Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts

Abstract

Rare sarcomere protein variants cause dominant hypertrophic and dilated cardiomyopathies. To evaluate whether allelic variants in eight sarcomere genes are associated with cardiac morphology and function in the community, we sequenced 3,600 individuals from the Framingham Heart Study (FHS) and Jackson Heart Study (JHS) cohorts. Out of the total, 11.2% of individuals had one or more rare nonsynonymous sarcomere variants. The prevalence of likely pathogenic sarcomere variants was 0.6%, twice the previous estimates; however, only four of the 22 individuals had clinical manifestations of hypertrophic cardiomyopathy. Rare sarcomere variants were associated with an increased risk for adverse cardiovascular events (hazard ratio: 2.3) in the FHS cohort, suggesting that cardiovascular risk assessment in the general population can benefit from rare variant analysis.

Figure 1

Stratified Framingham Cardiovascular Phenotypes (A) Longitudinal regression of LVWT scaled to height over time stratified by genetic risk only (defined by one or more sarcomere variants in the absence of physiological risk factors), presence of two or more physiological risk factors (hyperlipidemia, hypertension, obesity, or diabetes), or the combination of genetic and physiologic risk factors. The inset shows a bar graph of regression line slopes, with standard deviations. (B) Longitudinal regression of left ventricular diastolic diameter (LVDD) scaled to height, stratified as above. A statistically significant decline (p < 0.05) is observed between the slope of individuals with and without genetic risk factors in the absence of physiologic risk factors. (C) Kaplan-Meier curves showing age of first adverse cardiovascular event, stratified as described above. Increased risk for first adverse cardiovascular event conferred by genetic risk factor is significant (p < .01).