Genetic Predisposition to Neurological Symptoms in Lacunar Infarction

Abstract

Objective: Lacunar infarction is a unique stroke entity with characteristic symptoms. However, it is often silent clinically. The possible genetic predisposition to symptoms of lacunar infarction was investigated. Methods: One-hundred and fifty-one patients with lacunar stroke were consecutively recruited. Lacunar stroke was diagnosed based on both neurological symptoms and lacunar lesion(s), demonstrated by MRI, that were responsible for the symptoms. One-hundred and fifty control subjects with MRI-proven lacunar lesions without neurological symptoms served as controls. There was no significant difference in age, sex and prevalence of known risk factors between cases and controls. Insertion and deletion polymorphisms of the angiotensin-converting enzyme gene (ACE), M235T substitution of the angiotensinogen gene (AGT), and A1133C substitution of type 1 receptor of the angiotensin II gene were determined. Results: The frequency of ACE D allele was significantly higher in symptomatic patients compared with asymptomatic subjects (0.44 vs. 0.36, p < 0.05). The genotype distribution of AGT was significantly different between symptomatic and asymptomatic patients (χ² = 6.6, p = 0.037). Multiple logistic regression analysis revealed that ACE gene and AGT genotypes were independently associated with the neurological manifestation of lacunar infarction. In subjects with 1 lacuna, the odds ratio of the ACE DD genotype for symptomatic manifestation was 4.98 (95% CI 1.25–19.9). In subjects with 4 or more lacunae, the odds ratio of the ACE II genotype for symptomatic manifestation was 0.24 (95% CI 0.10–0.56). Furthermore, the ACE gene polymorphism was significantly different between symptomatic patients with a single lacuna and asymptomatic subjects with 4 or more multiple lacunar infarctions (χ² = 10.6, p = 0.005). Conclusion: These findings suggest that 2 subtypes of lacunar infarction, single symptomatic lacuna and multiple asymptomatic lacunae, may possess different genetic backgrounds. Subjects with the ACE DD genotype could be more predisposed to be symptomatic in first-ever lacunar stroke, while the ACE II genotype may convey resistance to symptoms even after multiple lacunar strokes. Polymorphism of genes of the renin-angiotensin system could be involved in the manifestation of neurological symptoms of lacunar infarction.

Increased Prevalence of Microangiopathic Brain Lesions among Siblings of Patients with Lacunar Stroke

“…This is supported by another MRI-based twin study which reported much higher concordance rates of MBL in monozygotic compared with dizygotic twin pairs, and in addition, revealed a MBL concordance rate of 38% among dizygotic twins, a result similar to our prevalence rate of 42% in affected sibs [24]. Moreover, recent association studies provide evidence for genetic susceptibility factors in lacunar infarction [25, 26]. However, given the lack of other studies focused on cerebral microangiopathy in siblings and the relatively small number of sib pairs in the present study, our results need to be confirmed in larger cohorts.…”

Single-Nucleotide Polymorphisms of MMP-2 Gene in Stroke Subtypes

“…Only the intron 4ab genotype of the eNOS gene was associated with isolated lacunar infarction and the AGT-20C allele may be a risk factor for leukoaraiosis [24,25,26,27]. Other studies have reported a strong association of the angiotensin-converting-enzyme genotype to lacunar stroke [28, 29] as well as a –174G/C polymorphism of interleukin 6 [30, 31] and a gene variant of α 1 -antichymotrypsin – a plasma protease inhibitor [32]. …”

From migraine to stroke

“…One form of migraine, familiar hemiplegic migraine, is known as a genetic disease [65]. Epidemiological surveys found that first-degree relatives have a higher risk to develop a migraine than people with a negative family history [66]. The angiotensin-converting enzyme gene deletion polymorphism (ACE-DD) and the methylenetetrahydrofolate reductase (MTHFR) C677-TT polymorphism are genetic factors that increase susceptibility to oxidative stress, endothelial dysfunction and stroke [16].…”