Dataset Information

Design and rationale of GUARDD-US: A pragmatic, randomized trial of genetic testing for APOL1 and pharmacogenomic predictors of antihypertensive efficacy in patients with hypertension.

ABSTRACT:

Rationale and objective

APOL1 risk alleles are associated with increased cardiovascular and chronic kidney disease (CKD) risk. It is unknown whether knowledge of APOL1 risk status motivates patients and providers to attain recommended blood pressure (BP) targets to reduce cardiovascular disease.

Study design

Multicenter, pragmatic, randomized controlled clinical trial.

Setting and participants

6650 individuals with African ancestry and hypertension from 13 health systems.

Intervention

APOL1 genotyping with clinical decision support (CDS) results are returned to participants and providers immediately (intervention) or at 6 months (control). A subset of participants are re-randomized to pharmacogenomic testing for relevant antihypertensive medications (pharmacogenomic sub-study). CDS alerts encourage appropriate CKD screening and antihypertensive agent use.

Outcomes

Blood pressure and surveys are assessed at baseline, 3 and 6 months. The primary outcome is change in systolic BP from enrollment to 3 months in individuals with two APOL1 risk alleles. Secondary outcomes include new diagnoses of CKD, systolic blood pressure at 6 months, diastolic BP, and survey results. The pharmacogenomic sub-study will evaluate the relationship of pharmacogenomic genotype and change in systolic BP between baseline and 3 months.

Results

To date, the trial has enrolled 3423 participants.

Conclusions

The effect of patient and provider knowledge of APOL1 genotype on systolic blood pressure has not been well-studied. GUARDD-US addresses whether blood pressure improves when patients and providers have this information. GUARDD-US provides a CDS framework for primary care and specialty clinics to incorporate APOL1 genetic risk and pharmacogenomic prescribing in the electronic health record.

Trial registration

ClinicalTrials.govNCT04191824.

SUBMITTER: Eadon MT

PROVIDER: S-EPMC9928488 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Design and rationale of GUARDD-US: A pragmatic, randomized trial of genetic testing for APOL1 and pharmacogenomic predictors of antihypertensive efficacy in patients with hypertension.

Eadon Michael T MT Cavanaugh Kerri L KL Orlando Lori A LA Christian David D Chakraborty Hrishikesh H Steen-Burrell Kady-Ann KA Merrill Peter P Seo Janet J Hauser Diane D Singh Rajbir R Beasley Cherry Maynor CM Fuloria Jyotsna J Kitzman Heather H Parker Alexander S AS Ramos Michelle M Ong Henry H HH Elwood Erica N EN Lynch Sheryl E SE Clermont Sabrina S Cicali Emily J EJ Starostik Petr P Pratt Victoria M VM Nguyen Khoa A KA Rosenman Marc B MB Calman Neil S NS Robinson Mimsie M Nadkarni Girish N GN Madden Ebony B EB Kucher Natalie N Volpi Simona S Dexter Paul R PR Skaar Todd C TC Johnson Julie A JA Cooper-DeHoff Rhonda M RM Horowitz Carol R CR

Contemporary clinical trials 20220601

<h4>Rationale and objective</h4>APOL1 risk alleles are associated with increased cardiovascular and chronic kidney disease (CKD) risk. It is unknown whether knowledge of APOL1 risk status motivates patients and providers to attain recommended blood pressure (BP) targets to reduce cardiovascular disease.<h4>Study design</h4>Multicenter, pragmatic, randomized controlled clinical trial.<h4>Setting and participants</h4>6650 individuals with African ancestry and hypertension from 13 health systems.<h ...[more]

PMID: 35660539

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Project description:BackgroundThe anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug.MethodsOptical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (n = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGB-exposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants.ResultsThe GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing.ConclusionWe set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here.

Dataset Information

Design and rationale of GUARDD-US: A pragmatic, randomized trial of genetic testing for APOL1 and pharmacogenomic predictors of antihypertensive efficacy in patients with hypertension.

Rationale and objective

Study design

Setting and participants

Intervention

Outcomes

Results

Conclusions

Trial registration

Publications

Design and rationale of GUARDD-US: A pragmatic, randomized trial of genetic testing for APOL1 and pharmacogenomic predictors of antihypertensive efficacy in patients with hypertension.

Similar Datasets

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