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

Simple Summary Even though in monogenic diseases a mutation will lead to a classic manifestation, many disorders exhibit great clinical variability that could be due to modifying genes also called minor genes. Fabry disease (FD) is an X-linked inborn error resulting from the deficient or absent activity of alpha-galactosidase A (alpha-GAL) enzyme, that leads to deposits of globotriaosylceramide. With our proprietary software SNPclinic v.1.0, we analyzed 110 single nucleotide polymorphisms (SNPs) in the proximal promoter of 14 genes that could be modifying the phenotype of FD. We found seven regulatory-SNP (rSNPs) in three genes (IL10, TGFB1 and EDN1) in five cell lines relevant to FD (cardiac myocytes, cardiac fibroblasts, astrocytes-cerebellar, endothelial cells and T helper cells 1-T(H)1). Each SNP was confirmed as a true rSNP in public eQTL databases and prediction of variants was suggested by additional software. The two proposed rSNPs in IL10, could explain components for the regulation of active B cells that influence the fibrosis process. The three predicted rSNPs in TGFB1, could act in apoptosis-autophagy regulation. The two putative rSNPs in EDN1, putatively regulate chronic inflammation. The rSNPs described here could act to modulate Fabry's clinical phenotype so we propose that IL10, TGFB1 and EDN1 be considered genetic modifiers in FD. Even though a mutation in monogenic diseases leads to a classic manifestation, many disorders exhibit great clinical variability that could be due to modifying genes also called minor genes. Fabry disease (FD) is an X-linked inborn error resulting from the deficient or absent activity of alpha-galactosidase A (alpha-GAL) enzyme, that leads to deposits of globotriaosylceramide. With our proprietary software SNPclinic v.1.0, we analyzed 110 single nucleotide polymorphisms (SNPs) in the proximal promoter of 14 genes that could modify the FD phenotype FD. We found seven regulatory-SNP (rSNPs) in three genes (IL10, TGFB1 and EDN1) in five cell lines relevant to FD (Cardiac myocytes and fibroblasts, Astrocytes-cerebellar, endothelial cells and T helper cells 1-T(H)1). Each SNP was confirmed as a true rSNP in public eQTL databases, and additional software suggested the prediction of variants. The two proposed rSNPs in IL10, could explain components for the regulation of active B cells that influence the fibrosis process. The three predicted rSNPs in TGFB1, could act in apoptosis-autophagy regulation. The two putative rSNPs in EDN1, putatively regulate chronic inflammation. The seven rSNPs described here could act to modulate Fabry's clinical phenotype so we propose that IL10, TGFB1 and EDN1 be considered minor genes in FD.

Automated summary

Even though monogenic diseases have classic manifestations caused by mutations, many disorders show clinical variability which may be attributed to modifying genes. This study identified regulatory-SNPs in IL10, TGFB1, and EDN1 genes that may modulate the clinical phenotype of Fabry disease (FD). These findings have significant implications for understanding and treating the disease.