Human essential hypertension: no significant association of polygenic risk scores with antihypertensive drug responses

Kimmo Porthan,Timo P Hiltunen,Kimmo K Kontula,Heini Sánez Tähtisalo,Frej Fyhrquist,Lasse Oikarinen,Juha Virolainen,Sanni Ruotsalainen,Nina Mars,Samuli Ripatti

doi:10.1038/s41598-020-68878-3

Abstract

Polygenic risk scores (PRSs) for essential hypertension, calculated from > 900 genomic loci, were recently found to explain a significant fraction of hypertension heritability and complications. To investigate whether variation of hypertension PRS also captures variation of antihypertensive drug responsiveness, we calculated two different PRSs for both systolic and diastolic blood pressure: one based on the top 793 independent hypertension-associated single nucleotide polymorphisms and another based on over 1 million genome-wide variants. Using our pharmacogenomic GENRES study comprising four different antihypertensive monotherapies (n ~ 200 for all drugs), we identified a weak, but (after Bonferroni correction) statistically nonsignificant association of higher genome-wide PRSs with weaker response to a diuretic. In addition, we noticed a correlation between high genome-wide PRS and electrocardiographic left ventricular hypertrophy. Finally, using data of the Finnish arm of the LIFE study (n = 346), we found that PRSs for systolic blood pressure were slightly higher in patients with drug-resistant hypertension than in those with drug-controlled hypertension (p = 0.03, not significant after Bonferroni correction). In conclusion, our results indicate that patients with elevated hypertension PRSs may be predisposed to difficult-to-control hypertension and complications thereof. No general association between a high PRS and less efficient drug responsiveness was noticed.

Highlights

With elevated BP7–10, but each locus mostly accounts for a very small degree of blood pressure (BP) variation
We calculated two different polygenic risk scores (PRSs) for both systolic blood pressure (SBP) and diastolic blood pressure (DBP): one based on the top 793 independent BP-associated SNPs (Top_PRS) and another based on 1 million genome-wide variants (GW_PRS)
We investigated whether variation of PRSs based on all presently known hypertension-associated SNPs signals variation on BP responses to four commonly used classes of antihypertensive drugs

Summary

Introduction

With elevated BP7–10, but each locus mostly accounts for a very small degree (typically, 0.2 mmHg) of BP variation. The recent extension of BP-associated genomic markers showed that a PRS calculated across 901 independent genetic loci identified was associated with approximately 10 mmHg BP difference between the top and bottom quintiles of the PRS d istribution[10]. In GENRES, the antihypertensive effects of four different drug classes (a diuretic, a beta blocker, a calcium channel blocker and an angiotensin receptor antagonist) were studied in a placebo-controlled, rotational fashion, and genotyping was performed for the DNA samples, permitting calculation of PRSs for hypertension. Our data set provides a tool to investigate whether PRSs for BP signifies antihypertensive drug responsiveness and whether any relation noted shows drug specificity

Methods

Results

Conclusion