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Abstract: A recent study suggests that the P86L polymorphism (rs2986017) in the calcium homeostasis modulator 1 (CALHM1) gene interferes with calcium homeostasis and increases amyloid β (Aβ) levels. Moreover, in vitro and in vivo data show that both calcium homeostasis and high levels of Aβ play an important role in the induction and maintenance of epileptic seizures in hippocampus, indicating CALHM1 might play a potential role in pathophysiological pathways involved in temporal lobe epilepsy (TLE). The aim of this study was to investigate the genetic contribution of CALHM1 to TLE. Five single-nucleotide polymorphisms (SNPs) of CALHM1 were selected and genotyped using polymerase chain reaction restriction fragment length polymorphism in 560 patients with TLE and 401 healthy controls. We found a positive association between rs11191692 and TLE, but a negative result between rs2986017 and TLE. The rs11191692-A allele frequency was found in 32.4% of the patients and in 26.2% of control subjects (OR=1.35, 95% CI=1.10–1.65, uncorrected P =0.003, corrected P =0.015). Furthermore, the positive association between rs11191692 and TLE independent of apolipoprotein E ε4 was supported by five SNPs haplotype analysis. The results of this study provide the first evidence that the SNP rs11191692 in CALHM1 confers highly increased susceptibility to TLE. [Copyright &y& Elsevier]