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Sex, genetic predisposition synergistic for stroke, MI risks in middle-aged people

Jairia Dela Cruz
10 Mar 2020

Being male and having a high genetic predisposition to sustain an acute vascular event (AVE) predict greater risks of stroke and myocardial infarction (MI) than either factor does alone in a population of middle-aged individuals without vascular risk factors, as shown in a study presented at the International Stroke Conference (ISC) 2020.

“Driven by ageing-related physiological changes, the incidence of stroke and MI rises rapidly in persons aged >40 years. A significant proportion of these AVE take place in persons without vascular risk factors,” according to a team of investigators led by Dr Guido Falcone from the Yale School of Medicine in New Haven, Connecticut, US.

Guido and colleagues tested the hypothesis that sex and genetic predisposition synergistically increased the risk of AVE in a UK Biobank cohort of 303,295 individuals aged 40–60 years without vascular risk factors. They constructed a polygenic risk score using 68 independent (R2<0.1) genetic variants known to be associated (p<5x10-8) with AVE, grouping participants according to tertiles of the score.

A total of 5,746 AVEs were documented, including 1,954 strokes (ischaemic and haemorrhagic) and 3,792 MIs. The cumulative risk of AVE according to age was 0.12 percent at 40 years (n=352), 0.46 percent (n=1,386) at 50 years and 1.32 percent (n=4,008) at 60 years (p-trend<0.001). [ISC 2020, abstract 71]

On Cox analysis, men had a twofold higher risk of AVE than women (hazard ratio [HR], 3.30, 95 percent confidence interval [CI], 3.08–3.53). In terms of genetic risk, the high and intermediate risk score tertiles conferred a 22-percent (HR, 1.22, 95 percent CI 1.13–1.32) and 52-percent (HR, 1.52, 95 percent CI, 1.41–1.65) risk increase, respectively, relative to the lowest tertile.

Sex and genetic predisposition showed a significant synergy, such that males with high genetic risk had about a fourfold higher risk of AVE as compared with females with low genetic predisposition (HR, 3.91, 95 percent CI, 3.58–4.26; pinteraction<0.001).

In light of the present data, Guido and his team noted that “genetic information constitutes a promising tool to risk stratify middle-aged persons without vascular risk factors.

“The synergistic effect of sex and genetic predisposition points to specific subgroups that could benefit from aggressive preventive interventions,” they added.

Stroke prevention aims at reducing the incidence through targeted modification of a single risk factor, or a cluster of multiple risk factors. A study defined three broad levels of stroke prevention: 1) primordial, which is the most generalizable and involves healthy living measures targeted to reduce the population incidence of physiologic stroke risk factors; 2) primary, which is directed at improving the risk factor profile of individuals who do not have a history of stroke or transient ischaemic attack (TIA) in order to prevent a first cerebrovascular event; and 3) secondary, which is the most targeted and is only implemented following a stroke or TIA, with the goal of preventing recurrence. [Circ Res 2017;120:472-495]

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