoding
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-377169 (URN)10.1016/j.ebiom.2019.01.041 (DOI)000460696900067 ()30711515 (PubMedID)
Funder
Swedish Research Council, 521-2011-2440Swedish Research Council, 521-2014-3370Swedish Research Council, 2018-03307Swedish Heart Lung Foundation, 20120557Swedish Heart Lung Foundation, 20140291Swedish Heart Lung Foundation, 20170711Erik, Karin och Gösta Selanders FoundationThuréus stiftelse för främjande av geriatrisk forskningSwedish Research Council, 2017-00641
Available from: 2019-02-15 Created: 2019-02-15 Last updated: 2019-05-13Bibliographically approved
Cavalli, M., Baltzer, N., Pan, G., Walls, J. R., Garbulowska, K. S., Kumar, C., . . . Wadelius, C. (2019). Studies of liver tissue identify functional gene regulatory elements associated to gene expression, type 2 diabetes, and other metabolic diseases. HUMAN GENOMICS, 13, Article ID 20.
Open this publication in new window or tab >>Studies of liver tissue identify functional gene regulatory elements associated to gene expression, type 2 diabetes, and other metabolic diseases
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2019 (English)In: HUMAN GENOMICS, ISSN 1473-9542, Vol. 13, article id 20Article in journal (Refereed) Published
Abstract [en]

Background:

Genome-wide association studies (GWAS) of diseases and traits have found associations to gene regions but not the functional SNP or the gene mediating the effect. Difference in gene regulatory signals can be detected using chromatin immunoprecipitation and next-gen sequencing (ChIP-seq) of transcription factors or histone modifications by aligning reads to known polymorphisms in individual genomes. The aim was to identify such regulatory elements in the human liver to understand the genetics behind type 2 diabetes and metabolic diseases.

Methods:

The genome of liver tissue was sequenced using 10X Genomics technology to call polymorphic positions. Using ChIP-seq for two histone modifications, H3K4me3 and H3K27ac, and the transcription factor CTCF, and our established bioinformatics pipeline, we detected sites with significant difference in signal between the alleles.

Results:

We detected 2329 allele-specific SNPs (AS-SNPs) including 25 associated to GWAS SNPs linked to liver biology, e.g., 4 AS-SNPs at two type 2 diabetes loci. Two hundred ninety-two AS-SNPs were associated to liver gene expression in GTEx, and 134 AS-SNPs were located on 166 candidate functional motifs and most of them in EGR1-binding sites.

Conclusions:

This study provides a valuable collection of candidate liver regulatory elements for further experimental validation.

Keywords
ChIP-seq, T2D, Regulatory SNPs
National Category
Medical Genetics Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:uu:diva-383513 (URN)10.1186/s40246-019-0204-8 (DOI)000466335200001 ()31036066 (PubMedID)
Available from: 2019-05-16 Created: 2019-05-16 Last updated: 2019-10-07Bibliographically approved
Cavalli, M., Pan, G., Nord, H., Wallén Arzt, E., Wallerman, O. & Wadelius, C. (2017). Genetic prevention of hepatitis C virus-induced liver fibrosis by allele-specific downregulation of MERTK. Hepatology Research, 47(8), 826-830
Open this publication in new window or tab >>Genetic prevention of hepatitis C virus-induced liver fibrosis by allele-specific downregulation of MERTK
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2017 (English)In: Hepatology Research, ISSN 1386-6346, E-ISSN 1872-034X, Vol. 47, no 8, p. 826-830Article in journal (Refereed) Published
Abstract [en]

AIM: Infection by hepatitis C virus (HCV) can result in the development of liver fibrosis and may eventually progress into cirrhosis and hepatocellular carcinoma. However, the molecular mechanisms for this process are not fully known. Several genome-wide association studies have been carried out to pinpoint causative variants in HCV-infected patient cohorts, but these variants are usually not the functional ones. The aim of this study was to identify the regulatory single nucleotide polymorphism associated with the risk of HCV-induced liver fibrosis and elucidate its molecular mechanism.

METHODS: We utilized a bioinformatics approach to identify a non-coding regulatory variant, located in an intron of the MERTK gene, based on differential transcription factor binding between the alleles. We validated the results using expression reporter assays and electrophoresis mobility shift assays.

RESULTS: Chromatin immunoprecipitation sequencing indicated that transcription factor(s) bind stronger to the A allele of rs6726639. Electrophoresis mobility shift assays supported these findings and suggested that the transcription factor is interferon regulatory factor 1 (IRF1). Luciferase report assays showed lower enhancer activity from the A allele and that IRF1 may act as a repressor.

CONCLUSIONS: Treatment of hepatitis C with interferon-α results in increased IRF1 levels and our data suggest that this leads to an allele-specific downregulation of MERTK mediated by an allelic effect on the regulatory element containing the functional rs6726639. This variant also shows the hallmarks for being the driver of the genome-wide association studies for reduced risk of liver fibrosis and non-alcoholic fatty liver disease at MERTK.

