Familial frequency of ischaemic stroke and transient ischaemic attack in relation to clinical subtype and intermediate phenotypes
Susceptibility to cerebral ischaemia is influenced by genetic factors. However, although a number of rare Mendelian syndromes have been characterised, there have been few studies of the genetic epidemiology of the common forms of ischaemic stroke and TIA. Previous studies have not reported familial frequency in the specific clinical subtypes of ischaemic stroke, and have not assessed the extent to which familial susceptibility is related to intermediate phenotypes such as hypertension, diabetes and hyperlipidaemia. We studied family history of stroke in 544 ischaemic strokes (Oxfordshire Community Stroke Project: OCSP) and 469 TIAs (hospital-referred case series in Oxford). Information on history of stroke in first degree relatives (FDR) was obtained in 535 stokes and 467 TIAs. Stroke had occurred in a FDR of 40 (8%, 95% CI = 6 - 10) stroke cases. Positive family history was unrelated to clinical subtype (OCSP classification). In particular, it was no more common in lacunar than non-lacunar stroke. In the TIAs, there was a history of stroke in at least one FDR in 98 (21%, 95% CI = 17 - 25) cases: 80 (17%) with one FDR, 16 (3.4%) with two FDRs and 2 (0.4%) with 3+ FDRs. The frequency of hypertension increased with the number of FDRs affected (P=0.003): nil - 105/373 (28%), one - 32/78 (41%); two or more - 12/18 (67%). Mean (SD) systolic blood pressure (mmHg) also increased across these groups (P=0.02): 157 (31), 162 (30) and 177 (36). In the strokes, a history of hypertension was also more frequent in those with a family history of stroke (P=0.02), and this was also shown by differences in measured blood pressure. In both cohorts, cases without hypertension, diabetes or hyperlipidaemia were least likely to have a family history of stroke. A history of stroke in a FDR was relatively infrequent, and was not related to the clinical subtype of stroke. However, in both the strokes and TIAs, family history of stroke was strongly related to intermediate phenotypes, particularly hypertension. These data suggest that genetic susceptibility to hypertension might account for a substantial proportion of the familial clustering of ischaemic stroke and TIA.