Abstract
Background: African-Americans (AAs) have a 3.5% carrier prevalence of Transthyretin (TTR) Val122Ile mutation (rs76992529), which is the genetic cause of a hereditary form of amyloidosis. Methods: We investigated the medical history of Val122Ile carriers and assessed the role of a non-coding variation in 4361 unrelated AAs. Results: We observed that the Ile122 allele was associated with a 6.8-fold increase in the odds of having 10 or more outpatient surgeries (p = 7.81 × 10−5). Stratifying the analysis by sex, the Ile122 allele was associated with a 15.2-fold increase in the odds of having 10 or more outpatient surgeries in men (p = 6.49 × 10−7). A similar sex difference was observed with respect to the association of Val122Ile with musculoskeletal and connective-tissue disorders in an independent cohort of British subjects (n = 361,194, p = 2.47 × 10−13; nmale = 167,020, pmale = 4.02 × 10−24). In Val122Ile African-American carriers, we observed that haplotypes in the upstream region regulating TTR hepatic expression are associated with having 10 or more outpatient surgeries (p = 2.56 × 10−9). Conclusions: TTR Val122Ile showed a large effect with respect to an extreme phenotype identified in medical history that may be related to osteoarthritis, an early sign of the disease. Additionally, the non-coding variation appears to accelerate the negative consequences associated with Val122Ile mutation via TTR expression regulation.
Highlights
Transthyretin (TTR) amyloidosis is a life-threatening disease (Online Mendelian Inheritance in Man: #105210) caused by coding mutations in the TTR gene
The generally lower socioeconomic status among the AA population compared to European Americans is a possible explanation for the general lack of representation of TTR Val122Ile carriers among the cohorts of patients with hereditary cardiac amyloidosis [4]
The present study aimed to reduce the population disparity in TTR amyloidosis research, investigating two aspects of TTR Val122Ile pathogenicity: (i) The early phenotypic manifestation of the mutation in AA carriers; (ii) Whether non-coding variation in regulatory elements modulates the health status of AA carriers
Summary
Transthyretin (TTR) amyloidosis is a life-threatening disease (Online Mendelian Inheritance in Man: #105210) caused by coding mutations in the TTR gene. No analysis has been conducted previously to test this hypothesis on Val122Ile AA carriers, an in silico study based on the 1000 Genomes Project reference panel observed that some Ile122 haplotypes present different non-coding structures, including multiple regulatory variants [10]. Methods: We investigated the medical history of Val122Ile carriers and assessed the role of a non-coding variation in 4361 unrelated AAs. Results: We observed that the Ile122 allele was associated with a 6.8-fold increase in the odds of having 10 or more outpatient surgeries (p = 7.81 × 10−5). In Val122Ile African-American carriers, we observed that haplotypes in the upstream region regulating TTR hepatic expression are associated with having 10 or more outpatient surgeries (p = 2.56 × 10−9). The non-coding variation appears to accelerate the negative consequences associated with Val122Ile mutation via TTR expression regulation
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