MicroRNAs and rs1803274 SNP-based BuChe downregulation are associated with metabolic syndrome through ghrelin hydrolysis and expression quantitative traits loci regulation in PD patients

Guenson Chevalier^1*Lucas Daniel Udovin¹Matilde Otero-Losada¹Sofía Bordet^1,2Santiago Perez-Lloret^3,4Francisco Capani¹

• ¹Centro de Altos Estudios en Ciencias Humanas y de la Salud. Consejo Nacional de Investigaciones Científicas y Técnicas. CAECIHS.UAI-CONICET, Universidad Abierta Interamericana, Buenos Aires, Argentina
• ²Centro de Investigaciones en Psicología y Psicopedagogía (CIPP), Facultad de Psicología y Psicopedagogía,, Pontificia Universidad Catolica Argentina, Buenos Aires, Argentina
• ³Laboratorio de Investigación en Ciencia de Datos, Vicerrectorado de Investigación e Innovación Académica, Consejo Nacional de Investigaciones Científicas y Técnicas (UCA-CONICET)., Pontificia Universidad Catolica Argentina, Buenos Aires, Argentina
• ⁴Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina

Introduction. Metabolic syndrome (MetS) and Parkinson's disease (PD) share common pathophysiological and molecular impairments related to high PD incidence in MetS patients. In this study, we searched for independently MetS-associated single-nucleotide polymorphism variants (SNVs) in PD patients and sought to explain the molecular mechanism involved. Methods. We included 423 PD patients diagnosed by positron emission tomography (PET). Logistic regression model, chi-square and Fisher's exact test were applied to additive, dominant, and recessive genetic models of data obtained from the PPMI database. MirQTL and microRNA binding to 5'/3'-UTR and CDS region gene prediction analysis was performed. Expression quantitative trait loci mapping (eQTL) and gene prioritization of weighted co-expression network analysis were used to evaluate the molecular mechanisms. Chromosomal loci that explain variance in expression traits are called eQTLs. Results. The SNV variant rs1803274 was associated with MetS and increased cardiovascular risk and altered butyrylcholinesterase levels. Eleven microRNA binding to the BuChe 3'/'5-UTR and CDS region downregulated its expression. The rs1803274 variant was significantly enriched for neurotransmitter clearance, ghrelin secretion and deacylation, phosphatidylcholine synthesis, glycerophospholipid and lipid metabolism, and synaptic transmission. Forty-six eQTL proteins were associated with the SNV rs1803274. Thirteen of these were prioritized as potential therapeutic targets in a principal component analysis based on node degree parameters, betweenness centrality, and closeness centrality. Conclusion and interpretation. The SNV variant rs1803274 was associated with both MetS and PD and downregulated the expression of BuChe, which is involved in ghrelin hydrolysis. This variant was associated with several MetS-related eQTLs proteins or its components.