Insights into non-autoimmune type 1 diabetes with 13 novel loci in low polygenic risk score patients

Qu, Jingchun; Qu, Hui‐Qi; Bradfield, Jonathan P.; Glessner, Joseph; Chang, Xiao; Tian, Lifeng; March, Michael; Connolly, John J.; Roizen, Jeffrey D.; Sleiman, Patrick; Hákonarson, Hákon

doi:10.1038/s41598-021-94994-9

Cited by 7 publications

(8 citation statements)

References 63 publications

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“…In both the previous reports [ 20 , 25 ], BMI/T2D-associated SNPs with genome-wide significance (i.e., P ≤ 5E−08) were used as the instrumental variables (IVs). According to our study, the overall genetic risk of a complex disease/trait may be better captured at the cutoff of P-value ≤ 1E−05, while stricter cutoff may cause the missing of informative SNPs, and looser may introduce noise by including SNPs with spurious association [ 26 ]. Could the null effect of T2D be due to missing genetic information?…”

Section: Discussionmentioning

confidence: 99%

Mendelian randomization study of obesity and type 2 diabetes in hospitalized COVID-19 patients

Glessner

et al. 2022

Metabolism

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Background: Both obesity and type 2 diabetes (T2D) are reported to be highly enriched in hospitalized COVID-19 patients. Due to the close correlation between obesity and T2D, it is important to examine whether obesity and T2D are independently related to COVID-19 hospitalization. Objective: To examine the causal effect of obesity and T2D in hospitalized COVID-19 patients using Mendelian randomization (MR).Research design and methods: This two-sample MR analysis applied genetic markers of obesity identified in the genome wide association study (GWAS) by the GIANT Consortium as instrumental variables (IVs) of obesity; and genetic markers of T2D identified by the DIAGRAM Consortium as IVs of T2D. The MR analysis was performed in hospitalized COVID-19 patient by the COVID-19 Host Genetics Initiative using the MR-Base platform. Results: All 3 classes of obesity (Class 1/2/3) were shown as the causal risk factors of COVID-19 hospitalization; however, T2D doesn't increase the risk of hospitalization or critically ill COVID-19 as an independent factor. Conclusions: Obesity, but not T2D, is a primary risk factor of COVID-19 hospitalization.

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Section: Discussionmentioning

confidence: 99%

Mendelian randomization study of obesity and type 2 diabetes in hospitalized COVID-19 patients

Glessner

et al. 2022

Metabolism

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“…For the first time, the present study found that hsa-miR-98–5p was sponged by the LINC02432 and regulated HK2 in PAAD cells. To our knowledge, LINC02432 had only been reported to be highly expressed in the kidney and pancreas ( Fagerberg et al, 2014 ; Qu et al, 2021 ). There was no report about the function of LINC02432.…”

Section: Discussionmentioning

confidence: 98%

Glycolysis-Related LINC02432/Hsa-miR-98–5p/HK2 Axis Inhibits Ferroptosis and Predicts Immune Infiltration, Tumor Mutation Burden, and Drug Sensitivity in Pancreatic Adenocarcinoma

Tan

Liu

et al. 2022

Front. Pharmacol.

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Pancreatic adenocarcinoma (PAAD) is a malignant cancer with high incidence and mortality. Glycometabolic rearrangements (aerobic glycolysis) is a hallmark of PAAD and contributes to tumorigenesis and progression through numerous mechanisms. This study aimed to identify a novel glycolysis-related lncRNA-miRNA-mRNA ceRNA signature in PAAD and explore its potential molecular function. We first calculated the glycolysis score for each PAAD patient by the ssGSEA algorithm and found that patients with higher hallmark glycolysis scores had poorer prognosis. Subsequently, we obtained a novel glycolysis-related LINC02432/hsa-miR-98–5p/HK2 axis from the TCGA and GEO databases using comprehensive bioinformatics analysis and developed a nomogram to predict overall survival. Furthermore, functional characterization analysis revealed that LINC02432/hsa-miR-98–5p/HK2 axis risk score was negatively correlated with ferroptosis. The tumor immune infiltration analysis suggested positive correlations between ceRNA risk score and infiltrated M0 macrophage levels in PAAD. Correlation analysis found that ceRNA risk scores were positively correlated with four chemokines (CXCL3, CXCL5, CXCL8 and CCL20) and one immune checkpoint gene (SIGLEC15). Meanwhile, tumor mutation burden (TMB), an indicator for predicting response to immunotherapy, was positively correlated with ceRNA risk score. Finally, the drug sensitivity analysis showed that the high-risk score patients might be more sensitive to EGFR, MEK and ERK inhibitors than low-risk score patients. In conclusion, our study suggested that LINC02432/hsa-miR-98–5p/HK2 axis may serve as a novel diagnostic, prognostic, and therapeutic target in PAAD treatment.

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“…Associations with alleles and amino acids in the HLA region were estimated using stepwise logistic regression, as previously described [19]. Second, we used PRSice-2 in the tuning set [51,56,57] to select a set of SNPs to include in the PRS using clumping and thresholding. Clumping refers to a procedure in which the most significant of two correlated SNPs (r 2 > 0.1)in a window of size 250 kbp-is kept, whereas the rest is discarded [58].…”

Section: Clumping and Thresholdingmentioning

confidence: 99%

A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies

et al. 2023

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Background. Autoimmune Addison's disease (AAD) is the most common cause of primary adrenal insufficiency (PAI). Despite its exceptionally high heritability, tools to estimate disease susceptibility in individual patients are lacking. We hypothesized that polygenic risk score (PRS) for AAD could help investigate PAI pathogenesis in pediatric patients.Methods. We here constructed and evaluated a PRS for AAD in 1223 seropositive cases and 4097 controls. To test its clinical utility, we reevaluated 18 pediatric patients, whose whole genome we also sequenced. We next explored the individual PRS in more than 120 seronegative patients with idiopathic PAI.Results. The genetic susceptibility to AADquantified using PRS-was on average 1.5 standard deviations (SD) higher in patients compared with healthy controls (p < 2e − 16), and 1.2 SD higher in the young patients compared with the old (p = 3e − 4). Using the novel PRS, we searched for pediatric patients with strikingly low AAD susceptibility and identified cases of monogenic PAI, previously misdiagnosed as AAD. By stratifying seronegative adult patients by autoimmune comorbidities and disease duration we could delineate subgroups of PRS suggesting various disease etiologies.Conclusions. The PRS performed well for casecontrol differentiation and susceptibility estimation in individual patients. Remarkably, a PRS for AAD holds promise as a means to detect disease etiologies other than autoimmunity.

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Insights into non-autoimmune type 1 diabetes with 13 novel loci in low polygenic risk score patients

Cited by 7 publications

References 63 publications

Mendelian randomization study of obesity and type 2 diabetes in hospitalized COVID-19 patients

Mendelian randomization study of obesity and type 2 diabetes in hospitalized COVID-19 patients

Glycolysis-Related LINC02432/Hsa-miR-98–5p/HK2 Axis Inhibits Ferroptosis and Predicts Immune Infiltration, Tumor Mutation Burden, and Drug Sensitivity in Pancreatic Adenocarcinoma

A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies

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