title: 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.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bick
authors.forename: Jason
authors.initials: J
authors.lastname: Flannick
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ito
authors.forename: Susan
authors.initials: S
authors.lastname: Cheng
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.forename: Michael G
authors.initials: MG
authors.lastname: Parfenov
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Herman
authors.forename: Steven R
authors.initials: SR
authors.lastname: DePalma
authors.forename: Namrata
authors.initials: N
authors.lastname: Gupta
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Birgit H
authors.initials: BH
authors.lastname: Funke
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Rehm
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
authors.forename: Jayashri
authors.initials: J
authors.lastname: Aragam
authors.forename: Herman A
authors.initials: HA
authors.lastname: Taylor
authors.forename: Ervin R
authors.initials: ER
authors.lastname: Fox
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.forename: David M
authors.initials: DM
authors.lastname: Altshuler
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Christine
authors.initials: C
authors.lastname: Seidman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002311:Cardiomyopathy, Dilated / Q000235:genetics; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008955:Models, Cardiovascular; D012307:Risk Factors; D012518:Sarcomeres / Q000235:genetics*