Genetic variants affecting mitochondrial function provide further insights for kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes. METHODS: We used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients. RESULTS: Fourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI95%:4.440-21.980; P = 2.0E-08). In UK-ROI, AGXT2-rs71615838 and SURF1-rs183853102 were associated with diabetic nephropathies, and TFB1M-rs869120 with eGFR. CONCLUSIONS: We identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM.

Case report: Strong GAD antibody positivity and type 1 diabetes-HLA-susceptible haplotype-DRB1*04:05-DQB1*04:01 in a Japanese patient with immune checkpoint inhibitor-induced type 1 diabetes.

Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment; however, they can lead to immune-related adverse events, including immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM). While fulminant T1DM is common in East Asia, ICI-T1DM has predominantly been reported in Western countries. In this report, we present the case of a 66-year-old Japanese man with type 2 diabetes mellitus undergoing dialysis for diabetic nephropathy. The patient was diagnosed with left upper lobe lung cancer, and treatment with nivolumab and ipilimumab was initiated. After 48 days, the patient experienced impaired consciousness and difficulty moving. His blood glucose levels were 815 mg/dL, and metabolic acidosis was detected, leading to a diagnosis of diabetic ketoacidosis. The patient was subsequently treated with continuous intravenous insulin. However, his C-peptide levels rapidly depleted, and new-onset ICI-T1DM was diagnosed. Although most Japanese patients with ICI-T1DM test negative for glutamic acid decarboxylase (GAD) antibodies, this case exhibited a strong positivity. Thus, we reviewed the literature on 15 similar Japanese cases, revealing a mean HbA1c level at onset of 8.7% and a mean time from ICI administration to onset of 9.7 weeks, which was shorter than that in GAD-negative cases. Moreover, human leukocyte antigen typing revealed five cases of DRB1*04:05-DQB1*04:01, including the present case, and one case of DRB1*09:01-DQB1*03:03, both of which were susceptible to T1DM haplotypes. These findings suggest that GAD antibody positivity may be associated with acute onset and disease progression in some cases of Japanese patients with ICI-T1DM. Given that the prediction of new-onset ICI-T1DM is challenging, monitoring GAD antibody levels might be useful. However, further studies with large sample sizes and validation across different racial and ethnic populations are warranted.

Insights into the development of insulin-producing cells: Precursors correlated involvement of microRNA panels.

Type 1 diabetes (T1D) is a chronic autoimmune condition characterized by the destruction of pancreatic ß cells, recently estimated to affect approximately 8.75 million individuals worldwide. At variance with conventional management of T1D, which relies on exogenous insulin replacement and insulinotropic drugs, emerging therapeutic strategies include transplantation of insulin-producing cells (IPCs) derived from stem cells or fully reprogrammed differentiated cells. Through the in-depth analysis of the microRNAs (miRNAs) involved in the differentiation of human embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs), into insulin-producing cells, this review provides a comprehensive overview of the molecular mechanisms orchestrating the transformation of precursors to cells producing insulin. In addition to miR-375, involved in all differentiation processes, and to miR-7, mir-145 and miR-9, common to the generation of insulin-producing cells from at least two different sources, the literature reveals panels of miRNAs closely related to precursor cells and associated with specific events of the physiological ß cell maturation. Since the forced modulation of miRNAs can direct cells development towards insulin-producing cells or modify their fate, a more comprehensive knowledge of the miRNAs involved in the cellular events leading to obtain efficient ß cells could improve the diagnostic, prognostic, and therapeutic approaches to diabetes.

Downregulation of hsa-miR-100-5p May Be a Protective Factor in the Early Stages of Nephropathy in Type 1 Diabetes Mellitus.

