Danny R. Rose, Jr., MD

Traylor M, Bevan S, Baron JC, Hassan A, Lewis CM, and Markus HS. The Genetic Architecture of Lacunar Stroke. Stroke. 2015
The identification of genetic risk factors has opened new avenues for understanding disease pathogenesis. With the advent of genome-wide association studies (GWAS) over the last decade, insights have been gained into the contribution of single nucleotide polymorphisms (SNPs) to a variety of disease states. The potential for these types of studies to identify therapeutic targets and implicate particular biological pathways has made them particularly enticing to researchers, but previous GWAS for lacunar stroke have been inconclusive. It has been suggested through pathologic and radiographic analyses that lacunar stroke is not a pathologically homogeneous disease, and this phenotypic heterogeneity could obscure potential genetic association in GWAS analyses. In particular, it has been suggested that there may be two distinct lacunar subtypes: isolated lacunar infarcts (ILI) associated with microatheroma and multiple lacunar infarcts and leukoaraiosis (MLA/LA) associated with diffuse small vessel arteriopathy. Traylor et al. investigated the potential heritability of lacunar stroke and its subtypes by conducting a GWAS using a highly phenotyped cohort of MRI confirmed lacunar strokes.

This study included 1,029 Caucasian subjects less than 70 years of age with a clinical lacunar syndrome related to an anatomically compatible lesion on MRI.
Subjects with other potential causes of stroke were excluded, which included those with >50% stenosis of intracranial or extracranial vessels, previous carotid endarterectomy, moderate to high probability of cardioembolic stroke by TOAST criteria, cortical infarcts and subcortical infarcts >15mm in diameter, an identified etiology of their stroke (dissection, vasculitis, hypercoagulable state) and with NOTCH3 CADASIL or Fabry mutations.Those with lacunar disease were compared to age and sex stratified controls free of clinical cerebrovascular disease. Lacunar subjects were subtyped into two groups based on the presence and severity of leukoaraiosis using the semiquantitative Fazekas scale. Both subjects with lacunar disease and controls were assessed for known risk factors associated with lacunar stroke including hypertension, diabetes, hyperlipidemia, and smoking status.

Heritability was determined using genetic restricted maximum likelihood (GREML) analyses to estimate the proportion of phenotypic variance explained by the genetic relationships among subjects with common SNPs. This was performed versus controls for all MRI defined lacunar strokes as well as the two subtypes described previously. The authors also analyzed identified SNPs using information from a database of genotype-tissue expression studies that seeks to identify “functional” sites in the genome that influence expression, as well as sites where regulatory factors are thought to bind to the genome as evidenced by matched transcription factor binding sites and DNAse footprints. Lastly, the authors tested for the potential polygenic contribution from rare variation by calculating the ratio of risk to protective variants for all lacunar stroke cases and both subtypes versus controls.

It was found that lacunar stroke verified by MRI in the selected subjects was highly heritable for the population in aggregate (h2=0.2 0-0.25, p=0.00054) as well as the ILI (h2=0.15-0.18, p=0.029) and MLI/LA subtypes (h2=0.23-0.28, p=0.0035). The point estimate suggested a higher degree of heritability for the MLI/LA subtype, suggesting an increased contribution of genetic factors as compared to the ILI subtype, although this was viewed as speculative and needs to be confirmed. The heritability of lacunar stroke from this study is comparable to other neurologic diseases with strong genetic influences such as Alzheimer’s Disease and multiple sclerosis and should prompt additional research into using GWAS to gain more insights into the pathophysiology and genetic risk factors for this disease. This is further strengthened by the finding that a significant portion of the SNPs identified were found to have roles in either gene expression or regulation. Their analysis regarding polygenic contribution of rare variation showed an increase in the ratio of risk variants to protective variants at low allele frequencies in both subtypes of lacunar stroke, but not in both subgroups combined. This suggests a distinct role for the variants implicated for each of the pathologic subtypes.

This study represents a significant step forward in our understanding of the genetic basis of lacunar stroke and leukoaraiosis. The authors’ choice of including only MRI confirmed disease as well as the decision to divide lacunar stroke into distinct pathologic subtypes for analysis appears to be a large contributing factor to the success of this study compared to previous GWAS evaluating the genetic component of lacunar stroke. Additionally, their findings showing significant contribution of rare variants to both subtypes individually, but not as a whole, provides more evidence that these do represent distinct subtypes with potentially different pathologic mechanisms. Their successful precedent for separating lacunar strokes into these groups will likely influence future study design when evaluating the lacunar stroke population as a whole to determine novel associations and findings that may be specific to one group. Although this study was limited by a somewhat small sample size and the inherently incomplete nature of functional genetic databases, it represents a promising glimpse into the genetic basis of small vessel disease.