Epigenomic profiles of African American Transthyretin Val122Ile carriers reveals putatively dysregulated amyloid mechanisms

Abstract

The Val122Ile mutation in Transthyretin (TTR) gene causes a rare, difficult to diagnose hereditary form of cardiac amyloidosis. This mutation is most common in the United States and mainly present in people of African descent. The carriers have an increased risk of congestive heart failure and several other non-cardiac phenotypes such as carpal tunnel syndrome, peripheral edema, and arthroplasty which are top reasons for ambulatory/outpatient surgeries in the country. We conducted first-ever epigenome-wide association study in Val122Ile carriers of African descent for heart disease (HD) and multiple outpatient surgeries (OS)- an early disease indicator. Five differentially methylated sites (p≤ ;2.1e-08) in genes FAM129B, SKI, WDR27, GLS, and an intergenic site near RP11-550A5.2 and one differentially methylated region containing KCNA6 and GALNT3 (p=1.1e-12) were associated with HD. For OS, we observe four sites, two sites in UBE2E3 and SEC14L5, and other two in intergenic regions (p ≤ ;1.8e-07) and three regions overlapping SH3D21, EVA1B, LTB4R2 and CIDEB (p ≤ ;3.9e-07). Functional PPI module analysis identified ABCA1 (p=0.001) for HS. Six cis-mQTLs were associated with one of the significant CpG sites (FAM129B; p=4.1e-24). We replicated two CpG sites (cg18546846 and cg06641417; p<0.05) in an external cohort of biopsy- confirmed cases of TTR amyloidosis. The genes identified are involved in transport and clearance of amyloid deposits (GLS, ABCA1, FAM129B); cardiac fibrosis (SKI); and muscle tissue regulation (SKI, FAM129B). These findings highlight the link between a complex amyloid circuit and diverse symptoms of Val122Ile.

The integration of genetically-regulated transcriptomics and electronic health records highlights a pattern of medical outcomes related to increased hepatic transthyretin expression

“…Similarly, transcriptomic regulation appears to have a role in the onset of ATTRwt in non-carriers [20,21]. Other non-coding regulatory mechanisms such as epigenetic changes seem to affect ATTR genotype-phenotype correlation [22,23].…”

Deep embedded clustering by relevant scales and genome-wide association study in autism

“…; HCN1 and MRPS30 in Cluster 19, SMAD3 in Cluster 23, CSMD1 in Cluster 24, and HIVEP3 and NUBPL in Cluster 25 previously associated with Parkinson's disease[43][44][45][46][47][48][49]; GMPS in Cluster 28, THBS2, and WDR27 in Cluster 8, CSMD1 in Cluster 24, ADAM12 in Cluster 21, SCARB1 in Cluster 9, AATF in Cluster 31, TAFA5 in Cluster 23, and HCN1 in Cluster 19 previously associated with Alzheimer's disease[29,43,[50][51][52][53][54][55]; RPA3 in Cluster 17 previously associated with Machado-Joseph disease[56]; and NUFIP2 in Cluster 39 previously associated with microcephaly[57]; NCOR2 in Cluster 9 previously associated with spinal muscular atrophy [58]; PMP22 in Cluster 24 previously associated with neuropathy[59].In addition, several important genes associated with ASD symptoms from previous reports were included in our ndings as follows (Table 3): WDR27 in Cluster 8 previously associated with sleep disturbance [60], and HCN1 in Cluster 19 previously associated with post-traumatic stress disorder [61]. Furthermore, we observed signals in important genes associated with ASD pathways (Table 3): RGS3 in Cluster 24, which encodes a regulator of G protein signaling [62]; NUBPL in Cluster 25 is previously associated with mitochondrial disease [63] and OR13F1 in Cluster 8, which encodes an olfactory receptor [64].…”