In the two-generational, community-based, Framingham Study cohort followed prospectively for incident stroke and stroke risk factors over the past 4 decades, we observed that prospectively documented parental occurrence of stroke by age 65 years, was associated with a substantially increased risk of incident stroke in the offspring. This association was evident in analyses of all-stroke as well as in analyses limited to individual stroke subtypes, being consistent across sub-groups categorized by subtypes of parental
stroke; subtypes assessed include IS, ABI, and ABI and TIA. The impact of parental stroke was greatest on the offspring risk of an early stroke occurring before age 65 years, a finding consistent with previous studies.8
The detection of a familial aggregation in stroke risk leaves open the question of the relative contribution of shared genetic and environmental factors. Previous case-control and cohort studies examining the familial aggregation of stroke have been largely based on twin studies and sib pair analyses; there is a greater probability of confounding by shared environmental exposure in these studies. Observed associations of parental and offspring stroke have also been partly attributed to familial clustering of stroke risk factors such as hypertension and left ventricular hypertrophy.25, 26, 35
In case-control studies it is difficult to accurately determine the levels of stroke risk factors present prior to the event since measurements such as blood pressure may be altered by physiological consequences or pharmacological interventions following a stroke. The current analyses utilized the availability of stroke risk factor data that had been prospectively ascertained prior to the event to adjust for baseline stroke risk factors in the offspring and showed the risk associated with parental stroke could not be entirely attributed to the inheritance and expression of baseline stroke risk factors such as hypertension in the offspring with parental stroke since the effect persisted after adjustment for stroke risk factor levels in the offspring. Moreover, the increased risk conferred by parental stroke status was observed at each quintile of offspring 10-year stroke risk as determined by the FSRP score.
Our findings are consistent with prior studies reporting a marginally stronger association of paternal stroke (relative to maternal stroke) with offspring stroke.12, 14
One prior report had described a stronger association of maternal (compared to paternal) stroke with offspring stroke,6
an observation that our study failed to confirm. One difference between the two studies is that Touze et al., questioned the proband to ascertain the occurrence of parental strokes whereas stroke events were directly verified in the Framingham parental generation. It is possible that mothers may share their medical history, particularly with regard to transient events such as TIA, more readily with their offspring than would fathers. In a previous report from the Framingham study examining the accuracy of offspring reports
of parental cardiovascular disease, an offspring’s report of maternal stroke had a greater sensitivity and positive predictive value than an offspring’s report of paternal stroke.22
Touze et al., used a cross-sectional study design that may have detected the greater probability that women, with their higher life-expectancy, would express an inherited propensity to stroke.6
Our study design which used a survival analysis is less likely to be affected by the difference in survival between women and men. Finally, Touze et al., restricted their analysis to probands in whom parental stroke status was available for both mothers and fathers,6
but repeating our analyses to exclude Offspring with only one parent enrolled in the Framingham Original cohort did not alter our results (data not presented). We did observe that the association between maternal and offspring stroke was stronger in female offspring compared to male offspring, which was in agreement with the results of a meta-analysis by the same authors.7
The strengths of our study are the community-based sample, the prospective verification of both parental and offspring stroke status, and the careful classification of stroke subtypes based on neurological examination, record review and imaging. Further, the impact of vascular risk factors could be accurately assessed since these had been systematically measured prior to the stroke, both in the parents and in the offspring. Limitations of this study include the overwhelmingly European origin of the study sample and the limited number of events among individual stroke subtypes which restricted our ability to conduct separate subgroup analysis for stroke subtypes of cardioembolic and lacunar strokes although the latter was included in the category of atherothrombotic strokes. Finally we did not adjust for newer stroke risk factors such as plasma homocysteine and CRP levels. It remains possible that the observed aggregation may be attributable to familial aggregation of unidentified environmental, behavioral, and lifestyle- related factors.
Of particular preventive interest, although family history or familial occurrence of stroke is appropriately considered to be a non-modifiable risk factor for stroke, we find that the level of conventional risk factors amplifies the increased stroke risk associated with a positive family history, particularly in the upper two quintiles of the FSRP (). Thus, attention to control of modifiable risk factors for stroke prevention, particularly in the presence of a positive familial occurrence (or history) of premature stroke, is strongly supported by these data.
Nevertheless, the demonstrated strong association of parental and offspring strokes and the particularly strong association demonstrable between IS in parent and offspring suggest that there is indeed a substantial genetic contribution to the risk of all-stroke and IS. This is unlikely to be due to shared environmental factors alone since the increased risk persisted after adjustment for levels of conventional stroke risk factors. Candidate gene studies36
and more recently genome-wide association (GWA) analyses37, 38
have identified several putative genes that may underlie this genetic propensity. It is probable that there are genes increasing the risk of all stroke types and other genes that specifically increase the risk of IS and IS subtypes. The Framingham study is currently relating 550K GWA data to the risk of incident stroke; the observed strong familial aggregation suggests that such efforts should prove fruitful. Finally, the three-fold, independent, increase in risk associated with premature parental stroke (by age 65 years in our study) suggests that this simple measure might prove a useful risk marker in clinical risk prediction. ‘Parental stroke status’ and ‘age of parent at stroke’ may be measures worth incorporating in future revisions of the Framingham and other stroke risk prediction algorithms.
The Framingham Heart Study has prospectively verified data on occurrence of stroke across two generations of participants, the Original (parental) and Offspring cohorts. We studied incident stroke risk among 3443 stroke-free Offspring (53% female, mean age 48±14 years) with verified parental stroke status (by age 65 years). Using multivariable Cox models, adjusted for age-, sex-, sib-ship and baseline stroke risk factors, we observed that over a period of 77,534 person-years, verified parental stroke by age 65 resulted in a near 3-fold, independent, increase in risk of offspring stroke (HR 2.79, 95% CI: 1.68–4.66; p<0.001 for all stroke, and HR 3.15, 95% CI: 1.69–5.88; p<0.001 for ischemic stroke). This was true for both maternal and paternal stroke. The increased risk persisted after adjustment for conventional stroke risk factors. Thus, parental stroke status might serve as a simple, clinically useful, aggregate measure of an individual’s hereditary propensity to stroke. It has been suggested that for many polygenic diseases and traits, testing for multiple risk alleles may not improve upon the use of ‘family history’ as a risk marker.