Search

BACKGROUND: It is increasingly clear that genetic and non-genetic factors account for the association of family history with disease risk in offspring. We sought to distinguish the genetic and non-genetic contributions of family history of stroke and heart disease on incident events by examining adopted and non-adopted individuals. METHODS: We examined associations between family history of stroke and heart disease with incident stroke and myocardial infarction (MI) in 495,640 participants of the UK Biobank (mean age 56.5 years, 55% female) stratified by early childhood adoption status into adoptees (n=5,747) and non-adoptees (n=489,893). We estimated hazard ratios (HRs) per affected nuclear family member, and for polygenic risk scores (PRS) for stroke and MI in Cox models adjusted for baseline age and sex. RESULTS: 12,518 strokes and 23,923 MIs occurred over a 13-year follow-up. In non-adoptees, family history of stroke and heart disease were associated with increased stroke and MI risk, with the strongest association of family history of stroke for incident stroke (HR 1.16 [1.12, 1.19]) and family history of heart disease for incident MI (HR 1.48 [1.45, 1.50]). In adoptees, family history of stroke associated with incident stroke (HR 1.41 [1.06, 1.86]), but family history of heart disease did not associate with incident MI (p>0.5). PRS showed strong disease-specific associations in adoptees and non-adoptees. In non-adoptees, the stroke PRS mediated 6% risk between family history of stroke and incident stroke, and the MI PRS mediated 13% risk between family history of heart disease and MI. CONCLUSIONS: Family history of stroke and heart disease increase risk for their respective conditions. Family history of stroke contains a substantial proportion of potentially modifiable non-genetic risk, indicating a need for further research to elucidate these elements for novel prevention strategies, whereas family history of heart disease represents predominantly genetic risk.

Background: It is increasingly clear that genetic and non-genetic factors account for the association of family history with disease risk in offspring. We sought to distinguish the genetic and non-genetic contributions of family history of stroke and heart disease on incident events by examining adopted and non-adopted individuals., Methods: We examined associations between family history of stroke and heart disease with incident stroke and myocardial infarction (MI) in 495,640 participants of the UK Biobank (mean age 56.5 years, 55% female) stratified by early childhood adoption status into adoptees (n=5,747) and non-adoptees (n=489,893). We estimated hazard ratios (HRs) per affected nuclear family member, and for polygenic risk scores (PRS) for stroke and MI in Cox models adjusted for baseline age and sex., Results: 12,518 strokes and 23,923 MIs occurred over a 13-year follow-up. In non-adoptees, family history of stroke and heart disease were associated with increased stroke and MI risk, with the strongest association of family history of stroke for incident stroke (HR 1.16 [1.12, 1.19]) and family history of heart disease for incident MI (HR 1.48 [1.45, 1.50]). In adoptees, family history of stroke associated with incident stroke (HR 1.41 [1.06, 1.86]), but family history of heart disease did not associate with incident MI (p>0.5). PRS showed strong disease-specific associations in adoptees and non-adoptees. In non-adoptees, the stroke PRS mediated 6% risk between family history of stroke and incident stroke, and the MI PRS mediated 13% risk between family history of heart disease and MI., Conclusions: Family history of stroke and heart disease increase risk for their respective conditions. Family history of stroke contains a substantial proportion of potentially modifiable non-genetic risk, indicating a need for further research to elucidate these elements for novel prevention strategies, whereas family history of heart disease represents predominantly genetic risk.

Valproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions. To overcome this limitation, we applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke. We derived a genetic score for valproate response using genome-wide association data of seizure response after valproate intake from the Epilepsy Pharmacogenomics Consortium. We then tested this score among valproate users of the UK Biobank for association with incident and recurrent ischemic stroke using Cox proportional hazard models. Among 2,150 valproate users (mean 56 years, 54% females), 82 ischemic strokes occurred over a mean 12-year follow-up. Higher valproate response genetic score was associated with higher serum valproate levels (+5.78 μg/ml per one SD, 95% CI [3.45, 8.11]). After adjusting for age and sex, higher valproate response genetic score was associated with lower ischemic stroke risk (HR per one SD 0.73, [0.58, 0.91]) with a halving of absolute risk in the highest compared to the lowest score tertile (4.8% vs 2.5%, p-trend=0.027). Among 194 valproate users with prevalent stroke at baseline, a higher valproate response genetic score was associated with lower recurrent ischemic stroke risk (HR per one SD 0.53, [0.32, 0.86]) with reduced absolute risk in the highest compared to the lowest score tertile (3/51, 5.9% vs. 13/71, 18.3%, p-trend=0.026). The valproate response genetic score was not associated with ischemic stroke among the 427,997 valproate non-users (p=0.61), suggesting minimal pleiotropy. In an independent cohort of 1,241 valproate users of the Mass General Brigham Biobank with 99 ischemic stroke events over 6.5 years follow-up, we replicated our observed associations between the valproate response genetic score and ischemic stroke (HR per one SD 0.77, 95% CI: [0.61, 0.97]). These results demonstrate that a genetically predicted favorable seizure response to valproate is associated with higher serum valproate levels and reduced ischemic stroke risk among valproate users, providing causal support for valproate effectiveness in ischemic stroke prevention. The strongest effect was found for recurrent ischemic stroke, suggesting potential dual-use benefits of valproate for post-stroke epilepsy. Clinical trials will be required in order to identify populations that may benefit most from valproate for stroke prevention.