title: Association of a novel GABRG2 splicing variation and a PTGS2/COX-2 single nucleotide polymorphism with Taiwanese febrile seizures.
abstract: Febrile seizure (FS) is the most common type of convulsion in infants and young children. The occurrence of FS in a subset of children with febrile illness suggested genetic factors may have an important effect on the predisposition of the disease. Using targeted next generation sequencing (NGS), a novel splicing variation (NM_198903.2:c.1249-1G>T) was identified in the γ-aminobutyric acid type A (GABA-A) receptor γ2 subunit (GABRG2) gene of a FS patient. To investigate possible association of FS with single nucleotide polymorphisms (SNPs) in prostaglandin-endoperoxide synthase-2 (prostaglandin G/H synthase-2; PTGS2/cyclooxygenase-2; COX2) gene involving in thermoregulatory pathway, eight SNPs, rs689465, rs689466, rs20417, rs13306038, rs201931599, rs689470, rs4648306 and rs4648308, along with 2 previously reported variations in IL1RN (86-bp VNTR) and IL10 (rs1900872) were genotyped and utilized for case-control association studies on 35 FS and 31 non-FS controls. A single SNP (rs689466) localized at 5'-1192 of the PTGS2 gene exhibited significant association with FS (p=0.045) based on case-control allelic association analyses. A significant decrease in the frequency of the G allele in FS (0.357) was observed compared to that in controls (0.536) with an estimated odds ratio (OR) of 0.48 (95% CI, 0.23-0.99) for the G versus A allele. Using case-control genotypic association analysis, the -1192 A allele is most likely to confer susceptibility to FS by a recessive action model (p=0.045, pointwise empirical p value (EMP1)=0.049). The association of SNPs in PTGS2, in addition to IL6, IL-6 receptor (IL6R) and prostaglandin E receptor 3 (PTGER3) in prior reports, with FS suggests their possible action in concert to modulate phenotypes in FS as well as the involvement of thermoregulatory pathway in pathogenesis of FS.
authors.affiliation: School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, ROC; Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan, ROC.
authors.forename: Kun-Long
authors.initials: KL
authors.lastname: Hung
authors.affiliation: Department of Pediatrics, Far Eastern Memorial Hospital, New Taipei City, Taiwan, ROC.
authors.forename: Jao-Shwann
authors.initials: JS
authors.lastname: Liang
authors.affiliation: School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, ROC.
authors.forename: Jinn-Shyan
authors.initials: JS
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan, ROC; Department of Pediatric Neurology, MacKay Children's Hospital, Taipei, Taiwan, ROC.
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Chen
authors.affiliation: School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, ROC.
authors.forename: Li-Ju
authors.initials: LJ
authors.lastname: Lin
authors.affiliation: School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, ROC. Electronic address: jflu9421@gmail.com.
authors.forename: Jyh-Feng
authors.initials: JF
authors.lastname: Lu
mesh_terms: D044466:Asian People; D016022:Case-Control Studies; D051546:Cyclooxygenase 2 / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms; D011963:Receptors, GABA-A / Q000235:genetics*; D003294:Seizures, Febrile / Q000235:genetics*; D013624:Taiwan
chemical_list: C546279:GABRG2 protein, human; C508609:IL10 protein, human; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D020033:Protein Isoforms; D011963:Receptors, GABA-A; D016753:Interleukin-10; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
keywords: Association study; Febrile seizure; GABRG2; PTGS2/COX-2; Single nucleotide polymorphism (SNP); Targeted next generation DNA sequencing