Type 1 Diabetes Mellitus (T1DM) can generate severe complications, such as Diabetic Kidney Disease (DKD) or Diabetic Nephropathy (DN), with it emerging as the leading cause of terminal (end-stage) renal disease all over the world. For T1DM, the clinical evaluation of DKD uses markers like the Glomerular Filtration Rate (GFR) and the Urinary Albumin Excretion (UAE). However, early diagnosis of DKD is still a challenge. For this reason, investigating molecular markers, such as microRNAs (miRNAs), offers a promising perspective to an early diagnosis, highlighting the stability and the ability to reflect incipient molecular manifestations. Thus, here we investigated four miRNAs (hsa-let-7i-5p, hsa-miR-143-3p, hsa-miR-501-3p, and hsa-miR-100-5p) regarding nephropathy in patients with T1DM, considering the albuminuria (micro and macro) as a standard to evaluate the groups. As a result, we found a reduced expression of miR-100-5p in patients with MIC, indicating a protective role in nephropathy. Beyond that, expression levels between the groups (Non vs. UAE) were not significant when comparing the miRNAs miR-501-3p and miR-143-3p. Finally, miR-143-3p and miR-100-5p were linked to some target genes such as AKT1, MMP13, and IGF1R, that are connected to signal pathways and cellular metabolism.

The effect of type 1 diabetes protection and susceptibility associated HLA class II genotypes on DNA methylation in immune cells.

The HLA region, especially HLA class I and II genes, which encode molecules for antigen presentation to T cells, plays a major role in the predisposition to autoimmune disorders. To clarify the mechanisms behind this association, we examined genome-wide DNA methylation by microarrays to cover over 850,000 CpG sites in the CD4+ T cells and CD19+ B cells of healthy subjects homozygous either for DRB1*15-DQA1*01-DQB1*06:02 (DR2-DQ6, n = 14), associated with a strongly decreased T1D risk, DRB1*03-DQA1*05-DQB1*02 (DR3-DQ2, n = 19), or DRB1*04:01-DQA1*03-DQB1*03:02 (DR4-DQ8, n = 17), associated with a moderately increased T1D risk. In total, we discovered 14 differentially methylated CpG probes, of which 10 were located in the HLA region and six in the HLA-DRB1 locus. The main differences were between the protective genotype DR2-DQ6 and the risk genotypes DR3-DQ2 and DR4-DQ8, where the DR2-DQ6 group was hypomethylated compared to the other groups in all but four of the differentially methylated probes. The differences between the risk genotypes DR3-DQ2 and DR4-DQ8 were small. Our results indicate that HLA variants have few systemic effects on methylation and that their effect on autoimmunity is conveyed directly by HLA molecules, possibly by differences in expression levels or function.

The causal relationship between autoimmune diseases and age-related macular degeneration: A two-sample mendelian randomization study.

OBJECTIVE: The aim of this study is to investigate the potential causal relationship between autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and Type 1 diabetes, and age-related macular degeneration (AMD). By utilizing the two-sample Mendelian Randomization (MR) approach, we endeavor to address this complex medical issue. METHODS: Genome-wide association study (GWAS) data for autoimmune diseases and AMD were obtained from the IEU Open GWAS database and the FinnGen consortium. A series of stringent SNP filtering steps was applied to ensure the reliability of the genetic instruments. MR analyses were conducted using the TwoSampleMR and MR-PRESSO packages in R. The inverse-variance weighted (IVW) method served as the primary analysis, complemented by multiple supplementary analyses and sensitivity tests. RESULTS: Within the discovery sample, only a statistically significant inverse causal relationship between multiple sclerosis (MS) and AMD was observed (OR = 0.92, 95% CI: 0.88-0.97, P = 0.003). This finding was confirmed in the replication sample (OR = 0.85, 95% CI: 0.80-0.89, P = 3.32×10-12). No statistically significant associations were detected between systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, and Type 1 diabetes and AMD. CONCLUSION: Strong evidence is provided by this study to support the existence of an inverse causal relationship between multiple sclerosis and age-related macular degeneration. However, no causal evidence was found linking other autoimmune diseases with AMD. These findings not only offer novel insights into the potential etiological mechanisms underlying AMD but also suggest possible directions for future clinical interventions.

Whole-genome sequencing identifies variants in ANK1, LRRN1, HAS1, and other genes and regulatory regions for stroke in type 1 diabetes.

