Contribution of TIMP4 rs3755724 polymorphism to susceptibility to focal epilepsy in Malaysian Chinese

- TIMP4 is highly expressed in brain and involves in neuroinflammation.
- TIMP4 rs3755724 is a risk factor for focal epilepsy in Malaysian Chinese.
- Rs3773364-rs3755724-rs2920502 haplotypes were not associated to focal epilepsy.

Neuroinflammation can damage the brain and plays a critical role in the pathophysiology of epilepsy. Tissue inhibitor of metalloproteinase 4 (TIMP4) is an inflammation-induced apoptosis and matrix turnover factor involved in several neuronal disorders and inflammatory diseases. Evidence has shown linkage disequilibrium between rs3755724 (-55C/T) of this gene with synapsin 2 (SYN2) rs3773364 and peroxisome proliferator-activated G receptor (PPARG) rs2920502 loci, which contribute to epilepsy in Caucasians. The aim of this study was to examine the association of these loci alone or their haplotypes with the risk of epilepsy in the Malaysian population. Genomic DNA of 1241 Malaysian Chinese, Indian, and Malay subjects (670 patients with epilepsy and 571 healthy individuals) was genotyped for the candidate loci by using the Sequenom MassArray method. Allele and genotype association of rs3755724 with susceptibility to epilepsy was significant in the Malaysian Chinese with focal epilepsy under codominant and dominant models (C vs. T: 1.5 (1.1-2.0), p = 0.02; CT vs. TT: 1.8 (1.2-2.8), p = 0.007 and 1.8 (1.2-2.7), p = 0.006, respectively). The T allele and the TT genotype were more common in patients than in controls. No significant association was found between rs2920502 and rs3773364-rs3755724-rs2920502 haplotypes for susceptibility to epilepsy in each ethnicity. This study provides evidence that the promoter TIMP4 rs3755724 is a new focal epilepsy susceptibility variant that is plausibly involved in inflammation-induced seizures in Malaysian Chinese.