The Role Of Genetic Polymorphism And DNA Methylation In The Pathogenesis Of Infantile Spasms

Objective: Infantile spasms (IS) are a kind of age-specific disease that occurs in infancy,which is difficult to control with conventional anti-epileptic drugs. The pathophysiologyof infantile spasms remains unclear. Prenatal stress and dysfunction of HPA axis haveinvolved in the pathogenesis of infantile spasms. We select NR3C1gene which encodethe glucocorticoid receptor as candidate gene to investigate its association with IS.Methods:128cases and131controls were recruited and9single nucleotidepolymorphisms (SNPs) of NR3C1gene were genotyped by SNaPshot technique.Asscociation analysis was performed on the genotyped data.Results: Two SNPs, rs10482672and rs2963155, showed nominal associations with IS(P=0.018, OR=1.89,95%CI=1.11-3.22, for rs10482672; P=0.04, OR=1.70,95%CI=1.03-2.81for rs2963155) under the assumption of a dominant model. The haplotypeTG of two SNPs (rs6877893and rs4912905) was associated with a decreased risk of IS(P=0.038, OR=0.66,95%CI=0.45-0.98), whereas haplotype TC being homozygous wasassociated with an increased risk of IS (P=0.015, OR=2.60,95%CI=1.20-5.60). Thers6866893were also associated with the responsiveness of adrenocorticotropic hormone(P=0.047,OR=2.56,95%CI=1.01-6.50).Conclusions: The results of the study suggest that the NR3C1gene polymorphism isassociated with the genetic susceptibility and ACTH responsiveness to IS in a Chinesepopulation. Objective: Infantile spasms are a kind of age-specific disease that occurs in infancy,which is difficult to control with conventional anti-epileptic drugs. The pathophysiologyof infantile spasms remains unclear. Prenatal stress and dysfunction of HPA axis haveinvolved in the pathogenesis of infantile spasms. We select CRHR1gene which encodethe corticotropin-reieasing hormone receptor as candidate gene to investigate itsassociation with IS.Methods: We recruited128cases and131controls in our study. Five SNPs (rs4458044,rs171440, rs17689966, rs28364026, rs242948) of CRHR1gene were genotyped bySnaPshot technique. Asscociation analysis was performed on the genotyped data.Results: The distributions of genotypic frequencies and haplotype of these five SNPsshow no significant difference between cases and controls. And there were also noassociation of the effect of ACTH with genotype of CRHR1gene.Conclusions: We found no association of disease risk between CRHR1gene and Objective: Infantile spasms is a kind of devastating childhood epileptic syndrome withunique features, including age onset during infancy, characteristic epileptic spasms, andspecific electrographic hypsarrhythmia. However, the pathophysiology of infantilespasms remains largely unclear. Considering the correlations of global DNAmethylation with several major pathologies, including cancer, syndromes involvingAlzheimer's disease and schizophrenia, we hypothesized that infantile spasms' patientsexhibited a different levels of leukocyte global DNA methylation compared withhealthy controls.Methods: DNA was extracted from peripheral blood leukocytes of20cryptogenicinfantile spasms' patients and20gender-and age-matched healthy controls. Percentageof global genome DNA methylation was measured using a global DNA methylationquantification kit.Results: Levels of global DNA methylation of peripheral blood lymphocytes in thedrug-free patients with cryptogenic infantile spasms (23.4±4.4%) was significantlylower than the gender-and age-matched healthy controls (46.8±8.2%). Furthermore, wedid not find any association between the levels of DNA methylation and effectiveness ofACTH treatment.Conclusions: Our present study demonstrates global DNA hypomethylation ofperipheral blood lymphocytes is correlated with the onset of infantile spasms. Thisfinding provides information for better understanding the onset of infantile spasms, andsuggests that the development of 'epigenetic therapies' might be a promising strategy fortreatment of infantile spasms.