Pseudohypoxia caused by germline genetic alterations in the VHL gene is associated with increased diabetes and cardiovascular risk: a UK biobank study

Abstract

Background: Von 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.

Methods: Demographic, 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.

Results: VHL 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.

Conclusions: VHL gene variant carriers have an increased risk of diabetes and CVA. Mediation analysis suggests pseudohypoxia as a possible mechanism.

Keywords: Cardiovascular risk; Cerebrovascular accident; Diabetes; UK biobank; Von Hippel-Lindau.

Fig. 1

Lollypop plot chart of VHL gene structure with variant distribution along the gene. Variant classification is depicted according to CLINVAR. Empty circles indicate variants that are not classified according to CLINVAR

Fig. 2

Panel A demonstrates the level of biochemical parameters, and Panel B demonstrates the risk of cardiovascular events according to variant type and location along the VHL gene. A1C– glycated hemoglobin A1C, CV– cardiovascular, CVA– cerebrovascular attack, HDL—high-density lipoprotein, IHD– ischemic heart disease, LDL—low-density lipoprotein, PVD– peripheral vascular disease, TG– triglycerides

Fig. 3

Multivariable analysis for risk of DM according to VHL gene variant type demonstrating an increased risk of DM with a 5’UTR variant. Analysis was adjusted to the participant’s age, sex, diagnosis of obesity, degree of obesity, waist circumference, hypertension, and dyslipidemia. BMI– body mass index, DM– diabetes mellitus, FS– frameshift, HDL– high density lipoprotein, HTN– hypertension, LDL– low density lipoprotein; UTR– untranslated region, VHL– von Hippel-Lindau, WC– waist circumference. *High WC was defined as ≥ 88cm in women and ≥ 102cm in men

Fig. 4

Panel A Change in level of biochemical parameters in relation to reticulocyte level. There was a significantly positive slope for blood glucose, glycated hemoglobin A1C, and triglyceride and, inversely, for HDL level. Panel B Mediation analysis evaluating the contribution of reticulocyte count, a surrogate marker of pseudohypoxia, to the risk of developing cardiometabolic outcomes, comparing individuals with 5’UTR VHL variants to non-carriers. P values in blue represent the statistical significance of the additive effect of 5’UTR variant status on the mediation pathway. HDL– high-density lipoprotein