Keywords
MERTK, hepatitis C virus, liver fibrosis, single nucleotide polymorphism
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-318340 (URN)10.1111/hepr.12810 (DOI)000404794000012 ()27577861 (PubMedID)
Funder
Swedish Cancer Society, 15 0878Swedish Research Council, A0350501Swedish Diabetes Association, 2015-064
Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2018-01-13Bibliographically approved
Hallberg, P., Persson, M., Axelsson, T., Cavalli, M., Norling, P., Johansson, H.-E., . . . Wadelius, M. (2017). Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough: a genome-wide association study in a Swedish population. Pharmacogenomics (London), 18(3), 201-213
Open this publication in new window or tab >>Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough: a genome-wide association study in a Swedish population
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2017 (English)In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 18, no 3, p. 201-213Article in journal (Refereed) Published
Abstract [en]

Aim: We conducted a genome-wide association study on angiotensin-converting enzyme inhibitor-induced cough and used our dataset to replicate candidate genes iden-tified in previous studies. Patients & methods: A total of 124 patients and 1345 treated controls were genotyped using Illumina arrays. The genome-wide significance level was set to p < 5 x 10(-8). Results: We identified nearly genome-wide significant associations in CLASP1, PDE11A, KCNMB2, TGFA, SLC38A6 and MMP16. The strongest association was with rs62151109 in CLASP1 (odds ratio: 3.97; p = 9.44 x 10(-8)). All top hits except two were located in intronic or noncoding DNA regions. None of the candidate genes were significantly associated in our study. Conclusion: Angiotensin-converting enzyme inhibitor-induced cough is potentially associated with genes that are independent of bradykinin pathways.

Place, publisher, year, edition, pages
FUTURE MEDICINE LTD, 2017
Keywords
angiotensin converting enzyme inhibitors, bradykinin, cough, drug-related side effects and adverse reactions, enalapril, genome-wide association study, lisinopril, pharmacogenetics, quinapril, ramipril
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-318602 (URN)10.2217/pgs-2016-0184 (DOI)000393682600002 ()28084903 (PubMedID)
Funder
Swedish Research Council, Medicine 521-2011-2440 521-2014-3370Swedish Heart Lung Foundation, 20120557 20140291Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2018-01-13Bibliographically approved
Pan, G., Ameur, A., Enroth, S., Bysani, M., Nord, H., Cavalli, M., . . . Wadelius, C. (2017). PATZ1 down-regulates FADS1 by binding to rs174557 and is opposed by SP1/SREBP1c. Nucleic Acids Research, 45(5), 2408-2422
Open this publication in new window or tab >>PATZ1 down-regulates FADS1 by binding to rs174557 and is opposed by SP1/SREBP1c
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2017 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 5, p. 2408-2422Article in journal (Refereed) Published
Abstract [en]

The FADS1 and FADS2 genes in the FADS cluster encode the rate-limiting enzymes in the synthesis of long-chain polyunsaturated fatty acids (LC-PUFAs). Genetic variation in this region has been associated with a large number of diseases and traits many of them correlated to differences in metabolism of PUFAs. However, the causative variants leading to these associations have not been identified. Here we find that the multiallelic rs174557 located in an AluYe5 element in intron 1 of FADS1 is functional and lies within a PATZ1 binding site. The derived allele of rs174557, which is the common variant in most populations, diminishes binding of PATZ1, a transcription factor conferring allele-specific downregulation of FADS1 The PATZ1 binding site overlaps with a SP1 site. The competitive binding between the suppressive PATZ1 and the activating complex of SP1 and SREBP1c determines the enhancer activity of this region, which regulates expression of FADS1.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-317999 (URN)10.1093/nar/gkw1186 (DOI)000397286600024 ()27932482 (PubMedID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Research Council, 521-2010-3505 6212011-6052 521-2012-2884Swedish Diabetes AssociationSwedish Cancer Society, 15 0878
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2017-04-18Bibliographically approved
Cavalli, M., Pan, G., Nord, H., Arzt, E. W., Wallerman, O. & Wadelius, C. (2016). Allele-specific transcription factor binding in liver and cervix cells unveils many likely drivers of GWAS signals. Genomics, 107(6), 248-254
Open this publication in new window or tab >>Allele-specific transcription factor binding in liver and cervix cells unveils many likely drivers of GWAS signals
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2016 (English)In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 107, no 6, p. 248-254Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies (GWAS) point to regions with associated genetic variants but rarely to a specific gene and therefore detailed knowledge regarding the genes contributing to complex traits and diseases remains elusive. The functional role of GWAS-SNPs is also affected by linkage disequilibrium with many variants on the same haplotype and sometimes in the same regulatory element almost equally likely to mediate the effect. Using ChIP-seq data on many transcription factors, we pinpointed genetic variants in HepG2 and HeLa-S3 cell lines which show a genome-wide significant difference in binding between alleles. We identified a collection of 3713 candidate functional regulatory variants many of which are likely drivers of GWAS signals or genetic difference in expression. A recent study investigated many variants before finding the functional ones at the GALNT2 locus, which we found in our genome-wide screen in HepG2. This illustrates the efficiency of our approach.

