Background
Prolyl-hydroxylase (PHD) inhibitors are in clinical development for anaemia in chronic kidney disease. Epidemiological studies have reported conflicting results regarding safety of long-term therapeutic haemoglobin (Hgb) rises through PHD inhibition on risk of cardiovascular disease. Genetic variation in genes encoding PHDs can be used as partial proxies to investigate the potential effects of long-term Hgb rises.
Methods
We used Mendelian Randomisation to investigate the effect of long-term Hgb level rises through genetically proxied PHD inhibition on coronary artery disease (CAD: 60801 cases; 123 504 controls), myocardial infarction (MI: 42561 cases; 123 504 controls), or stroke (40 585 cases; 406 111 controls). To further characterise long-term effects of Hgb level rises, we performed a phenome-wide association study (PheWAS) in up to 451 099 UK Biobank individuals.
Results
Genetically proxied therapeutic PHD inhibition, equivalent to a 1.00 g/dL increase in Hgb levels, was not associated (at P < 0.05) with increased odds of CAD (odd ratio (OR) [95% confidence intervals (CI)] = 1.06 [0.84, 1.35]), MI (OR [95% CI] = 1.02 [0.79, 1.33]) or stroke (OR [95% CI] = 0.91 [0.66, 1.24]). PheWAS revealed associations with blood related phenotypes consistent with EGLN’s role, relevant kidney- and liver-related biomarkers like eGFR and microalbuminuria, and NAFLD (Bonferroni-adjusted P < 5.42E-05) but these were not clinically meaningful.
Conclusions
These findings suggest that long-term alterations in Hgb through PHD inhibition are unlikely to substantially increase cardiovascular disease risk; using large disease GWAS data, we could exclude odds ratios of 1.35 of cardiovascular risk for a 1.00 g/dL increase in Hgb.
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