The Functional ACTN3 577X Variant Increases the Risk of Falling in Older Females: Results From Two Large Independent Cohort Studies

Background. Falls among elderly people is a major issue in public health, causing debilitating outcomes including fracture. The identification of genetic risk factors for falling may provide a strategy for effectively targeting falls prevention programs. We investigated whether a common functional variant of skeletal muscle alpha-actinin-3 (ACTN3 p. R577X) previously associated with impairments in muscle strength, power, and physical functioning represents a risk factor for falls. Methods. Case-control analysis was conducted using two large cohorts of Caucasian postmenopausal women-the North of Scotland Osteoporosis Study (n = 1,245) and the Aberdeen Prospective Osteoporosis Screening Study (n = 2,918)-for whom self-reported falls status and DNA samples were available. Cross-sectional analysis of fallers versus nonfallers at baseline and follow-up was performed. In addition, individuals who reported having fallen at more than one timepoint (recurrent fallers) were compared with those who reported not falling at any timepoint. Results. Association between R577X genotype and falls was identified and validated. Carriage of 577X (one or two copies) was significantly associated with a 33% (10%-61%) increased risk of falling, with the effect apparent at both baseline and follow-up assessments (meta-analysis p =.003 and p =.02, respectively). No significant effect on recurrent falls was observed. Conclusion. This study reports for the first time that the functional ACTN3 R577X genotype represents a genetic risk factor for falling in older females.