Abstract
Ischemic stroke is a complicated disease which is affected by environmental factors and genetic factors. In this field, various studies using whole-exome sequencing (WES) have focused on novel and linkage variants in diverse diseases. Thus, we have investigated the various novel variants, which focused on their linkages to each other, in ischemic stroke. Specifically, we analyzed the N-methylpurine DNA glycosylase (MPG) gene, which plays an initiating role in DNA repair, and the nitrogen permease regulator-like 3 (NPRL3) gene, which is involved in regulating the mammalian target of rapamycin pathway. We took blood samples of 519 ischemic stroke patients and 417 controls. Genetic polymorphisms were detected by polymerase chain reaction (PCR), real-time PCR, and restriction fragment length polymorphism (RFLP) analysis. We found that two NPRL3 polymorphisms (rs2541618 C>T and rs75187722 G>A), as well as the MPG rs2562162 C>T polymorphism, were significantly associated with ischemic stroke. In Cox proportional hazard regression models, the MPG rs2562162 was associated with the survival of small-vessel disease patients in ischemic stroke. Our study showed that NPRL3 and MPG polymorphisms are associated with ischemic stroke prevalence and ischemic stroke survival. Taken together, these findings suggest that NPRL3 and MPG genotypes may be useful clinical biomarkers for ischemic stroke development and prognosis.
Highlights
In recent years, the advancement of whole-exome sequencing (WES) has allowed for enhanced screening of genetic diseases [1] and has become a useful tool for studying various diseases [2].the use of WES has resulted in large cohorts of subjects with neurodevelopmental disorders, from which numerous gene mutations have been identified, as well as the confirmation of a role for the identified variants in related pathways of more complex diseases [3,4]
adjusted ORs (AORs), adjusted odds ratio; HWE, Hardy–Weinberg equilibrium; 95% CI, 95% confidence interval; LAD, large-artery disease; SVD, small-vessel disease; CE, cardioembolism; NA, not applicable; nitrogen permease regulator-like 3 (NPRL3), nitrogen permease receptor like-3; MPG, N-methylpurine DNA glycosylase. * Adjusted by age, sex, hypertension, diabetes mellitus, hyperlipidemia, and smoking
We found that the NPRL3 rs2541618 C>T, NPRL3 rs75187722 G>A, and MPG
Summary
The use of WES has resulted in large cohorts of subjects with neurodevelopmental disorders, from which numerous gene mutations have been identified, as well as the confirmation of a role for the identified variants in related pathways of more complex diseases [3,4]. Using this approach, many genes underlying monogenic disorders have been established; the identification of genes involved in multi-genic diseases is more complicated [5]. Ischemic stroke is a multifactorial disease that is affected by both genetic [11,12] and environmental factors [13], including advanced age [14], diabetes mellitus [15], family or personal history of stroke [16], high cholesterol [17], smoking [18], hypertension [19], hyperlipidemia [20], and metabolic syndrome [21]
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