Genetically proxied therapeutic prolyl-hydroxylase inhibition and cardiovascular risk

Abstract

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. We used Mendelian randomization to investigate the effect of long-term Hgb level rises through genetically proxied PHD inhibition on coronary artery disease (CAD: 60 801 cases; 123 504 controls), myocardial infarction (MI: 42 561 cases; 123 504 controls) or stroke (40 585 cases; 406 111 controls). To further characterize long-term effects of Hgb level rises, we performed a phenome-wide association study (PheWAS) in up to 451 099 UK Biobank individuals. 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 estimated glomerular filtration rate and microalbuminuria, and non-alcoholic fatty liver disease (Bonferroni-adjusted P < 5.42E-05) but these were not clinically meaningful. These findings suggest that long-term alterations in Hgb through PHD inhibition are unlikely to substantially increase cardiovascular disease risk; using large disease genome-wide association study data, we could exclude ORs of 1.35 for cardiovascular risk with a 1.00 g/dl increase in Hgb.

Figure 1

The effect of a 1-unit change in Hgb levels on risk of CVD in the general population as genetically proxied by therapeutic PHD inhibition. The genetic effects per 1 standard deviation increase in circulating Hgb levels were rescaled to the typical Hgb level in the general population by multiplying the effects by the 0.81 to represent a 1-unit increase in Hgb levels (e.g. going from 14.2 to 15.2 g/dL). Based on the upper bound of the estimate, we could exclude increased odds of 1.35 for CAD, increased odds of 1.33 for MI and increased odds of 1.24 for stroke with genetically proxied therapeutic PHD inhibition. Plot was produced using forestplot package in R.

Figure 2

PheWAS of the EGLN-specific Hgb GRS with 923 traits in up to 451 099 unrelated, European UKB individuals. The Hgb GRS is most strongly associated with erythrocyte traits indicating that the EGLN-specific variants are likely acting through the hypoxic pathway and are valid and specific proxies for therapeutic PHD inhibition. We also found strong associations with relevant biomarkers. Long-term genetically mediated Hgb levels are unlikely to increase risk of additional comorbidities or unintended effects. The traits have been clustered into relevant categories.