Individuals with type 1 diabetes (T1D) carry a markedly increased risk of stroke, with distinct clinical and neuroimaging characteristics as compared to those without diabetes. Using whole-exome or whole-genome sequencing of 1,051 individuals with T1D, we aimed to find rare and low-frequency genomic variants associated with stroke in T1D. We analysed the genome comprehensively with single-variant analyses, gene aggregate analyses, and aggregate analyses on genomic windows, enhancers and promoters. In addition, we attempted replication in T1D using a genome-wide association study (N = 3,945) and direct genotyping (N = 3,263), and in the general population from the large-scale population-wide FinnGen project and UK Biobank summary statistics. We identified a rare missense variant on SREBF1 exome-wide significantly associated with stroke (rs114001633, p.Pro227Leu, p-value = 7.30 × 10-8), which replicated for hemorrhagic stroke in T1D. Using gene aggregate analysis, we identified exome-wide significant genes: ANK1 and LRRN1 displayed replication evidence in T1D, and LRRN1, HAS1 and UACA in the general population (UK Biobank). Furthermore, we performed sliding-window analyses and identified 14 genome-wide significant windows for stroke on 4q33-34.1, of which two replicated in T1D, and a suggestive genomic window on LINC01500, which replicated in T1D. Finally, we identified a suggestively stroke-associated TRPM2-AS promoter (p-value = 5.78 × 10-6) with borderline significant replication in T1D, which we validated with an in vitro cell-based assay. Due to the rarity of the identified genetic variants, future replication of the genomic regions represented here is required with sequencing of individuals with T1D. Nevertheless, we here report the first genome-wide analysis on stroke in individuals with diabetes.

A set of circulating microRNAs belonging to the 14q32 chromosome locus identifies two subgroups of individuals with recent-onset type 1 diabetes.

Circulating microRNAs (miRNAs) are linked to the onset and progression of type 1 diabetes mellitus (T1DM), thus representing potential disease biomarkers. In this study, we employed a multiplatform sequencing approach to analyze circulating miRNAs in an extended cohort of prospectively evaluated recent-onset T1DM individuals from the INNODIA consortium. Our findings reveal that a set of miRNAs located within T1DM susceptibility chromosomal locus 14q32 distinguishes two subgroups of individuals. To validate our results, we conducted additional analyses on a second cohort of T1DM individuals, confirming the identification of these subgroups, which we have named cluster A and cluster B. Remarkably, cluster B T1DM individuals, who exhibit increased expression of a set of 14q32 miRNAs, show better glycemic control and display a different blood immunomics profile. Our findings suggest that this set of circulating miRNAs can identify two different T1DM subgroups with distinct blood immunomics at baseline and clinical outcomes during follow-up.

Epigenetic Modulation of GPER Expression in Gastric and Colonic Smooth Muscle of Male and Female Non-Obese Diabetic (NOD) Mice: Insights into H3K4me3 and H3K27ac Modifications.

Type 1 diabetes (T1D) affects gastrointestinal (GI) motility, favoring gastroparesis, constipation, and fecal incontinence, which are more prevalent in women. The mechanisms are unknown. Given the G-protein-coupled estrogen receptor's (GPER) role in GI motility, we investigated sex-related diabetes-induced epigenetic changes in GPER. We assessed GPER mRNA and protein expression levels using qPCR and Western blot analyses, and quantified the changes in nuclear DNA methyltransferases and histone modifications (H3K4me3, H3Ac, and H3K27Ac) by ELISA kits. Targeted bisulfite and chromatin immunoprecipitation assays were used to evaluate DNA methylation and histone modifications around the GPER promoter by chromatin immunoprecipitation assays in gastric and colonic smooth muscle tissues of male and female control (CTR) and non-obese diabetic (NOD) mice. GPER expression was downregulated in NOD, with sex-dependent variations. In the gastric smooth muscle, not in colonic smooth muscle, downregulation coincided with differences in methylation ratios between regions 1 and 2 of the GPER promoter of NOD. DNA methylation was higher in NOD male colonic smooth muscle than in NOD females. H3K4me3 and H3ac enrichment decreased in NOD gastric smooth muscle. H3K4me3 levels diminished in the colonic smooth muscle of NOD. H3K27ac levels were unaffected, but enrichment decreased in NOD male gastric smooth muscle; however, it increased in the NOD male colonic smooth muscle and decreased in the female NOD colonic smooth muscle. Male NOD colonic smooth muscle exhibited decreased H3K27ac levels, not female, whereas female NOD colonic smooth muscle demonstrated diminished enrichment of H3ac at the GPER promoter, contrary to male NOD. Sex-specific epigenetic mechanisms contribute to T1D-mediated suppression of GPER expression in the GI tract. These insights advance our understanding of T1D complications and suggest promising avenues for targeted therapeutic interventions.

