Ischaemic Stroke Subtypes and Their Genetic Basis: A Comprehensive Meta-Analysis of Small and Large Vessel Stroke

Abstract

Background: The extent to which genetic effects on the different subtypes of small (SVD) and large vessel disease (LVD) ischaemic stroke differ remains controversial. Methods: A comprehensive genetic meta-analysis of all genes investigated by ischaemic stroke subtype was conducted. Odds ratio (OR) and 95% confidence intervals (CI) were determined for each gene disease association. Results: From the initial search of 526 manuscripts, 5 candidate genes were studied comprising 7,533 cases (LVD 4,181, SVD 3,352) and 9,835 control subjects. There was a preferential association for SVD compared to LVD with ACE/DD (SVD: OR 1.31, 95% CI 0.96–1.79; LVD: OR 1.02, 95% CI 0.82–1.26) and eNOS intron 4 ab polymorphism (SVD: OR 1.41, 95% CI 0.94–2.11; LVD: OR 1.07, 95% CI 0.77–1.49), although statistical significance was not reached. No such preference was observed for MTHFR C677T, ApoE/ε4 or PAI-1 4G/5G polymorphism. The overall number of studies and the number of subjects recruited per study in whom stroke subtype was classified were small when compared to previous published work without such phenotype classification. Conclusion: Our findings suggest that genetic effects may differ between small and large vessel subtypes, although the evidence base is small.

ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing

“…[45][46][47][48][49][50][51][52] The c.1286A→C variant has been studied less, but current evidence suggests that it is milder than the "thermolabile" variant. [53][54][55][56] Preliminary findings in combined genotypes have found that they are not significantly different from controls.…”

Down but Not Out

“…This is not surprising because stroke is a heterogeneous condition encompassing many subtypes with likely different etiology, with some subtypes may having a greater genetic liability. 11,12 Like other molecular variants that have been positively associated with vascular disease, the results of this work will need to be confirmed in other populations. The investigators studied individuals from Han Chinese ancestry.…”

The clinical manifestations and pathophysiology of cerebral small vessel disease

“…VAD is the second most common type of dementia, and SVD is one of the most frequent etiologies of VAD ( 74 % of SVD, 18 % of LVD, and 8 % of both) [13] .…”

“…This discrepancy is more significant in younger (≤ 60 years) patients. The association between Hp1 and lacunar stroke may relate to BBB dysfunction, or a special dependence of small vessel wall integrity on Hp2-2 related angiogenic potential [13] . Besides, the coagulation factor XIII subunit B gene (F13B) His95Arg variant is more common in LVD patients than in SVD patients, and none of the 21 other prothrombotic gene variants are associated with LVD or SVD [45] .…”