Clinical validation of a statin-benefit polygenic score using real-world cohorts of primary prevention participants

Background Polygenic risk scores derived from coronary artery disease genome-wide association studies are associated with statin relative risk reduction.

Examine the relationship between coronary artery disease polygenic risk scores that include variants below thresholds of genome-wide significance and statin primary prevention of major adverse cardiovascular events.

We generated coronary artery disease polygenic risk scores for participants with no past evidence of myocardial infarction from three electronic health record-linked genetic biobanks: All of Us Research Program, Genetic Epidemiology Research on Adult Health and Aging, and the Million Veteran Program. We scored each participant using three different polygenic risk scores: two with both genome-wide and sub-genome-wide significant variants (metaGRS and PRS2022) and one with only variants meeting genome-wide significance (164SNP). We used covariate-adjusted Cox regression models to compare risk of major adverse cardiovascular events between statin users and nonusers matched on age, sex, smoking status, type 2 diabetes mellitus, and hypertension within strata defined by polygenic risk. For the primary analysis, we performed a meta-analysis across the three cohorts for the delta hazard ratio of statin effectiveness between high and low polygenic risk.

Across all cohorts, statin use was more strongly associated with reduced risk of major adverse cardiovascular events among participants with no myocardial infarction at index in the highest versus lowest polygenic risk score group for the PRS2022 (interaction beta 0.19, standard error 0.07, interaction P=2.3E-3) and metaGRS (interaction beta 0.14, standard error 0.07, interaction P=.02) scores. However, the association was not statistically significant (interaction beta 0.09, standard error 0.07, interaction P=.08) for the 164SNP risk score.

We demonstrated that the association between coronary artery disease polygenic risk scores and statin relative risk reduction can by enhanced with the inclusion of sub-genome-wide variants, paving the way for more research to establish clinical utility. Competing Interest Statement JAL, CCT, and ALV report grants from Alnylam Pharmaceuticals, Inc., AstraZeneca Pharmaceuticals LP, Biodesix, Inc, Janssen Pharmaceuticals, Inc., Novartis International AG, Parexel International Corporation through the University of Utah or Western Institute for Veteran Research outside the submitted work. There are no other disclosures to report. Funding Statement This study is supported by National Institutes of Health (NIH) grant R56HL161518 Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Regulatory approval for these secondary data analyses were obtained from Kaiser Permanente Mid-Atlantic States, University of California San Francisco, and Veterans Health Administration (VHA) Central Institutional Review Boards. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes The figure and supplement were added to the main text file (previously omitted inadvertently). No changes were made. Data Availability All summary-level data produced in the present study are available upon reasonable request to the authors