Type 1 diabetes human enteroid studies reveal major changes in the intestinal epithelial compartment.

Lack of understanding of the pathophysiology of gastrointestinal (GI) complications in type 1 diabetes (T1D), including altered intestinal transcriptomes and protein expression represents a major gap in the management of these patients. Human enteroids have emerged as a physiologically relevant model of the intestinal epithelium but establishing enteroids from individuals with long-standing T1D has proven difficult. We successfully established duodenal enteroids using endoscopic biopsies from pediatric T1D patients and compared them with aged-matched enteroids from healthy subjects (HS) using bulk RNA sequencing (RNA-seq), and functional analyses of ion transport processes. RNA-seq analysis showed significant differences in genes and pathways associated with cell differentiation and proliferation, cell fate commitment, and brush border membrane. Further validation of these results showed higher expression of enteroendocrine cells, and the proliferating cell marker Ki-67, significantly lower expression of NHE3, lower epithelial barrier integrity, and higher fluid secretion in response to cAMP and elevated calcium in T1D enteroids. Enteroids established from pediatric T1D duodenum identify characteristics of an abnormal intestinal epithelium and are distinct from HS. Our data supports the use of pediatric enteroids as an ex-vivo model to advance studies of GI complications and drug discovery in T1D patients.

Association between diabetes mellitus and primary biliary cholangitis: a two-sample Mendelian randomization study.

Background: Previous observational studies have demonstrated a link between diabetes mellitus(DM) and primary biliary cholangitis (PBC). Nevertheless, since these relationships might be confused, whether there is any causal connection or in which direction it exists is unclear. Our investigation aimed to identify the causal associations between DM and PBC. Methods: We acquired genome-wide association study (GWAS) datasets for PBC, Type 1 diabetes(T1DM), and Type 2 diabetes(T2DM) from published GWASs. Inverse variance-weighted (IVW), MR-Egger, weighted median (WM), Simple mode, and weighted mode methods were used to determine the causal relationships between DM(T1DM or T2DM) and PBC. Sensitivity analyses were also carried out to ensure the results were robust. To determine the causal relationship between PBC and DM(T1DM or T2DM), we also used reverse MR analysis. Results: T1DM was associated with a higher risk of PBC (OR 1.1525; 95% CI 1.0612-1.2517; p = 0.0007) in the IVW method, but no evidence of a causal effect T2DM on PBC was found (OR 0.9905; 95% CI 0.8446-1.1616; p = 0.9071) in IVW. Results of the reverse MR analysis suggested genetic susceptibility that PBC was associated with an increased risk of T1DM (IVW: OR 1.1991; 95% CI 1.12-1.2838; p = 1.81E-07), but no evidence of a causal effect PBC on T2DM was found (IVW: OR 1.0101; 95% CI 0.9892-1.0315; p = 0.3420). Conclusion: The current study indicated that T1DM increased the risk of developing PBC and vice versa. There was no proof of a causal connection between PBC probability and T2DM. Our results require confirmation through additional replication in larger populations.

Exploring potential correlations between HLA class II and the risk of microvascular complications in Japanese patients with type 1 diabetes.

Managing complications in Type 1 diabetes (T1D) remains challenging. HLA genes, particularly DR and DQ, are linked to T1D susceptibility. We studied 48 Japanese T1D inpatients and revealed associations between DRB1*04:05-DQB1*04:01 and DRB1*09:01-DQB1*03:03 haplotypes and complications, offering a new perspective for future research.

A Targeted Deep Sequencing Method to Quantify Endogenous Retrovirus Gag Sequence Variants and Open Reading Frames Expressed in Nonobese Diabetic Mice.

Endogenous retroviruses (ERVs) are involved in autoimmune diseases such as type 1 diabetes (T1D). ERV gene products homologous to murine leukemia retroviruses are expressed in the pancreatic islets of NOD mice, a model of T1D. One ERV gene, Gag, with partial or complete open reading frames (ORFs), is detected in the islets, and it contains many sequence variants. An amplicon deep sequencing analysis was established by targeting a conserved region within the Gag gene to compare NOD with T1D-resistant mice or different ages of prediabetic NOD mice. We observed that the numbers of different Gag variants and ORFs are linked to T1D susceptibility. More importantly, these numbers change during the course of diabetes development and can be quantified to calculate the levels of disease progression. Sequence alignment analysis led to identification of additional markers, including nucleotide mismatching and amino acid consensus at specific positions that can distinguish the early and late stages, before diabetes onset. Therefore, the expression of sequence variants and ORFs of ERV genes, particularly Gag, can be quantified as biomarkers to estimate T1D susceptibility and disease progression.

