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

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. Elevated blood pressure (BP) has emerged as the leading risk factor for global disease burden, with a prevalence of 24% in males and 20% in females and totalling 1.1 billion affected adults worldwide 1. Hypertension has been estimated to account for approximately 9.4 million deaths annually 2. The insidious nature of hypertension is underscored by its high prevalence, its mostly asymptomatic nature, and slow progress in achievement of targets of treatment, calling for need of fundamental transformation in attempts of hypertension control 3. There is much hope that better understanding of the underlying genetic mechanisms would result in more precise ways of screening, diagnostic classification and drug treatment of hypertension. Although major progress has been encountered in studies on pathophysiology and individualized treatment of monogenic forms of hypertension 4-6 , the clinical usefulness of genomic techniques in patients with essential hypertension has remained limited. Genome-wide association studies (GWASs) have revealed up to 900 genetic loci associated

A Systematic Review and Analysis of the Use of Polygenic Scores in Pharmacogenomics

“…As reproducibility of PGSs is extremely important, we also examined how many articles provided information outside of the Polygenic Score Catalog regarding the variants included in the PGSs (e.g., reference single‐nucleotide variant identification, effect sizes, etc.) and found that an additional nine articles provided this information in their supplementary data 39,57,58,59,60,67,68,69,72 . While these data were not provided for articles falling into categories relating to mental health and behavioral disorders, in the majority of cases PGSs were derived from data obtained from the Psychiatric Genomics Consortium (PGC), for which the summary‐level data are easily accessible.…”

“…Three articles examined the association between a PGS derived from a coronary artery disease GWAS and response to low‐density lipoprotein lowering medications, with two reporting significant associations 38,56,57 . Of the two studies that examined antihypertensives responses, only one study reported a significant association; however, the base cohort that was used to inform the PGS was small ( n = 248) 58,59 . Finally, significant associations were reported for a PGS derived from a GWAS of QRS duration (electrical heart pattern) and Brugada syndrome/response to the antiarrhythmic agent ajmaline, 60 as well as for a diverticular disease PGS and nicorandil intolerance ( Table ) 61 …”

Hypertension genetics past, present and future applications

“…One such recent study evaluated the association of a genome‐wide PRS (>1 million SNPs) with antihypertensive drug responses. This was conducted across four BP drug classes based on data with a sample of n ∼200 per drug using BP data before and after 4 weeks on monotherapy; however, no association was established [68]. Utilizing risk scores in this way is an area of research in its infancy, and this is reflected in the small sample sizes studied and consequently lower power which could influence the results obtained so far.…”

Фенотиповий Портрет Есенціальної Гіпертензії, Як Інструмент Підвищення Ефективності Її Діагностики Та Прогресування У Чоловіків Носіїв Поліморфних Варіантів Гена Кардіотрофіна-1

“…Загалом -це близько 1,1 мільярда постраждалих дорослих у всьому світі. За оцінками, щорічно гіпертензія призводить до приблизно 9,4 мільйона смертей [1]. На сьогодні, згідно сучасним уявленням, есенціальна гіпертензія (ЕГ), як провідний фактор ризику розвитку серцево-судинних захворювань є результат поєднання генетичних, екологічних та соціальних детермінант [2].…”