East Asian–Specific Common Variant in TNNI3 Predisposes to Hypertrophic Cardiomyopathy

hypertrophy H ypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder characterized by unexplained left ventricular hypertrophy. 1 Although considered as a dominant Mendelian disease mainly caused by rare pathogenic variants in sarcomere genes, the genetic underpinnings of nearly half of patients remain unsolved. 2Increasing evidence implies that HCM has a more complex genetic architecture. 3We identified an East Asian-specific common missense variant in TNNI3 (rs3729712) associated with HCM in an exome-wide case-control association study of Chinese origin and replicated the finding in 3 independent studies (P=5.80×10 -2 ).Both the discovery study (986 cases and 761 controls) and the Beijing replication study 4 (529 cases and 307 controls) were from Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing.The other 2 replication studies, Xi'an-1 (646 cases and 468 controls) and Xi'an-2 (670 cases and 577 controls), were from Xijing Hospital of Fourth Military Medical University, Xi'an, Shaanxi.HCM was diagnosed by the presence of a maximal ventricular wall thickness ≥15 mm, or ≥13 mm in individuals with a family history of HCM, in the absence of any abnormal loading conditions capable of producing such a magnitude of hypertrophy.HCM was excluded in all the controls by a lack of primary left ventricular hypertrophy on echocardiography.The study protocols were approved by the ethics committees of both hospitals.Written informed consent was obtained from each participant.Detailed methods and results are available from the corresponding author on reasonable request and in accordance with the data sharing agreement.The discovery study samples underwent whole exome sequencing.Both single-variant association screen for common variants and gene-based association screen for rare variants were performed.As expected, rare variants in MYH7 and MYBPC3, the 2 most common causal genes of HCM, were greatly enriched in patients (Figure A).There was no novel gene attaining genome-wide significance.The single-variant association screen identified a common variant rs3729712 in TNNI3 (NC_000019:g.55667616G>A;NM_000363:c.235C>T;NP_000354:p.Arg79Cys) associated with HCM (Figure B).The minor allele frequency (MAF) of this variant was significantly higher in patients (0.055) than in controls (0.016), with the odds ratio (95% CI) per risk allele estimated to be 3.31 (2.12, 5.15; P=1.28×10 -7 ).The association was confirmed in each of the 3 replication studies, among which the Beijing replication samples and Xi'an-1 cases were genotyped by a panel sequencing of cardiomyopathy candidate genes, and the Xi'an-1 controls and Xi'an-2 samples by Sanger sequencing.The fixed-effects meta-analysis of all 4 studies estimated the odds ratio (95% CI) per risk allele to be 4. Figure C).We further classified patients into SARC+ and SARC-groups by the presence or absence of any variant of pathogenic, likely pathogenic, or unknown significance in the 8 sarcomere genes (MYH7,