Genetic variations of adenosine kinase as predictable biomarkers of efficacy of vagus nerve stimulation in patients with pharmacoresistant epilepsy

Yifan Zhang MD2, Xiongfei Wang MD, PhD1, Chongyang Tang MD, PhD1, Yuguang Guan MD, PhD1, Fan Chen MD2,3, Qing Gao MD2, Jing Wang MD, PhD3, Jian Zhou MD, PhD1, Feng Zhai MD, PhD1, Detlev Boison PhD4, Guoming Luan MD, PhD1, and Tianfu Li MD, PhD2,3
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  • 1 Department of Neurosurgery, Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing Key Laboratory of Epilepsy Research, Sanbo Brain Hospital, Capital Medical University, Beijing, China;
  • | 2 Department of Brain Institute, Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing Key Laboratory of Epilepsy Research, Sanbo Brain Hospital, Capital Medical University, Beijing, China;
  • | 3 Department of Neurology, Center of Epilepsy, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, China; and
  • | 4 Department of Neurosurgery, Robert Wood Johnson & New Jersey Medical Schools, Rutgers University, Piscataway, New Jersey
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OBJECTIVE

Vagus nerve stimulation (VNS) is an alternative treatment option for individuals with refractory epilepsy, with nearly 40% of patients showing no benefit after VNS and only 6%–8% achieving seizure freedom. It is presently unclear why some patients respond to treatment and others do not. Therefore, identification of biomarkers to predict efficacy of VNS is of utmost importance. The objective of this study was to explore whether genetic variations in genes involved in adenosine kinase (ADK), ecto-5′-nucleotidase (NT5E), and adenosine A1 receptor (A1R) are linked to outcome of VNS in patients with refractory epilepsy.

METHODS

Thirty single-nucleotide polymorphisms (SNPs), including 9 in genes encoding ADK, 3 in genes encoding NT5E, and 18 in genes encoding A1R, were genotyped in 194 refractory epilepsy patients who underwent VNS. The chi-square test and binary logistic regression were used to determine associations between genetic differences and VNS efficacy.

RESULTS

A significant association between ADK SNPs rs11001109, rs7899674, and rs946185 and seizure reduction with VNS was found. Regardless of sex, age, seizure frequency and type, antiseizure drug use, etiology, and prior surgical history, all patients (10/10 patients [100%]) with minor allele homozygosity at rs11001109 (genotype AA) or rs946185 (AA) achieved > 50% seizure reduction and 4 patients (4/10 [40%]) achieved seizure freedom. VNS therapy demonstrated higher efficacy among carriers of minor allele rs7899674 (CG + GG) (68.3% vs 48.8% for patients with major allele homozygosity).

CONCLUSIONS

Homozygous ADK SNPs rs11001109 (AA) and rs946185 (AA), as well as minor allele rs7899674 (CG + GG), may serve as useful biomarkers for prediction of VNS therapy outcome.

ABBREVIATIONS

A1R = adenosine A1 receptor; ADK = adenosine kinase; AMP = adenosine monophosphate; ASD = antiseizure drug; ATP = adenosine triphosphate; LD = linkage disequilibrium; NPV = negative predictive value; NT5E = ecto-5′-nucleotidase; PPV = positive predictive value; SNP = single-nucleotide polymorphism; VNS = vagus nerve stimulation.

Supplementary Materials

    • Table S1 (PDF 553 KB)

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