Autoimmune CD8+ T cells in type 1 diabetes: from single-cell RNA sequencing to T-cell receptor redirection.

Type 1 diabetes (T1D) is an organ-specific autoimmune disease caused by pancreatic ß cell destruction and mediated primarily by autoreactive CD8+ T cells. It has been shown that only a small number of stem cell-like ß cell-specific CD8+ T cells are needed to convert normal mice into T1D mice; thus, it is likely that T1D can be cured or significantly improved by modulating or altering self-reactive CD8+ T cells. However, stem cell-type, effector and exhausted CD8+ T cells play intricate and important roles in T1D. The highly diverse T-cell receptors (TCRs) also make precise and stable targeted therapy more difficult. Therefore, this review will investigate the mechanisms of autoimmune CD8+ T cells and TCRs in T1D, as well as the related single-cell RNA sequencing (ScRNA-Seq), CRISPR/Cas9, chimeric antigen receptor T-cell (CAR-T) and T-cell receptor-gene engineered T cells (TCR-T), for a detailed and clear overview. This review highlights that targeting CD8+ T cells and their TCRs may be a potential strategy for predicting or treating T1D.

A Causal Relationship Between Type 1 Diabetes and Risk of Osteoporosis: A Univariable and Multivariable Mendelian Randomization Study.

Objective: This Mendelian randomization (MR) analysis aims to investigate the causal relationship between type 1 diabetes (T1D) and osteoporosis (OP). Methods: Single nucleotide polymorphisms (SNPs) associated with T1D were selected from the summary statistics of the genome-wide association study (GWAS) in European ancestry as instrumental variables (IVs) for univariable MR (UVMR) to explore the causal relationship between T1D and OP. Inverse variance weighting (IVW) was the primary method used to assess possible causality between T1D and OP. MR-PRESSO and MR-Egger intercepts were used to assess the horizontal pleiotropy of the IVs, and Q tests and the "leave-one-out" method were used to test for heterogeneity of MR results. Multivariable MR (MVMR) analysis was used to account for potential confounders such as smoking, obesity, drinking, and serum 25-hydroxyvitamin D (25OHD) concentrations. Result: Inverse variance weighted estimates suggest T1D may increase risk of OP (UVMR: OR = 1.06, 95% CI: 1.02-1.10, p = 0.002) (MVMR: OR = 1.50, 95% CI: 1.07-1.90, p < 0.001). Conclusion: Our findings suggest that T1D can increase the risk of OP.

Monocytes in type 1 diabetes families exhibit high cytolytic activity and subset abundances that correlate with clinical progression.

Monocytes are immune regulators implicated in the pathogenesis of type 1 diabetes (T1D), an autoimmune disease that targets insulin-producing pancreatic ß cells. We determined that monocytes of recent onset (RO) T1D patients and their healthy siblings express proinflammatory/cytolytic transcriptomes and hypersecrete cytokines in response to lipopolysaccharide exposure compared to unrelated healthy controls (uHCs). Flow cytometry measured elevated circulating abundances of intermediate monocytes and >2-fold more CD14+CD16+HLADR+KLRD1+PRF1+ NK-like monocytes among patients with ROT1D compared to uHC. The intermediate to nonclassical monocyte ratio among ROT1D patients correlated with the decline in functional ß cell mass during the first 24 months after onset. Among sibling nonprogressors, temporal decreases were measured in the intermediate to nonclassical monocyte ratio and NK-like monocyte abundances; these changes coincided with increases in activated regulatory T cells. In contrast, these monocyte populations exhibited stability among T1D progressors. This study associates heightened monocyte proinflammatory/cytolytic activity with T1D susceptibility and progression and offers insight to the age-dependent decline in T1D susceptibility.

Integrated analysis of blood DNA methylation, genetic variants, circulating proteins, microRNAs, and kidney failure in type 1 diabetes.