Keywords
Allele-specific regulation, Association to GWAS/eQTLs, Functional variants
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-299903 (URN)10.1016/j.ygeno.2016.04.006 (DOI)000378623700004 ()27126307 (PubMedID)
Funder
Swedish Research Council, 2010-3505Swedish Diabetes Association, 2015-064
Available from: 2016-07-29 Created: 2016-07-29 Last updated: 2018-01-10Bibliographically approved
Cavalli, M., Pan, G., Nord, H., Wallerman, O., Arzt, E. W., Berggren, O., . . . Wadelius, C. (2016). Allele-specific transcription factor binding to common and rare variants associated with disease and gene expression. Human Genetics, 135(5), 485-497
Open this publication in new window or tab >>Allele-specific transcription factor binding to common and rare variants associated with disease and gene expression
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2016 (English)In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 135, no 5, p. 485-497Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies (GWAS) have identified a large number of disease-associated SNPs, but in few cases the functional variant and the gene it controls have been identified. To systematically identify candidate regulatory variants, we sequenced ENCODE cell lines and used public ChIP-seq data to look for transcription factors binding preferentially to one allele. We found 9962 candidate regulatory SNPs, of which 16 % were rare and showed evidence of larger functional effect than common ones. Functionally rare variants may explain divergent GWAS results between populations and are candidates for a partial explanation of the missing heritability. The majority of allele-specific variants (96 %) were specific to a cell type. Furthermore, by examining GWAS loci we found >400 allele-specific candidate SNPs, 141 of which were highly relevant in our cell types. Functionally validated SNPs support identification of an SNP in SYNGR1 which may expose to the risk of rheumatoid arthritis and primary biliary cirrhosis, as well as an SNP in the last intron of COG6 exposing to the risk of psoriasis. We propose that by repeating the ChIP-seq experiments of 20 selected transcription factors in three to ten people, the most common polymorphisms can be interrogated for allele-specific binding. Our strategy may help to remove the current bottleneck in functional annotation of the genome.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-297809 (URN)10.1007/s00439-016-1654-x (DOI)000374459200004 ()26993500 (PubMedID)
Funder
Swedish National Infrastructure for Computing (SNIC), b2010003Swedish National Infrastructure for Computing (SNIC), b2011107Swedish Research Council, 541-2013-8161Swedish Diabetes AssociationKnut and Alice Wallenberg Foundation
Available from: 2016-06-28 Created: 2016-06-28 Last updated: 2018-01-10Bibliographically approved
Cavalli, M., Pan, G., Nord, H. & Wadelius, C. (2016). Looking beyond GWAS: allele-specific transcription factor binding drives the association of GALNT2 to HDL-C plasma levels. Lipids in Health and Disease, 15, Article ID 18.
Open this publication in new window or tab >>Looking beyond GWAS: allele-specific transcription factor binding drives the association of GALNT2 to HDL-C plasma levels
2016 (English)In: Lipids in Health and Disease, ISSN 1476-511X, E-ISSN 1476-511X, Vol. 15, article id 18Article in journal (Refereed) Published
Abstract [en]

Background: Plasma levels of high-density lipoprotein cholesterol (HDL-C) have been associated to cardiovascular disease. The high heritability of HDL-C plasma levels has been an incentive for several genome wide association studies (GWASs) which identified, among others, variants in the first intron of the GALNT2 gene strongly associated to HDL-C levels. However, the lead GWAS SNP associated to HDL-C levels in this genomic region, rs4846914, is located outside of transcription factor (TF) binding sites defined by chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) experiments in the ENCODE project and is therefore unlikely to be functional. In this study we apply a bioinformatics approach which rely on the premise that ChIP-seq reads can identify allele specific binding of a TF at cell specific regulatory elements harboring allele specific SNPs (AS-SNPs). EMSA and luciferase assays were used to validate the allele specific binding and to test the enhancer activity of the regulatory element harboring the AS-SNP rs4846913 as well as the neighboring rs2144300 which are in high LD with rs4846914. Findings: Using luciferase assays we found that rs4846913 and the neighboring rs2144300 displayed allele specific enhancer activity. We propose that an inhibitor binds preferentially to the rs4846913-C allele with an inhibitory boost from the synergistic binding of other TFs at the neighboring SNP rs2144300. These events influence the transcription level of GALNT2. Conclusions: The results suggest that rs4846913 and rs2144300 drive the association to HDL-C plasma levels through an inhibitory regulation of GALNT2 rather than the reported lead GWAS SNP rs4846914.

Keywords
AS-SNPs, GWAS, HDL-C, GALNT2
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-279591 (URN)10.1186/s12944-016-0183-x (DOI)000369362800001 ()26817450 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes Association
Available from: 2016-03-02 Created: 2016-03-02 Last updated: 2017-11-30Bibliographically approved
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