Abstract
Objective:We investigated whether oxidative phosphorylation (OXPHOS) abnormalities were associated with lacunar stroke, hypothesizing that these would be more strongly associated in patients with multiple lacunar infarcts and leukoaraiosis (LA).Methods:In 1,012 MRI-confirmed lacunar stroke cases and 964 age-matched controls recruited from general practice surgeries, we investigated associations between common genetic variants within the OXPHOS pathway and lacunar stroke using a permutation-based enrichment approach. Cases were phenotyped using MRI into those with multiple infarcts or LA (MLI/LA) and those with isolated lacunar infarcts (ILI) based on the number of subcortical infarcts and degree of LA, using the Fazekas grading. Using gene-level association statistics, we tested for enrichment of genes in the OXPHOS pathway with all lacunar stroke and the 2 subtypes.Results:There was a specific association with strong evidence of enrichment in the top 1% of genes in the MLI/LA (subtype p = 0.0017) but not in the ILI subtype (p = 1). Genes in the top percentile for the all lacunar stroke analysis were not significantly enriched (p = 0.07).Conclusions:Our results implicate the OXPHOS pathway in the pathogenesis of lacunar stroke, and show the association is specific to patients with the MLI/LA subtype. They show that MRI-based subtyping of lacunar stroke can provide insights into disease pathophysiology, and imply that different radiologic subtypes of lacunar stroke subtypes have distinct underlying pathophysiologic processes.
Highlights
Our results implicate the oxidative phosphorylation (OXPHOS) pathway in the pathogenesis of lacunar stroke, and show the association is specific to patients with the multiple infarcts or LA (MLI/LA) subtype
We investigated whether common genetic variants within the OXPHOS pathway were involved in the pathogenesis of MRI-confirmed lacunar stroke using a permutation-based enrichment approach, evaluating the strength of genetic associations within genes in the OXPHOS complex compared to the background of random genes across the autosome, and determining whether strength of any associations differed by lacunar stroke subtype
Details of the study population are given in table 1; 1,012 cases and 964 controls remained after genotyping quality control steps, with 502 cases in the multiple lacunar infarcts (MLI)/LA subtypes and 501 in the isolated lacunar infarcts (ILI) subtype; in 9 cases, clear separation into different phenotypes was not possible based on brain imaging
Summary
In 1,012 MRI-confirmed lacunar stroke cases and 964 age-matched controls recruited from general practice surgeries, we investigated associations between common genetic variants within the OXPHOS pathway and lacunar stroke using a permutation-based enrichment approach. All patients underwent full stroke investigation, including brain MRI, imaging of the extracerebral arteries, arteries, and ECG. An additional 82 Caucasian patients with lacunar stroke were recruited from St. George’s Hospital, London, as part of the GENESIS study. The same inclusion and exclusion criteria were used as in the DNA-lacunar study except that older patients were included, and a similar investigation protocol was used with all patients having brain MRI
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