Variation in DNA methylation (DNAmet) in white blood cells and other cells/tissues has been implicated in the etiology of progressive diabetic kidney disease (DKD). However, the specific mechanisms linking DNAmet variation in blood cells with risk of kidney failure (KF) and utility of measuring blood cell DNAmet in personalized medicine are not clear. We measured blood cell DNAmet in 277 individuals with type 1 diabetes and DKD using Illumina EPIC arrays; 51% of the cohort developed KF during 7 to 20 years of follow-up. Our epigenome-wide analysis identified DNAmet at 17 CpGs (5'-cytosine-phosphate-guanine-3' loci) associated with risk of KF independent of major clinical risk factors. DNAmet at these KF-associated CpGs remained stable over a median period of 4.7 years. Furthermore, DNAmet variations at seven KF-associated CpGs were strongly associated with multiple genetic variants at seven genomic regions, suggesting a strong genetic influence on DNAmet. The effects of DNAmet variations at the KF-associated CpGs on risk of KF were partially mediated by multiple KF-associated circulating proteins and KF-associated circulating miRNAs. A prediction model for risk of KF was developed by adding blood cell DNAmet at eight selected KF-associated CpGs to the clinical model. This updated model significantly improved prediction performance (c-statistic = 0.93) versus the clinical model (c-statistic = 0.85) at P = 6.62 × 10-14. In conclusion, our multiomics study provides insights into mechanisms through which variation of DNAmet may affect KF development and shows that blood cell DNAmet at certain CpGs can improve risk prediction for KF in T1D.

Previously undiagnosed genetic disease in adult patient with hepatic masses and reported history of congenital hyperinsulinism.

Glycogen storage disease type 1A (GSD1A), also known as Von Gierke's disease, is a rare autosomal recessive disorder affecting glycogen metabolism in the liver. It most commonly presents in infancy with hypoglycaemia and failure to thrive, but cases have been reported as undiagnosed until adulthood. A woman in her early 20s with diabetes mellitus presented with right upper quadrant pain and was found to have several haemorrhagic hepatic adenomas. This patient had insulin-dependent diabetes since a pancreatectomy at age 9 months due to continued episodes of hypoglycaemia and suspected insulinoma. During the hospital stay, the hepatic adenomas were embolised, but significant lactic acidosis and hypoglycaemia continued. Further workup revealed a chronic lactic acid level, during several hospital stays, of above 5 mmol/L. After cytology of hepatic tissue ruled out hepatocellular carcinoma, the patient was discharged and recommended to follow-up for genetic testing, which confirmed the diagnosis of GSD1A.

Gene association analysis to determine the causal relationship between immune-mediated inflammatory diseases and frozen shoulder.

Multiple studies have indicated a potential correlation between immune-mediated inflammatory diseases (IMIDs) and Frozen shoulder (FS). To explore the genetic causal relationship between IMIDs and FS using 2-sample Mendelian randomization (MR) analysis. Genome-wide association study (GWAS) summary data for FS were obtained from Green's study, while data for 10 IMIDs were sourced from the FinnGen Consortium. The MR analysis was performed using inverse variance weighting, MR Egger, and weighted median methods. IVW, as the primary MR analysis technique, was complemented with other sensitivity analyses to validate the robustness of the results. Additionally, reverse MR analysis was further conducted to investigate the presence of reverse causal relationships. In the forward MR analysis, genetically determined 4 IMIDs are causally associated with FS: rheumatoid arthritis (odds ratio [OR] (95% confidence interval [95% CI]) = 1.05 [1.02-1.09], P < .01); type 1 diabetes (OR [95% CI] = 1.06 [1.03-1.09], P < .01); hypothyroidism (OR [95% CI] = 1.07 [1.01-1.14], P = .02); and Celiac disease (OR [95% CI] = 1.02 [1.01-1.04], P = .01). However, no causal relationship was found between 6 IMIDs (autoimmune hyperthyroidism, Crohn disease, ulcerative colitis, psoriasis, sicca syndrome and systemic lupus erythematosus) and FS. Sensitivity analyses did not detect any heterogeneity or horizontal pleiotropy. In the reverse MR analysis, no causal relationship was observed between FS and IMIDs. In conclusion, this MR study suggests a potential causal relationship between rheumatoid arthritis, type 1 diabetes, hypothyroidism, and Celiac disease in the onset and development of FS. Nevertheless, more basic and clinical research will be needed in the future to support our findings.