| Title: | Pseudohypoxia caused by germline genetic alterations in the VHL gene is associated with increased diabetes and cardiovascular risk: a UK biobank study |
| Journal: | Cardiovascular Diabetology |
| Published: | 4 Jun 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40468346/ |
| DOI: | https://doi.org/10.1186/s12933-025-02799-1 |
| URL: | https://cardiab.biomedcentral.com/counter/pdf/10.1186/s12933-025-02799-1 |
Publication 15071
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Abstract
BackgroundVon Hippel-Lindau protein deficiency leads to cellular and tissue false sense of hypoxia (pseudohypoxia), driving erythropoiesis, angiogenesis, and dysglycemia. The impact of partial VHL protein deficiency, caused by heterozygous VHL gene alterations on diabetes and cardiovascular risk has not been investigated. Hence, in the current study we assessed a possible association between VHL genotype and cardiovascular risk based on a the UK Biobank genomic and clinical data.MethodsDemographic, clinical and biochemical data were extracted, and exome analysis, focusing on the VHL gene locus was performed for all patients (n = 460,430). Variant severity was sub-categorized into low (5' - and 3' - untranslated region (UTR)), medium (missense, in-frame indels), and high-risk (nonsense, splice-site, and frameshift). Metabolic and cardiovascular outcomes were compared between VHL variant carriers vs. non-carriers.ResultsVHL gene variant carriers (n = 2516) had an increased risk of diabetes (p = 0.04) and cerebrovascular accidents (CVA, p = 0.03) vs. controls, more pronounced in higher severity variants. 5'UTR variants were associated with an increased risk of diabetes (p < 0.001) and a younger age at diabetes diagnosis (p = 0.003) compared to other variants. In multivariable analysis, 5'UTR variants were associated with an increased risk of diabetes (odds ratio 2.97, 95% confidence interval 1.78-4.80, p < 0.001). Increasing reticulocyte levels positively correlated with metabolic syndrome markers (serum glucose, glycated hemoglobin, and triglyceride levels) and mediated the increased diabetes risk of 5'UTR variant carriers.ConclusionsVHL gene variant carriers have an increased risk of diabetes and CVA. Mediation analysis suggests pseudohypoxia as a possible mechanism.Graphical abstract</p>
21 Keywords
- Adult
- Aged
- Biological Specimen Banks
- Cardiovascular Diseases
- Case-Control Studies
- Diabetes Mellitus
- Female
- Genetic Association Studies
- Genetic Predisposition to Disease
- Germ-Line Mutation
- Heart Disease Risk Factors
- Heterozygote
- Humans
- Male
- Middle Aged
- Phenotype
- Risk Assessment
- UK Biobank
- United Kingdom
- Von Hippel-Lindau Tumor Suppressor Protein
- von Hippel-Lindau Disease
4 Authors
- Reut Halperin
- Roi Horwitz
- Yair Schwarz
- Amit Tirosh
1 Application
| Application ID | Title |
|---|---|
| 70580 | Impact of germline VHL variants on oncologic and metabolic phenotypes in adult Biobank participants |
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