Islet Gene View—a tool to facilitate islet research

Asplund, Olof; Storm, Petter; Chandra, Vikash; Hatem, Gad; Ottosson-Laakso, Emilia; Mansour-Aly, Dina; Krus, Ulrika; Ibrahim, Hazem; Ahlqvist, Emma; Tuomi, Tiinamaija; Renström, Erik; Korsgren, Olle; Wierup, Nils; Ibberson, Mark; Solimena, Michele; Marchetti, Piero; Wollheim, Claes B.; Artner, Isabella; Mulder, Hindrik; Hansson, Ola; Otonkoski, Timo; Groop, Leif; Prasad, Rashmi B.

doi:10.26508/lsa.202201376

Cited by 27 publications

(30 citation statements)

References 43 publications

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“…2n). Likewise, the adult islet RNA-seq dataset 19 (n = 191) showed a strong positive correlation between TYK2 and INS expression (r = 0.77; p = 4.4E-39; Fig. 2o), suggesting a regulatory role of TYK2 in the pancreatic endocrine lineage.…”

Section: Loss or Inhibition Of Tyk2 Results In Defective Ep Formationmentioning

confidence: 82%

“…8b). In agreement with the experimental data, a strong positive correlation between TYK2 and HLA-A (r = 0.52; p = 6.53E-15); HLA-B (r = 0.42; p = 1.06E-9); HLA-C (r = 0.60; p = 1.55E-20); and HLA-E (r = 0.51; p = 3.65E-14) was observed in the human islet RNA-seq dataset (n = 191) 19 (Supplementary Fig. 8c).…”

Section: Tyk2 Regulates the Ifnα Response In Sc-isletsmentioning

confidence: 99%

“…Data from human pancreatic islets were processed as described 19 . Briefly, human islets (n = 191) were obtained through the EXODIAB network from the Nordic Network for Clinical Islet Transplantation.…”

Section: Human Pancreatic Islets Rnaseq For Correlation Studiesmentioning

confidence: 99%

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The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α

et al. 2022

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Type 1 diabetes (T1D) is an autoimmune disease that results in the destruction of insulin producing pancreatic β-cells. One of the genes associated with T1D is TYK2, which encodes a Janus kinase with critical roles in type-Ι interferon (IFN-Ι) mediated intracellular signalling. To study the role of TYK2 in β-cell development and response to IFNα, we generated TYK2 knockout human iPSCs and directed them into the pancreatic endocrine lineage. Here we show that loss of TYK2 compromises the emergence of endocrine precursors by regulating KRAS expression, while mature stem cell-islets (SC-islets) function is not affected. In the SC-islets, the loss or inhibition of TYK2 prevents IFNα-induced antigen processing and presentation, including MHC Class Ι and Class ΙΙ expression, enhancing their survival against CD8+ T-cell cytotoxicity. These results identify an unsuspected role for TYK2 in β-cell development and support TYK2 inhibition in adult β-cells as a potent therapeutic target to halt T1D progression.

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Section: Loss or Inhibition Of Tyk2 Results In Defective Ep Formationmentioning

confidence: 82%

Section: Tyk2 Regulates the Ifnα Response In Sc-isletsmentioning

confidence: 99%

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The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α

et al. 2022

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“…We used the 99% credible sets for each novel signal to annotate their genomic effect using the VEP [30] (GRCh38.p7) and SNPNEXUS [31] applications. We used GTEx V8 [32] to assess the influence of the variants in gene-level expression, as well as the TIGER Portal [33] for evaluating the gene-level expression in pancreatic islets and the Islet Gene View [34] for assessing the gene co-expression in human islets. We also assessed individual variant associations with a variety of common phenotypes and diseases using the Common Metabolic Disease Knowledge Portal (cmdgenkp.org.…”

Section: Genomic Annotationmentioning

confidence: 99%

The power of TOPMed imputation for the discovery of Latino enriched rare variants associated with type 2 diabetes

Huerta-Chagoya

Schroeder

Mandla

et al. 2022

Preprint

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Hypothesis: The prevalence of type 2 diabetes is higher in Latino populations compared with other major ancestry groups. Not only has the Latino population been systematically underrepresented in large-scale genetic analyses, but previous studies relied on the imputation of ungenotyped variants based on the 1000 Genomes (1000G) imputation reference panel, which results in suboptimal capture of low-frequency or Latino-enriched variants. The NHLBI Trans-Omics for Precision Medicine (TOPMed) reference panel represents a unique opportunity to analyze rare genetic variations in the Latino population. Methods: We evaluate the TOPMed imputation performance using genotyping array and whole-exome sequence data in 6 Latino cohorts. To evaluate the ability of TOPMed imputation of increasing the identified loci, we performed a Latino type 2 diabetes GWAS meta-analysis in 8,150 type 2 diabetes cases and 10,735 controls and replicated the results in 6 additional cohorts including whole-genome sequence data from the All of Us cohort. Results: We show that, compared to imputation with 1000G, the TOPMed panel improves the identification of rare and low-frequency variants. We identified 26 distinct signals including a novel genome-wide significant variant (minor allele frequency 1.6%, OR=2.0, P=3.4−10-9) near ORC5. A Latino-tailored polygenic score constructed from our data and GWAS data from East Asian and European populations improves the prediction accuracy in a Latino target dataset, explaining up to 7.6% of the type 2 diabetes risk variance. Conclusions: Our results demonstrate the utility of TOPMed imputation for identifying low-frequency variation in understudied populations, leading to the discovery of novel disease associations and the improvement of polygenic scores.

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“…Previous studies have explored the differences in transcripts associated with donor sex, age, and BMI in human islets [7,8,[15][16][17]. However, knowledge of transcriptomic variations in human islets at non-coding RNA (such as microRNA) level due to differences in sex, age and BMI of donors is lacking.…”

Section: Introductionmentioning

confidence: 99%

Identification and functional validation of human islet microRNAs associated with donor trait

Wong

Joglekar

Cheng

et al. 2022

Preprint

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Human islets are widely used in research for understanding pathophysiological mechanisms leading to diabetes. Sex, age, and body mass index (BMI) are key donor traits influencing insulin secretion. Islet function is also regulated by an intricate network of microRNAs. Here, we profiled 754 microRNAs and 58,190 transcripts in up to 131 different human islet donor preparations (without diabetes) and assessed their association with donor traits. MicroRNA analyses identified miR-199a-5p and miR-214-3p associated with sex, age and BMI; miR-147b with sex and age; miR-378a-5p with sex and BMI; miR-542-3p, miR-34a-3p, miR-34a-5p, miR-497-5p and miR-99a-5p with age and BMI. There were 959 mRNA transcripts associated with sex (excluding those from sex-chromosomes), 940 with age and 418 with BMI. MicroRNA-199a-5p and miR-214-3p levels inversely associate with transcripts critical in islet function, metabolic regulation, and senescence. Our analyses identify human islet cell microRNAs influenced by donor traits.

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Islet Gene View—a tool to facilitate islet research

Cited by 27 publications

References 43 publications

The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α

The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α

The power of TOPMed imputation for the discovery of Latino enriched rare variants associated with type 2 diabetes

Identification and functional validation of human islet microRNAs associated with donor trait

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