Disease phenocode analysis identifies SNP-guided microRNA maps (MirMaps) associated with human "master" disease genes.
Recently we reported the results of a genome-wide disease phenocode analysis interrogating the relationships between structural features and gene expression patterns of disease-linked SNPs, microRNAs and mRNAs of protein-coding genes in association to phenotypes of 15 common human disorders (Cell Cycle 2008;7:2570-83; 3564-76). One of the main implications of this analysis is that transcriptionally co-regulated SNP sequence-bearing RNAs are more likely to exert a cumulative effect in trans on phenotypes. In this work, we test the validity of a disease phenocode concept within a genomic context of distinct continuously spaced sets of disease-linked SNPs and mRNAs of relevant proteincoding genes. We report a sequence homology profiling of two sets of disease-linked SNPs which are located within continuous genomic regions associated with individual protein-coding genetic loci (NLRP1 and STAT4) and are likely to exhibit common profiles of transcriptional activity. Most of microRNAs (15 of 19; 79%) homologous to the NLPRP1-associated disease-linked SNPs have potential protein-coding mRNA targets among the principal components of the nuclear import pathway (NIP) and/or inflammasome pathways, including KPNA1, NLRP1 and NLRP3 genes. We demonstrate that estimates of cumulative targeting effects of microRNAs on mRNAs within distinct allelic contexts of disease-linked SNPs are in agreement with microarray analysis-defined gene expression phenotypes associated with human genotypes of Crohn's disease (CD) and rheumatoid arthritis (RA) populations. Microarray experiments and disease phenocode analysis identify ten-gene expression signatures which seem to reflect the activated status of disease-linked SNPs/microRNAs/mRNAs axis in peripheral blood mononuclear cells (PBMC) of 66% CD patients and 80% RA patients. Comparisons of ten-gene signature expression profiles and NLRP3/NLRP1 mRNA expression ratios in PBMC of individual CD and RA patients and control subjects indicate that measurements of these markers may be useful for diagnostic applications. Our findings demonstrate that NLPRP1- and STAT4-associated disease-linked SNPs have common sequence-defined features which are recapitulating the essential phenotype-affecting features of genome-wide disease-linked SNPs, suggesting that NLRP1 (NALP1) and STAT4 genetic loci may constitute "master" disease genes. We conclude that both genome-wide SNP variations and SNP polymorphisms associated with "master" disease genes may cause similar genetically-defined malfunctions of the NIP and inflammasome/innate immunity pathways which are likely to contribute to pathogenesis of multiple common human disorders.
Glinsky
Gennadi V
GV
Department of Pathology and Laboratory Medicine, Albany Medical College, Ordway Cancer Center, Albany, New York 12208, USA. gglinsky@ordwayresearch.org
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000483:Alleles; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001172:Arthritis, Rheumatoid / Q000235:genetics; D001483:Base Sequence; D003424:Crohn Disease / Q000235:genetics; D004194:Disease / Q000235:genetics*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000235:genetics; D028884:Karyopherins / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D000070576:NLR Proteins; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D025341:Principal Component Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D028884:Karyopherins; D035683:MicroRNAs; D000070576:NLR Proteins; C427903:NLRP1 protein, human; D012333:RNA, Messenger; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human