Identification and validation of six acute myocardial infarction-associated variants, including a novel prognostic marker for cardiac mortality.

Background: Acute myocardial infarction (AMI) is one of the leading causes of death worldwide, and approximately half of AMI-related deaths occur before the affected individual reaches the hospital. The present study aimed to identify and validate genetic variants associated with AMI and their role as prognostic markers. Materials and methods: We conducted a replication study of 29 previously identified novel loci containing 85 genetic variants associated with early-onset AMI using a new independent set of 2,920 Koreans [88 patients with early- and 1,085 patients with late-onset AMI, who underwent percutaneous coronary intervention (PCI), and 1,747 healthy controls]. Results: Of the 85 previously reported early-onset variants, six were confirmed in our genome-wide association study with a false discovery rate of less than 0.05. Notably, rs12639023, a cis-eQTL located in the intergenic region between LINC02005 and CNTN3, significantly increased longitudinal cardiac mortality and recurrent AMI. CNTN3 is known to play a role in altering vascular permeability. Another variant, rs78631167, located upstream of PLAUR and known to function in fibrinolysis, was moderately replicated in this study. By surveying the nearby genomic region around rs78631167, we identified a significant novel locus (rs8109584) located 13 bp downstream of rs78631167. The present study showed that six of the early-onset variants of AMI are applicable to both early- and late-onset cases. Conclusion: Our results confirm markers that can potentially be utilized to predict, screen, prevent, and treat candidate patients with AMI and highlight the potential of rs12639023 as a prognostic marker for cardiac mortality in AMI.

A method for early diagnosis of lung cancer from tumor originated DNA fragments using plasma cfDNA methylome and fragmentome profiles.

Early detection is critical for minimizing mortality from cancer. Plasma cell-free DNA (cfDNA) contains the signatures of tumor DNA, allowing us to quantify the signature and diagnose early-stage tumors. Here, we report a novel tumor fragment quantification method, TOF (Tumor Originated Fragment) for the diagnosis of lung cancer by quantifying and analyzing both the plasma cfDNA methylation patterns and fragmentomic signatures. TOF utilizes the amount of ctDNA predicted from the methylation density information of each cfDNA read mapped on 6243 lung-tumor-specific CpG markers. The 6243 tumor-specific markers were derived from lung tumor tissues by comparing them with corresponding normal tissues and healthy blood from public methylation data. TOF also utilizes two cfDNA fragmentomic signatures: 1) the short fragment ratio, and 2) the 5' end-motif profile. We used 298 plasma samples to analyze cfDNA signatures using enzymatic methyl-sequencing data from 201 lung cancer patients and 97 healthy controls. The TOF score showed 0.98 of the area under the curve in correctly classifying lung cancer from normal samples. The TOF score resolution was high enough to clearly differentiate even the early-stage non-small cell lung cancer patients from the healthy controls. The same was true for small cell lung cancer patients.