SNP-guided microRNA maps (MirMaps) of 16 common human disorders identify a clinically accessible therapy reversing transcriptional aberrations of nuclear import and inflammasome pathways.
We report the results of a 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 16 major human disorders, which was enabled by multiple independent studies of up to 451,012 combined samples including 194,258 disease cases and 256,754 controls. SNP sequence homology-guided microRNA maps (MirMaps) identify consensus components of a disease phenocode consisting of 81 SNPs and 17 microRNAs. microRNAs of the consensus set are associated with at least 4 common human diseases (range 4 to 7 diseases) and manifest sequence homology/complementarity to at least 4 distinct disease-linked SNPs (range 4 to 14 SNPs). Nearly all microRNAs (15 of 17; 88%) of the consensus set has potential protein-coding mRNA targets among the principal components of the nuclear import pathway (NIP) and/or inflammasome pathways including KPNA1, NLRP1 (NALP1) and NLRP3 (NALP3) genes. Analysis of expression profiling experiments of peripheral blood mononuclear cells (PBMC) demonstrates statistically significant KPNA1-, NLRP1- and NLRP3-gene expression phenotypes associated with human genotypes of Crohn's disease (CD), Huntington's disease (HD) and rheumatoid arthritis (RA) populations. Unexpectedly, microarray analysis of PBMC from patients treated with chloroquine reveals a reversal of disease-linked KPNA1-, NLRP1- and NLRP3-gene expression phenotypes, implying that chloroquine could serve as a readily clinically available drug for targeted correction of identified aberrations. We conclude that genetically-defined malfunctions of the NIP and inflammasome pathways are likely to contribute to pathogenesis of multiple common human disorders and PBMC-based genetic tests may be useful for monitoring the individual's response to therapy. Prescription of chloroquine, an FDA-approved drug which is widely utilized for treatment of malaria, RA and systemic lupus erythematosus (SLE), may have a therapeutic value in clinical management of a large spectrum of human disorders.
Glinsky
Gennadi V
GV
Translational and Functional Genomics Laboratory, Department of Pathology and Laboratory Medicine, Albany Medical College, New York 12208, USA. gglinsky@ordwayresearch.org
D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001172:Arthritis, Rheumatoid / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002738:Chloroquine / Q000494:pharmacology; D003424:Crohn Disease / Q000235:genetics; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D006816:Huntington Disease / Q000235:genetics; D007249:Inflammation / Q000235:genetics*; D007963:Leukocytes, Mononuclear; D035683:MicroRNAs; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; D020641:Polymorphism, Single Nucleotide; D049490:Systems Biology / Q000379:methods*; D028901:alpha Karyopherins / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C423142:KPNA1 protein, human; D035683:MicroRNAs; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000070576:NLR Proteins; C427903:NLRP1 protein, human; C453881:NLRP3 protein, human; D028901:alpha Karyopherins; D002738:Chloroquine