Researchers conducting a large epigenome-wide association study identified several methylation sites associated with hereditary transthyretin amyloidosis (hATTR), a rare, life-threatening disorder caused by amyloidogenic coding mutations in the TTR gene.
Researchers conducting a large epigenome-wide association study identified several methylation sites associated with hereditary transthyretin (TTR) amyloidosis (hATTR), a rare, life-threatening disorder caused by amyloidogenic coding mutations in the TTR gene. Study findings were published in Clinical Epigenetics.
hATTR is caused by the misfolding of the TTR protein, which results in amyloid fibril deposition in tissues, including that of the heart and gastrointestinal tract. Specifically, heart failure, restrictive cardiomyopathy, and rhythm disturbances are the main clinical signs that occur after the accumulation of the misfolded protein. It is estimated approximately 1 in 100,000 individuals have hATTR, although the condition is characterized by extreme clinical heterogeneity, such as variations in age of onset, penetrance, and clinical display.
“In the context of monogenic disorders, methylation studies investigate the role of epigenetic changes involved in the phenotypic expression observed among carriers of disease-causing mutations,” the authors wrote. To identify DNA methylation sites associated with hATTR and compare patients affected with the disorder with asymptomatic carriers and noncarriers, they tested more than 700,000 sites in 80 participants.
Thirty-eight symptomatic patients and 10 asymptomatic TTR mutations carriers were recruited from 3 centers in Italy, in addition to 32 controls. “A reference-based method was employed to adjust for the heterogeneity due to the cell type composition of the whole blood samples investigated,” the researchers wrote. Cell proportions for 5 cell types were detected: B cells, granulocytes, monocytes, natural killer cells, and T cells. A linear regression was also applied.
The researchers observed “significant methylation change at cg09097335 site located in [the] Beta-secretase 2 (BACE2) gene (standardized regression coefficient = −0.60, P = 6.26 × 10–8),” which is involved in molecular pathways related to amyloid-beta metabolism, amyloid fiber formation, and Alzheimer disease.
Additional analyses revealed:
Overall, the transcriptomic analysis “showed that BACE2 is expressed in tissues affected by TTR amyloid deposits (ie, heart, nerves, colon, small intestine, and adipose tissues). Accordingly, the methylation change observed in the TTR mutation carriers is possibly due to the role of BACE2 in response to the inflammation induced by TTR amyloidogenic process in peripheral tissues,” the authors wrote.
The study’s relatively small sample size marks a limitation, and large samples will be needed to further investigate how epigenetic changes affect hATTR symptoms and differences across TTR amyloidogenic mutations.
“Further studies will be needed to characterize specific mechanisms underlying the epigenetic associations with particular attention to the potential role of amyloid-beta metabolic process and inflammatory response,” the researchers concluded. “The understanding of how methylation changes modulate the penetrance and the severity of TTR mutations could lead to the identification of novel targets to develop treatments and screening tools for the carriers.”
De Lillo A, Pathak GA, De Angelis F, et al. Epigenetic profiling of Italian patients identified methylation sites associated with hereditary transthyretin amyloidosis. Clin Epigenetics. 2020;12(1):176. doi:10.1186/s13148-020-00967-6