iCOD: an integrated clinical omics database based on the systems-pathology view of disease.

BACKGROUND: Variety of information relating between genome and the pathological findings in disease will yield a wealth of clues to discover new function, the role of genes and pathways, and future medicine. In addition to molecular information such as gene expression and genome copy number, detailed clinical information is essential for such systematic omics analysis. RESULTS: In order to provide a basic platform to realize a future medicine based on the integration of molecular and clinico-pathological information of disease, we have developed an integrated clinical omics database (iCOD) in which comprehensive disease information of the patients is collected, including not only molecular omics data such as CGH (Comparative Genomic Hybridization) and gene expression profiles but also comprehensive clinical information such as clinical manifestations, medical images (CT, X-ray, ultrasounds, etc), laboratory tests, drug histories, pathological findings and even life-style/environmental information. The iCOD is developed to combine the molecular and clinico-pathological information of the patients to provide the holistic understanding of the disease. Furthermore, we developed several kinds of integrated view maps of disease in the iCOD, which summarize the comprehensive patient data to provide the information for the interrelation between the molecular omics data and clinico-pathological findings as well as estimation for the disease pathways, such as three layer-linked disease map, disease pathway map, and pathome-genome map. CONCLUSIONS: With these utilities, our iCOD aims to contribute to provide the omics basis of the disease as well as to promote the pathway-directed disease view. The iCOD database is available online, containing 140 patient cases of hepatocellular carcinoma, with raw data of each case as supplemental data set to download. The iCOD and supplemental data can be accessed at http://omics.tmd.ac.jp/icod_pub_eng.

SHROOM3, the gene associated with chronic kidney disease, affects the podocyte structure.

Chronic kidney disease is a public health burden and it remains unknown which genetic loci are associated with kidney function in the Japanese population, our genome-wide association study using the Biobank Japan dataset (excluding secondary kidney diseases, such as diabetes mellitus) clearly revealed that almost half of the top 50 single nucleotide polymorphisms associated with estimated glomerular filtration rate are located in the SHROOM3 gene, suggesting that SHROOM3 will be responsible for kidney function. Thus, to confirm this finding, supportive functional analyses were performed on Shroom3 in mice using fullerene-based siRNA delivery, which demonstrated that Shroom3 knockdown led to albuminuria and podocyte foot process effacement. The in vitro experiment shows that knockdown of Shroom3 caused defective formation of lamellipodia in podocyte, which would lead to the disruption of slit diaphragm. These results from the GWAS, in vivo and in vitro experiment were consistent with recent studies reporting that albuminuria leads to impairment of kidney function.

A gene variant in the Atp10d gene associates with atherosclerotic indices in Japanese elderly population.

BACKGROUND: ATP10D belongs to a subfamily of P-type ATPases implicated in phospholipids translocation from the exoplasmic to the cytoplasmic leaflet of cellular biological membrane. Previous genome-wide association study (GWAS) identified that a variant in Atp10d gene (rs2351791) associates with serum lipid profile and myocardial infarction. The objective of this study is to assess the effect of this variant on atherosclerosis in Japanese elderly population. METHOD: Consecutive autopsy cases registered in JG-SNP study were recruited (n = 1536). The samples were pathologically assessed for atherosclerosis using macroscopic examination of the formalin-fixed arteries, and coronary stenotic index (CSI), intracranial atherosclerotic index (ICAI) and pathological atherosclerotic index (PAI), which represent systemic arteries were calculated. The variant rs2351791 (G/T) in Atp10d gene was genotyped by Taqman genotyping assay and association determined. RESULT: Both CSI and ICAI were significantly higher in GG genotype than GT genotype and TT genotype (p = 0.003 and p = 0.001, respectively). Both associations remained significant in minor allele dominant model after adjusting for age, hypertension, diabetes, HDL, smoking and drinking (p = 0.001 and p = 0.001, respectively). PAI was not associated with this variant. Consistent with the previous report, plasma HDL cholesterol level was lower in GG genotype compared to GT + TT genotypes (p = 0.001). CONCLUSION: The rs2351791 SNP in the Atp10d gene affects the susceptibility for cardiac and intracranial vascular stenosis in the elderly Japanese population.