Transthyretin (TTR) gene has a causal role in a hereditary form of amyloidosis (ATTRm) and is potentially involved in the risk of wild-type transthyretin amyloidosis (ATTRwt). To understand the genetics of ATTRm and ATTRwt, we conducted a phenome-wide association study of TTR gene in 361,194 participants of European descent testing coding and non-coding variants. Among the 382 clinically relevant phenotypes tested, TTR non-coding variants were associated with 26 phenotypic traits after multiple testing correction. These included signs related to both ATTRm and ATTRwt such as chronic ischaemic heart disease (rs140226130, p = 2.00 × 10), heart failure (rs73956431, p = 2.74 × 10), atrial fibrillation (rs10163755, p = 4.63 × 10), dysphagia (rs2949506, p = 3.95 × 10), intestine diseases (rs970866, p = 7.14 × 10) and anxiety (rs554521234, p = 8.85 × 10). Consistent results were observed for TTR disease-causing mutation Val122Ile (rs76992529) with respect to carpal tunnel syndrome (p = 6.41 × 10) and mononeuropathies of upper limbs (p = 1.22 × 10). Sex differences were also observed in line with ATTRm and ATTRwt epidemiology. Additionally, we explored possible modifier genes related to TTR function, observing convergent associations of RBP4 variants with the clinical phenotypes associated with TTR locus. In conclusion, we provide novel insights regarding the molecular basis of ATTRm and ATTRwt based on large-scale cohort, expanding our understanding of the phenotypic spectrum associated with TTR gene variation.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1007/s00439-019-02078-6 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Clinical and Cardiovascular Magnetic Resonance Imaging Features of Cardiac Amyloidosis.
Rev Cardiovasc Med
October 2023
Internal Medicine and Cardiovascular Ultrasound Unit, Medical Department, SS. Annunziata Hospital, 66100 Chieti, Italy.
Article Synopsis
- Amyloidosis is a systemic disease where insoluble protein aggregates damage organs, particularly the heart, resulting in a condition known as cardiac amyloidosis (CA).
- The two main proteins involved in CA are transthyretin and misfolded immunoglobulin light chains, leading to different forms: transthyretin amyloidosis (ATTR-CA) and light-chain amyloidosis (AL-CA).
- Early detection is important for CA as it can lead to serious heart complications, and cardiovascular magnetic resonance imaging is highlighted as a useful tool for identifying it early.
Cardiac amyloidosis: diagnostic challenges and recent advancement in the treatment of transthyretin amyloidosis (ATTR).
Oxf Med Case Reports
August 2021
Department of Cardiology, St. Luke's Hospital, Chesterfield, MO, USA.
ATTR-CA is an under-reported cause of congestive heart failure (CHF) and cardiac arrhythmias. Heightened clinical suspicion along with a multimodal investigative approach is often required in diagnosing this potentially fatal condition. Tafamidis and inotersen have shown promising results in terms of progression-free survival by ameliorating CHF symptoms and peripheral neuropathies in clinical trials.
View Article and Find Full Text PDFTenosynovial complications identify TTR cardiac amyloidosis among patients with hypertrophic cardiomyopathy phenotype.
J Intern Med
June 2021
From the, Tuscan Regional Amyloidosis Centre, Careggi University Hospital, Florence, Italy.
Unlabelled: Recent evidence suggests that carpal tunnel syndrome (CTS) and brachial biceps tendon rupture (BBTR) represent red flags for ATTR cardiac amyloidosis (ATTR-CA). The prevalence of upper limb tenosynovial complications in conditions entering differential diagnosis with CA, such as HCM or Anderson-Fabry disease (AFD), and hence their predictive accuracy in this setting, still remains unresolved.
Objective: To investigate the prevalence of CTS and BBTR in a consecutive cohort of ATTR-CA patients, compared with patients with HCM or AFD and with individuals without cardiac disease history.
Association of Low Plasma Transthyretin Concentration With Risk of Heart Failure in the General Population.
JAMA Cardiol
March 2021
Section for Molecular Genetics, Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Importance: Several lines of evidence support low plasma transthyretin concentration as an in vivo biomarker of transthyretin tetramer instability, a prerequisite for the development of both wild-type transthyretin cardiac amyloidosis (ATTRwt) and hereditary transthyretin cardiac amyloidosis (ATTRm). Both ATTRm and ATTRwt cardiac amyloidosis may manifest as heart failure (HF). However, whether low plasma transthyretin concentration confers increased risk of incident HF in the general population is unknown.
View Article and Find Full Text PDFWild-type transthyretin-associated (ATTRwt) amyloidosis is an age-related disease that causes heart failure in older adults. This disease frequently features cardiac amyloid fibril deposits that originate from dissociation of the tetrameric protein, transthyretin (TTR). Unlike hereditary TTR (ATTRm) amyloidosis, where amino acid replacements destabilize the native protein, in ATTRwt amyloidosis, amyloid-forming TTR lacks protein sequence alterations.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!