Alnylam Pharmaceuticals, Inc., the leading RNAi therapeutics company, presented new results from an analysis of the UK Biobank – a prospective cohort study with genetic, physical, and health data on approximately 500,000 individuals across the United Kingdom – demonstrating a significant association of the V122I mutation, a highly prevalent mutation in the transthyretin (TTR) gene, with a clinical diagnosis of polyneuropathy. These results were presented at the Heart Failure Society of America (HFSA) 23rd Annual Scientific Meeting being held September 13-16, in Philadelphia, PA.
Founded in 2002, headquartered in Cambridge, Massachusetts, Alnylam is leading the translation of RNA interference (RNAi) into a new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system/ocular diseases. Alnylam employs over 1,200 people worldwide.
The V122I variant is the most common pathogenic TTR mutation implicated in hereditary ATTR (hATTR) amyloidosis in the US, with a reported prevalence of approximately four percent in African Americans. Historically, the V122I variant has been associated with a predominantly cardiac phenotype.
Alnylam presented findings from a phenome-wide association study demonstrating a significant association of the TTR V122I genotype with a clinical diagnosis of polyneuropathy (based on International Classification of Diseases, 10th revision [ICD10] diagnosis codes) in the black subpopulation of the UK Biobank.
Among the 6,063 unrelated black participants, 243 subjects (mean age of 52.6 years) were carriers of the TTR V122I mutation, equating to an allele frequency of two percent. Among the carriers, polyneuropathy was significantly associated with the V122I genotype (odds ratio [OR] equals 11.2; 95% confidence interval [CI]; p equals 1.1×10–6). The significant association of V122I with polyneuropathy was further replicated in the Penn Medicine Biobank from 5,737 black participants with 190 subjects who were V122I carriers.
In addition, there was nominally significant evidence that carriers of V122I were at an increased risk for other signs and symptoms of hATTR amyloidosis, including carpal tunnel syndrome and urinary retention. There was no association of V122I with cardiomyopathy, potentially due to the younger age of the carriers in the UK Biobank at the time of analysis (mean age of 52.6 years) as compared to the age at which hATTR amyloidosis with cardiomyopathy typically presents (over 65 years in the V122I population, as reported in the literature).
“The data we and collaborators presented at HFSA indicate that carriers of V122I – a TTR mutation previously thought to be associated with a phenotype presenting primarily with cardiac manifestations – have a significantly increased likelihood of a clinical diagnosis of polyneuropathy.” … “These findings demonstrate an association of V122I with the presence of a mixed clinical phenotype, supporting the need for a broader assessment of a patient’s overall health to look for multisystem manifestations of hereditary ATTR amyloidosis, which often include both cardiomyopathy and polyneuropathy.” – Eric Green, Senior Vice President and General Manager, TTR Program, Alnylam