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Background  The genetic basis of stroke susceptibility remains to be elucidated.  STR 1 quantitative trait locus ( STR 1/ QTL ) was identified on rat chromosome 1 of stroke‐prone spontaneously hypertensive rat ( SHRSP ) upon Japanese‐style stroke‐permissive diet ( JD ), and it contributes to 20% of the stroke phenotype variance.    Methods and Results  Nine hundred eighty‐six probe sets mapping on  STR 1 were selected from the Rat  RAE 230A array and screened through a microarray differential expression analysis in brains of  SHRSP  and stroke‐resistant  SHR  ( SHRSR ) fed with either regular diet or  JD . The gene encoding Ndufc2 ( NADH  dehydrogenase [ubiquinone] 1 subunit), mapping 8 Mb apart from  STR 1/ QTL  Lod score peak, was found significantly down‐regulated under  JD  in  SHRSP  compared to  SHRSR .  Ndufc2  disruption altered complex I assembly and activity, reduced mitochondrial membrane potential and  ATP  levels, and increased reactive oxygen species production and inflammation both in vitro and in vivo.  SHRSR  carrying heterozygous  Ndufc2  deletion showed renal abnormalities and stroke occurrence under  JD , similarly to  SHRSP . In humans, T allele variant at  NDUFC 2/rs11237379 was associated with significant reduction in gene expression and with increased occurrence of early‐onset ischemic stroke by recessive mode of transmission (odds ratio [ OR ], 1.39;  CI,  1.07–1.80;  P =0.012). Subjects carrying  TT /rs11237379 and A allele variant at  NDUFC 2/rs641836 had further increased risk of stroke ( OR =1.56;  CI , 1.14–2.13;  P =0.006).    Conclusions  A significant reduction of  Ndufc2  expression causes complex I dysfunction and contributes to stroke susceptibility in  SHRSP . Moreover, our current evidence may suggest that Ndufc2 can contribute to an increased occurrence of early‐onset ischemic stroke in humans.

Ndufc2 Gene Inhibition Is Associated With Mitochondrial Dysfunction and Increased Stroke Susceptibility in an Animal Model of Complex Human Disease