Increased Risk of Multiple Outpatient Surgeries in African-American Carriers of Val122Ile Mutation Is Modulated by Non-Coding Variants.

African-Americans (AAs) have a 3.5% carrier prevalence of () Val122Ile mutation (rs76992529), which is the genetic cause of a hereditary form of amyloidosis. : We investigated the medical history of Val122Ile carriers and assessed the role of a non-coding variation in 4361 unrelated AAs. : We observed that the Ile122 allele was associated with a 6.8-fold increase in the odds of having 10 or more outpatient surgeries ( = 7.81 × 10). 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 ( = 6.49 × 10). 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 ( = 361,194, = 2.47 × 10; = 167,020, = 4.02 × 10). In Val122Ile African-American carriers, we observed that haplotypes in the upstream region regulating hepatic expression are associated with having 10 or more outpatient surgeries ( = 2.56 × 10). : 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 expression regulation.