Are polygenic risk scores for systolic blood pressure and LDL-cholesterol associated with treatment effectiveness, and clinical outcomes among those on treatment?

Abstract

Aims Many studies have investigated associations between polygenic risk scores (PRS) and the incidence of cardiovascular disease (CVD); few have examined whether risk factor-related PRS predict CVD outcomes among adults treated with risk-modifying therapies. We assessed whether PRS for systolic blood pressure (PRSSBP) and for low-density lipoprotein cholesterol (PRSLDL-C) were associated with achieving SBP and LDL-C-related targets, and with major adverse cardiovascular events (MACE: non-fatal stroke or myocardial infarction, CVD death, and revascularization procedures). Methods and results Using observational data from the UK Biobank (UKB), we calculated PRSSBP and PRSLDL-C and constructed two sub-cohorts of unrelated adults of White British ancestry aged 40–69 years and with no history of CVD, who reported taking medications used in the treatment of hypertension or hypercholesterolaemia. Treatment effectiveness in achieving adequate risk factor control was ascertained using on-treatment blood pressure (BP) or LDL-C levels measured at enrolment (uncontrolled hypertension: BP ≥ 140/90 mmHg; uncontrolled hypercholesterolaemia: LDL-C ≥ 3 mmol/L). We conducted multivariable logistic and Cox regression modelling for incident events, adjusting for socioeconomic characteristics, and CVD risk factors. There were 55 439 participants using BP lowering therapies (51.0% male, mean age 61.0 years, median follow-up 11.5 years) and 33 787 using LDL-C lowering therapies (58.5% male, mean age 61.7 years, median follow-up 11.4 years). PRSSBP was associated with uncontrolled hypertension (odds ratio 1.70; 95% confidence interval: 1.60–1.80) top vs. bottom quintile, equivalent to a 5.4 mmHg difference in SBP, and with MACE [hazard ratio (HR) 1.13; 1.04–1.23]. PRSLDL-C was associated with uncontrolled hypercholesterolaemia (HR 2.78; 2.58–3.00) but was not associated with subsequent MACE. Conclusion We extend previous findings in the UKB cohort to examine PRSSBP and PRSLDL-C with treatment effectiveness. Our results indicate that both PRSSBP and PRSLDL-C can help identify individuals who, despite being on treatment, have inadequately controlled SBP and LDL-C, and for SBP are at higher risk for CVD events. This extends the potential role of PRS in clinical practice from identifying patients who may need these interventions to identifying patients who may need more intensive intervention.

Combining pharmacogenetics and patient characteristic polygenic scores to improve outcome prediction for Calcium Channel Blocker treatment

“…Analyses of data from a randomized controlled trial (RCT) 10 found that age and baseline BP were associated with CCB response in ∼60 patients. Also, a UK Biobank study that included patients who reported antihypertensive use at baseline found SBP polygenic score was associated with uncontrolled BP (Odds ratio: 1.70; 95% CI: 1.6-1.8) 27 , top vs. bottom quintile. Another UK Biobank study testing cardiovascular associations with SBP polygenic score at baseline found high SBP increased the cardiovascular outcomes in untreated hypertension with 1.04-fold and in treated hypertension with 1.06-fold 44 .…”

“…Analyses of data from a randomized controlled trial (RCT) 10 found that age and baseline BP were associated with CCB response in ~60 patients. Also, a UK Biobank study that included patients who reported antihypertensive use at baseline found SBP polygenic score was associated with uncontrolled BP (Odds ratio: 1.70; 95% CI: 1.6-1.8) 27 , top vs. bottom quintile.…”

“…In addition to individual prediction, polygenic scores have been used to model the effects of risk traits, including BMI 23 for hypertension and CHD, and systolic and diastolic blood pressure genetic risk for phenotypic hypertension or diagnose cardiovascular diseases 24,25,26 . A recent UK Biobank study examining BP and low-density lipoprotein polygenic scores found that, among those treated for hypertension, an increased SBP polygenic score was still associated with uncontrolled hypertension 27 . However, there have been few studies utilizing polygenic scores and pharmacogenetic variants to predict clinical outcomes.…”

Possible clinical usefulness of polygenic risk scores among patients with established atherosclerotic cardiovascular disease

“…It has been demonstrated that PRS add predictive value to current clinical risk algorithms and are largely independent of disease family history [6,7]. Systolic blood pressure (SBP) and LDL-cholesterol (LDL-C) are robustly predicted by the appropriate PRS developed in several studies including meta-analysis [8][9][10][11]. Risk algorithms are proposed to be useful for NCDs, and for diseases for which lifestyle or medical therapy to decrease causative risk is available [9].…”

“…Systolic blood pressure (SBP) and LDL-cholesterol (LDL-C) are robustly predicted by the appropriate PRS developed in several studies including meta-analysis [8][9][10][11]. Risk algorithms are proposed to be useful for NCDs, and for diseases for which lifestyle or medical therapy to decrease causative risk is available [9]. Atherosclerotic cardiovascular diseases would fulfil both criteria, and including genetic information in risk models could potentially contribute to the improvement of personalized cardiovascular risk prediction or to the identification of high-risk patients, who might benefit from stricter treatment goals through treatments, as reported previously [12].…”