A potential involvement of PCSK9 in autism etiology: sequence variations, protein concentration and promoter methylation

Abstract Beside its main role in controlling blood cholesterol, PCSK9 has a role in regulating neuronal development and apoptosis. Therefore, we suggested, for the first time, a possible involvement of PCSK9 as susceptibility gene for autism. This case-control study used sanger sequencing to analyze sequence variations in the twelve exons of PCSK9 gene and their flanking intronic sequences. ELISA assay was used to determine plasma PCSK9 concentration. Methylation percentage of PCSK9 promoter-associated CpG island was assessed by methylation specific PCR(MSP). Forty-three variants were found; out of them, seven variants were differentially- existed between autistic cases and controls. rs45448095, rs45613943, rs630431, rs529500286 and rs45439391 are considered as risk factors for autism, while rs11800231 and rs483462 are protective variants. Plasma level of PCSK9 concentration is significantly elevated and promoter methylation percentage is significantly reduced in autistic cases than control subjects (P = 0.000 and 0.002, respectively). Roc curve analysis identified area under curve (AUC) for plasma PCSK9 concentration as 0.915 and for promoter methylation percentage as 0.693. Additionally, two novel variants (g.23809C > T in intron 11 and g.24071T > G in 3 ̀ UTR) were identified. This is the first study to correlate PCSK9 and autism and concluded a possible involvement of PCSK9 in autism pathogenesis as a new susceptibility gene and recommend further studies with a greater number of subjects.