Construction of a Transcriptome-Driven Network at the Early Stage of Infection with Influenza A H1N1 in Human Lung Alveolar Epithelial Cells

We aimed to understand the molecular changes in host cells that accompany infection by the seasonal influenza A H1N1 virus because the initial response rapidly changes owing to the fact that the virus has a robust initial propagation phase. Human epithelial alveolar A549 cells were infected and total RNA was extracted at 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, and 48 h post infection (h.p.i.). The differentially expressed host genes were clustered into two distinct sets of genes as the infection progressed over time. The patterns of expression were significantly different at the early stages of infection. One of the responses showed roles similar to those associated with the enrichment gene sets to known ‘gp120 pathway in HIV.’ This gene set contains genes known to play roles in preventing the progress of apoptosis, which infected cells undergo as a response to viral infection. The other gene set showed enrichment of ‘Drug Metabolism Enzymes (DMEs).’ The identification of two distinct gene sets indicates that the virus regulates the cell's mechanisms to create a favorable environment for its stable replication and protection of gene metabolites within 8 h.

Genome-Wide Association Study of Metabolic Syndrome in Koreans

Metabolic syndrome (METS) is a disorder of energy utilization and storage and increases the risk of developing cardiovascular disease and diabetes. To identify the genetic risk factors of METS, we carried out a genome-wide association study (GWAS) for 2,657 cases and 5,917 controls in Korean populations. As a result, we could identify 2 single nucleotide polymorphisms (SNPs) with genome-wide significance level p-values (<5 x 10(-8)), 8 SNPs with genome-wide suggestive p-values (5 x 10(-8) < or = p < 1 x 10(-5)), and 2 SNPs of more functional variants with borderline p-values (5 x 10(-5) < or = p < 1 x 10(-4)). On the other hand, the multiple correction criteria of conventional GWASs exclude false-positive loci, but simultaneously, they discard many true-positive loci. To reconsider the discarded true-positive loci, we attempted to include the functional variants (nonsynonymous SNPs [nsSNPs] and expression quantitative trait loci [eQTL]) among the top 5,000 SNPs based on the proportion of phenotypic variance explained by genotypic variance. In total, 159 eQTLs and 18 nsSNPs were presented in the top 5,000 SNPs. Although they should be replicated in other independent populations, 6 eQTLs and 2 nsSNP loci were located in the molecular pathways of LPL, APOA5, and CHRM2, which were the significant or suggestive loci in the METS GWAS. Conclusively, our approach using the conventional GWAS, reconsidering functional variants and pathway-based interpretation, suggests a useful method to understand the GWAS results of complex traits and can be expanded in other genomewide association studies.

Replication of Interactions between Genome-Wide Genetic Variants and Body Mass Index in Fasting Glucose and Insulin Levels

The genetic regulation of glucose and insulin levels might be modified by adiposity. With regard to the genetic factors that are altered by adiposity, a large meta-analysis on the interactions between genetic variants and body mass index with regard to fasting glucose and insulin levels was reported by the Meta-Analyses of Glucose- and Insulin-related trait Consortium (MAGIC), based on European ancestry. Because no replication study has been performed in other ethnic groups, we first examined the link between reported single-nucleotide polymorphisms (SNPs) and fasting glucose and insulin levels in a large Korean cohort (Korean Genome and Epidemiology Study cohort [KoGES], n = 5,814). The MAGIC study reported 7 novel SNPs for fasting glucose levels and 6 novel SNPs for fasting insulin levels. In this study, we attempted to replicate the association of 5 SNPs with fasting glucose levels and 5 SNPs with fasting insulin levels. One SNP (rs2293941) in PDX1 was identified as a significant obesity-modifiable factor in Koreans. Our results indicate that the novel loci that were identified by MAGIC are poorly replicated in other ethnic groups, although we do not know why.