Dna Methylation Profiles Of African American Val122ile-Transthyretin Mutation Carriers Reveals Genes Involved In Amyloidosis Regulation

The Transthyretin ( TTR ) Val122Ile mutation causes a rare life-threatening disorder attributable to amyloid deposition. This mutation is mainly present in people of African descent; carriers have an increased risk of congestive heart failure and several other non-cardiac phenotypes such as carpal tunnel syndrome, peripheral edema, and arthroplasty. Cardiac disease in Val122Ile carriers may not depend solely on this mutation and other uninvestigated factors could contribute to clinical heterogeneity. One possible mechanism is through DNA methylation, the addition of a methyl group on CG-dinucleotides, which can result in altered gene expression. We investigated methylation changes contributing to heart disease in Val122Ile carriers to identify non-TTR regulatory mechanisms. We investigated 96 Val122Ile carriers of genetically-confirmed African descent using the Illumina EPIC array, which covers 850,000 methylation sites across the genome. We found changes in five methylated sites associated with heart disease. These map to FAM129B, SKI, WDR27, GLS , and an intergenic site near RP11-550A5.2 (p=1.6 to 4.6e-8), and a methylated region containing KCNA6 and GALNT3 (p=1.1e-12). Weighted methylated sites mapped to PPI network analysis identified ABCA1 gene (p=0.001). We also found six cis-mQTLs associated with the FAM129B CpG site (p=4.1e-24 to 2.8e-14). We replicated two of the aforementioned CpG sites near RP11-550A5.2 (p=0.021) and in FAM129B (p=0.016) at nominal significance in a case-control analysis of confirmed cases of TTR amyloidosis. GLS encodes glutaminase, which catalyzes the conversion of glutamine to glutamate. Its expression is increased in amyloid-beta neurons and neurofibrillary tangles. ABCA1 regulates cholesterol transport and interacts with APOA1 and APP ; its dysregulation increases amyloid deposition. Increasing FAM129B expression improves the clearance of amyloid deposits and rescues hippocampal neurons from apoptosis. The SKI expression modulates TGF-beta , resulting in cardiac fibrosis. Of note, SKI and FAM129B together are involved in the regularion of various muscle tissues. Collectively, these findings suggest that a complex amyloid-related gene circuit could explain diverse symptoms in Val122Ile carriers.