Background: Previous studies of genotype-phenotype correlations in hypertrophic cardiomyopathy (HCM) have presented inconsistent conclusions, potentially reflecting small studies and non-uniform phenotyping. Objectives: We aimed to identify genotype-phenotype correlations in sarcomeric variant-positive HCM cardiac magnetic resonance (CMR) imaging and adverse outcome data in the National Heart, Lung, and Blood Institute (NHLBI) HCM Registry. Methods: Of 2750 overall patients, 915 sarcomeric variant-positive ones were subgrouped by genotype. CMR measures of left ventricular (LV) hypertrophy, fibrosis and function, and adverse events, were compared. Findings were meta-analyzed with prior studies from systematic review. Results: Patients with pathogenic variants in thick-filament genes had greater hypertrophy than those in thin-filament genes - maximal LV wall thickness (maxLVWT) (21.7 {+/-} 5.0 vs. 20.0 {+/-} 4.4mm, P<0.01) and indexed LV mass (81.9 {+/-} 26.0 vs. 71.7 {+/-} 13.3g/m2, P<0.001). Of the former, MYBPC3 carriers had greater maxLVWT than MYH7 carriers (22.2 {+/-} 5.2 vs. 20.9 {+/-} 4.5mm, P<0.01) but lower LV ejection fraction (63.1 {+/-} 8.4 vs. 65.3 {+/-} 8.4%, P<0.001). Findings remained significant after covariate adjustment and meta-analysis. 23 (~1%) patients had >1 disease-linked variants with only 3 (~0.11%) carrying >1 pathogenic variants. MYBPC3 carriers had lower risk of a multiple event composite than MYH7 carriers. Conclusions: In the largest CMR-based study to date, we identified significant phenotypic differences that characterize disease-gene subgroups and resolved prior discrepancies through systematic review and meta-analysis. However, carriage of >1 sarcomeric variants did not contribute much to variation in phenotypic severity in the general HCM population due to its rarity.
J. H. Chan, C. Grace, K. Thomson et al.· medRxiv· 0 citations
BACKGROUND
Most drugs target proteins, and proteome-wide genetic analyses in diverse populations could discover potential novel and repurposed targets for improved prevention and treatment of ischemic heart disease (IHD) beyond statin therapy.
OBJECTIVES
The purposes of this study were to use cis-acting single nucleotide polymorphisms (cis-pQTLs) identified for plasma proteins in East Asians and Europeans to discover and validate potential drug targets for IHD.
METHODS
We measured plasma levels of 9,520 (Olink/SomaScan: 2,923/7,297) proteins in a case-cohort study of IHD (1,976 incident cases and 2,001 subcohort controls) in statin-free individuals in the prospective China Kadoorie Biobank (CKB). Genome-wide association studies identified 2,895 (Olink/SomaScan: 1,301/1,594) cis-pQTLs for these proteins in CKB. Two-sample Mendelian randomization (MR) and colocalization analyses assessed associations of all available cis-pQTLs for these proteins with IHD in East Asians (n = 29,319 cases), with further replication in Europeans (n = 181,522 cases) and comparison with findings in previous MR studies.
RESULTS
In CKB observational analyses, a total of 959 (Olink/SomaScan: 426/533) proteins were associated at false discovery rate-corrected P < 0.05 with IHD after adjusting for major IHD risk factors. Two-sample MR analyses provided genetic support for 54 unique (Olink/SomaScan: 36/28) proteins in IHD etiology. Colocalization analyses confirmed shared gene-protein-IHD associations (posterior probability of hypothesis 4 [PPH4] ≥0.8) for 15 unique (Olink/SomaScan: 10/10) proteins, including 8 lipid-related, 3 inflammation-related, 1 blood pressure-related, and 3 alcohol-related proteins in East Asians. In Europeans, MR analyses of 12 non-alcohol-related proteins showed directionally concordant results for 8 proteins, with 5 having strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8), including 4 lipid-related (proprotein convertase subtilisin/kexin type 9, LPA, APOE, cadherin-1) and 1 systolic blood pressure-related (fibroblast growth factor 5) protein. However, 4 proteins showed directionally discordant MR results, including 2 lipid-related (APOA5, SORT1) and 1 inflammation-related (transforming growth factor beta 1) proteins with strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8). Comparison with previous MR studies revealed little consistency across studies in the number and identity of target proteins for IHD beyond well-established lipid-related (low-density lipoprotein cholesterol, lipoprotein(a), and triglycerides) or inflammation-related (interleukin-6) protein targets.
CONCLUSIONS
The findings support a role for lipid-driven chronic inflammation in IHD etiology, and treatment strategies simultaneously targeting multiple lipid and inflammation pathways should be prioritized for further research to improve drug treatment of IHD beyond statin therapy.
Mohsen Mazidi, N. Wright, A. Pozarickij et al.· Journal of the American Coll...· 1 citation
