The Impacts Of Mitochondrial DNA Haplogroup On Short-Term Neurological Outcomes Of Acute Ischemic Stroke

Part Ⅰ The effect of mitochondrial DNA haplogroup on ischemic stroke severityObjectives:A hospital-based moderate to severe ischemic stroke cohort was enrolled for analysis of the differences of cerebrovascular predictors between mitochondrial DNA haplogroups. To compare the stroke severity of different mitochondrial DNA haplogroups.Methods:Participants of this study is acute ischemic stroke patients who registered in Nanjing Stroke Registry Program (NSRP) from December 2009 to October 2013. Han Chinese patients with first-ever ischemic stroke, and aged≥18 years were included. Patients who had neuropathy or other diseases that may influence the stroke outcome were excluded. Additional limitation of NIHSS (National Institutes of Health Stroke Scale) score between 5 and 20 was also applied on participants. Finally, those had history of inherited disease were excluded. Data of demography, cerebrovascular risk factors, laboratory examinations, TOAST (Trial of Org 10172 in Acute Stroke Treatment) subtypes and clinical assessments were collected. Stroke severity was assessed with NIHSS. Three segments of mitochondrial DNA:m.15901-m.16497, m.42-m.385 and m.10400-m.10915, were selected for mitochondrial DNA haplogroups assignment; and they were sequenced with the Sanger method. MitoTool 1.1.2 released (PhyloTree Build 16 database) was used for haplogroups assignment. The clinical data of patients were compared according to haplogroups.Results:A total of 303 participants were enrolled in this study. There were 252 (82.5%) 22 were assigned into 8 major haplogroups:A (22 [6.6%]), B (44 [13.5%]), D (64 [21.1%]), G (16 [5.3%]), M7 (25 [8.3%]), M8 (27 [8.9%]), N9 (19 [6.3%]) and R9 (40 [13.2%]); the other 51 (16.8%) patients of the minor haplogroups were classified as "other". Among haplogroups, variables such age (P=0.525), sex (P=0.138), hypertension (P=0.260), diabetes mellitus (P=0.653), atrial fibrillation (P=0.912), smoking (P=0.305), alcohol drinking (P=0.638), triglyceride (P=0.458), cholesterol (P=0.747), high density lipoprotein cholesterol (P=0.846), low density lipoprotein cholesterol (P=0.903) and TOAST subtypes (P=0.466) did not differed significantly. Kruskal-Wallis test shown significant differences among mitochondrial DNA haplogroups (P=0.049); the group with the highest NIHSS score was haplogroup G (10 [7.25-12.75]), while that with the lowest NIHSS score group was haplogroup R9 (6.5 [5-8.75]); however, post-hoc comparison shown no significant difference (P= 0.012, Bonferroni corrected P=0.187).Conclusions:Mitochondrial DNA haplogroups did not influence the common predictors of ischemic stroke. Frequencies of TOAST subtypes among haplogroups observed no significant differences. Neurological deficits of ischemic stroke were differed by mtDNA haplogroups. The result did not imply which haplogroups should be responsible for the differences because the power and sample size did not meet the requirement of this problem.Part Ⅱ Impacts of Mitochondrial DNA Haplogroup on Short-Term Neurological Outcomes of Ischemic StrokeObjectives:According to the changes of 14-day NIHSS scores (with comparison of baseline NIHSS score) and 14-day mRS score, patients were grouped into neurological outcome groups and clinical outcome groups. The differences of cerebrovascular predictors were tested among neurological outcome groups and between clinical outcome groups. To evaluate the impact of mitochondrial DNA haplogroups on neurological outcome and clinical outcome.Methods:Participants of this part were the 303 patients in Part Ⅰ. According to the changes between 14-day NIHSS scores and baseline NIHSS scores, patients were grouped into neurological improved (NIHSS score decreased by ≥2 points), stabilized (NIHSS score deceased by< 2 point) and worsened (NIHSS score increased by ≥1 point) groups. In this part, data of in-hospital treatments were also collected and analyzed. According to 14-day mRS score, patients were grouped into favorable group (mRS≤ 2) and poor group (mRS>2). Demographic data, cerebrovascular risk factors, laboratory examinations, TOAST subtypes and in-hospital treatments were analyzed to conclude the predictors of neurological outcome and clinical outcome. Regression analysis were used to evaluated the association of mitochondrial DNA haplogroups and neurological outcome and clinical outcome of ischemic stroke.Results:In the analysis on neurological outcome,162 (53.5%) patients had improved neurological function; 103 (34.0%) patients neurologically stabilized; 38 (12.5%) patients were in worsened neurologic condition. Variables of hypertension (P< 0.001), diabetes mellitus (P=0.006), use of antihypertensive drugs (P=0.023), glucose-lowering drugs(P=0.022) and statin drugs (P=0.019) shown significant differences among neurological outcome groups. Ordinal regression demonstrated that mitochondrial DNA haplogroup N9 was an independent predictor against short-term neurological outcome in post-stroke patients after adjusted for variables of age, hypertension, diabetes mellitus, use of antihypertensive drugs, glucose-lowering drugs and statin drugs (OR=0.39,95% CI:0.20-0.75, P=0.005). In the analysis of clinical outcome, baseline NIHSS scores (P< 0.001) and TOAST subtypes (P=0.007) differed between two groups. In this study, no haplogroup was associated with clinical outcomes significantly.Conclusions:Mitochondrial DNA haplogroup N9 was an independent protective factor against short-term neurological worsened. This result indicated that mitochondrial DNA may play an important role in the mechanism of response to brain tissue responses to ischemia.