Potential confounding by intermediate phenotypes in studies of the genetics of ischaemic stroke.

Family history (FHx) of stroke is perceived to be an important risk factor for ischaemic stroke. However, there are several intermediate phenotypes that are often involved in the aetiology of ischaemic stroke and that have a substantial genetic component themselves. We studied FHx of ischaemic heart disease (IHD), hypertension (HTN) and diabetes mellitus (DM) as risk factors for ischaemic stroke. We performed a systematic review of case-control and cohort studies reporting on FHx(IHD), FHx(HTN) or FHx(DM) as risk factors for stroke using bibliographic databases, and by hand searching reference lists and journals. Odds ratios of FHx as a risk factor for stroke were calculated within individual studies. We included unpublished data from two Oxfordshire population-based studies to assess effects on subtypes of ischaemic stroke. We identified 54 studies that investigated the odds of stroke conferred by a positive FHx, 24 of which reported data on FHx of one or more intermediate phenotypes in addition to FHx of stroke. Most studies reported an increased frequency of FHx(IHD) and FHx(HTN) in stroke patients versus controls. The association was significant in 6 out of 14 studies for FHx(IHD) and 4 out of 11 studies for FHx(HTN). In contrast, FHx(DM) was not associated with stroke. FHx(IHD) was particularly associated with large vessel strokes (OR 1.72, CI 1.3-2.2, p = 0.00004). FHx(IHD) and FHx(HTN) are both risk factors for stroke. It is likely that the apparent heritability of stroke is partly accounted for by heritability of HTN and large vessel atherosclerosis. Analyses of heritability of stroke and candidate gene studies should be adjusted accordingly.