Prediction of Regulatory SNPs in Putative Minor Genes of the Neuro-Cardiovascular Variant in Fabry Reveals Insights into Autophagy/Apoptosis and Fibrosis

Biology (Basel). 2022 Aug 30;11(9):1287. doi: 10.3390/biology11091287.

PMID: 36138766

Andrea Virginia Ruiz Ramírez, Ernesto Prado Montes de Oca, Luis E Figuer

Highlights: This study analyses 110 single nucleotide polymorphisms (SNPs) in the proximal promoter of 14 genes that could modify the phenotype of Fabry disease (FD).

Abstract:

Background: Even though a mutation in a monogenic disease results in a "classic" manifestation, many disorders have highly variable clinical manifestations that may be caused by modifying genes also called minor genes. Alpha-galactosidase A (α-GAL) enzyme activity is weak or missing in Fabry disease (FD), an X-linked inborn error that results in deposits of globotriaosylceramide.

Methods and results: 110 single nucleotide polymorphisms (SNPs) were examined in the proximal promoter of 14 genes that may affect the FD phenotype using the in-house developed SNPclinic v.1.0 program. In five cell lines relevant to FD (cardiac myocytes and fibroblasts, Astrocytes-cerebellar, endothelial cells, and T helper cells 1-TH), seven regulatory-SNP (rSNPs) were discovered in three genes (IL10, TGFB1, and EDN1). In open eQTL databases, each SNP was verified as a true rSNP, and additional software offered the variant prediction. The two hypothesized rSNPs in IL10 may help to understand how active B cell control affects the fibrosis process. The three TGFB1 predicted rSNPs may influence the control of apoptosis and autophagy. The two EDN1 putative rSNPs may control chronic inflammation.

Conclusion: This study suggests that IL10, TGFB1, and EDN1 be regarded as minor genes in FD since the seven rSNPs revealed here may act to modify the clinical phenomenology of Fabry disease.

Keywords: EDN1, Fabry disease, IL10, TGFB1, clinical variability, modifying genes, promoter, regulatory SNPs