Main findings
obesity, PRS, AF, stroke, cardioembolic stroke, hypertension
OBESITY, STROKE, DISEASE, EVENTS, HYPERTENSION
Early rhythm-control therapy reduces cardiovascular events in patients with AF across the spectrum of genetic risk for AF or stroke. As expected, the PRS-AF was associated with an increased risk for recurrent AF, but the attributable risk was modest (HR 1.08) reflecting the effectiveness of early rhythm-control therapy across the spectrum of genetic AF risk. Unexpectedly, PRS-stroke was associated with HF hospitalizations but not with stroke in this well-anticoagulated cohort. The association of the PRS-stroke with HF hospitalization was validated in the UK Biobank. This study shows that early rhythm control is effective cross the spectrum of genetic AF and stroke risk and that comprehensive AF therapy including anticoagulation on >90% of the patients and therapy of concomitant cardiovascular conditions reduces the otherwise observed association of PRS-stroke with stroke.One of the goals of genomics in medicine is to tailor therapies to an individual patient to maximize efficacy while maintaining safety.Using this data set from a randomized trial with capture of adjudicated events over a mean follow-up of over 5 years provides insight into the role PRS could have in AF care. While polygenic risk is thought to provide an additional layer of risk information that can be independent of clinical risk factors, the use in patients who have disease to inform treatment strategies is less well understood.Our findings are in accordance with earlier reports showing an association between the first genetic risk variant on chromosome 4q25, the locus that remains prominent in current GWAS for incident AF risk, with recurrent AF on different rhythm control interventions.Clinical risk factors for AF such as obesity, alcohol, or hypertension not only enable risk assessment but also provide an actionable target to modify the risk of events such as stroke whereas PRS are not modifiable.In the present data set containing well-anticoagulated patients with AF, this PRS-stroke was not predictive of stroke but the genetic risk was associated with an increased risk of HF hospitalization. In the MEGASTROKE GWAS on which the PRS-stroke is based, the association of cardioembolic stroke with known loci for incident AF risk may provide an explanation for this observation and hint to not-anticoagulated AF as a confounding factor. The lack of association of the PRS-stroke with stroke in the EAST-AFNET 4 data set could be due to low power (51 stroke events in this sub-sample of EAST-AFNET 4). Alternatively, it could also be a consequence of the high anticoagulation rate in the trial (>90%) which is much higher than in the observed in the UK Biobank (∼30%).Our analysis in the UKB confirms the finding in the EAST-AFNET4 data set that the PRS-stroke score is associated with HF events. Variants on the These hypothesis-generating findings call for further research characterizing the interactions between genetic risk for stroke and AF and cardiovascular therapies. Our data highlight that it may be premature to use PRS as selection or inclusion criteria in prospective trials as recently suggested