Genetic variation of the transthyretin gene in wild-type transthyretin amyloidosis (ATTRwt)

Abstract

Wild-type transthyretin amyloidosis (ATTRwt), typically diagnosed as congestive heart failure in elderly Caucasian men, features myocardial amyloid deposits of wild-type plasma protein transthyretin (TTR). ATTRwt is sporadic, its pathogenesis is poorly understood, and currently there are no biomarkers for diagnosis or prognosis. Genetic studies of variant-associated transthyretin amyloidosis (ATTRm) have suggested that non-coding TTR gene variants modulate disease. We hypothesized that cis-acting regulatory elements in the TTR gene non-coding regions may modify expression, affecting ATTRwt onset and progression. We studied an ATTRwt cohort consisting of 108 Caucasian males ranging in age from 59–87 years with cardiomyopathy due to wild-type TTR deposition; results were compared to 118 anonymous controls matched by age, sex, and race. Four predicted non-coding regulatory regions and all exons in the TTR gene were sequenced using the Sanger method. Eleven common variants were identified; 3 variants were significantly associated with ATTRwt (p < 0.05), though only one, rs72922940, remained near significance (pcorrected = 0.083) after multiple testing correction. Exon analyses demonstrated the occurrence of the p.G26S (G6S) polymorphism in 7% of ATTRwt subjects and 12% of controls; this variant was predicted to be a protective factor (p = 0.051). Four variants were significantly associated with age at onset and survival. In this first genetic study of a large, well-characterized cohort of ATTRwt, non-coding and coding variants associated with disease, age at onset, and survival were identified. Further investigation is warranted to determine the prevalence of these variants in ATTRwt, their regulatory function, and potential role in assessing disease risk.

Features of atrial fibrillation in wild‐type transthyretin cardiac amyloidosis: a systematic review and clinical experience

“…There was no difference in survival when stratified by AF type, paroxysmal (hazard ratio 1.04, P = 0.89) or long standing (hazard ratio 1.37, P = 0.29). We have recently reported that a TTR concentration of <180 mg/dL was associated with reduced survival in ATTRwt . Among patients with AF, we observed borderline significant survival differences with this threshold (hazard ratio 2.0, P = 0.059; Figure B ).…”

“…We have recently reported that a TTR concentration of <180 mg/dL was associated with reduced survival in ATTRwt. 17,18 Among patients with AF, we observed borderline significant survival differences with this threshold (hazard ratio 2.0, P = 0.059; Figure 2B). The primary cause of death with heart failure which was noted in 22 of 39 (56%) of desceased patients with AF, and 8 of 10 (80%) of deceased patients without AF.…”

Maternal total T4 during the first half of pregnancy: physiologic aspects and the risk of adverse outcomes in comparison with free T4

“…In addition to interindividual differences in common genetic variants of the transthyretin and TBG gene, differences in exposure to endocrine disrupting compounds (EDCs) may also contribute to the relatively large differences in overlap between abnormal TT4 and FT4 levels observed in our study. [24][25][26] There is a rapid increase in human exposure to EDCs, 27 and many EDCs have been shown to be potent competitive binders to thyroid hormone binding protein such as transthyretin and TBG. 28,29 To our knowledge, this is the first study that systematically investigated the feasibility of the use of TT4 as a marker of maternal thyroid function during the first half pregnancy.…”

Population diversity of the genetically determined TTR expression in human tissues and its implications in TTR amyloidosis

“…It occurs as cardiomyopathy in elderly men with European ancestry, and TTR amyloid fibrils can be found in the hearts of the 25% of elderly individuals over 80 years of age [35]. A recent study provided suggestive evidences regarding the role of non-coding regulatory regions in wild-type TTR amyloidosis [36]. Together with these previous findings, our data suggest that TTR non-coding variation and its effect on transcription regulation are strong candidates as casual factors in the non-inherited form of TTR amyloidosis.…”