title: Interactome-transcriptome analysis discovers signatures complementary to GWAS Loci of Type 2 Diabetes.
abstract: Protein interactions play significant roles in complex diseases. We analyzed peripheral blood mononuclear cells (PBMC) transcriptome using a multi-method strategy. We constructed a tissue-specific interactome (T2Di) and identified 420 molecular signatures associated with T2D-related comorbidity and symptoms, mainly implicated in inflammation, adipogenesis, protein phosphorylation and hormonal secretion. Apart from explaining the residual associations within the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) study, the T2Di signatures were enriched in pathogenic cell type-specific regulatory elements related to fetal development, immunity and expression quantitative trait loci (eQTL). The T2Di revealed a novel locus near a well-established GWAS loci AChE, in which SRRT interacts with JAZF1, a T2D-GWAS gene implicated in pancreatic function. The T2Di also included known anti-diabetic drug targets (e.g. PPARD, MAOB) and identified possible druggable targets (e.g. NCOR2, PDGFR). These T2Di signatures were validated by an independent computational method, and by expression data of pancreatic islet, muscle and liver with some of the signatures (CEBPB, SREBF1, MLST8, SRF, SRRT and SLC12A9) confirmed in PBMC from an independent cohort of 66 T2D and 66 control subjects. By combining prior knowledge and transcriptome analysis, we have constructed an interactome to explain the multi-layered regulatory pathways in T2D.
authors.affiliation: Hong Kong Bioinformatics Centre, School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.|Division of Genomics and Bioinformatics, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Jing-Woei
authors.initials: JW
authors.lastname: Li
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
authors.forename: Heung-Man
authors.initials: HM
authors.lastname: Lee
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
authors.forename: Amy Hin-Yan
authors.initials: AH
authors.lastname: Tong
authors.affiliation: Hong Kong Bioinformatics Centre, School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.|Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Department of Computer Science and Engineering, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Kevin Y
authors.initials: KY
authors.lastname: Yip
authors.affiliation: Hong Kong Bioinformatics Centre, School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.|Division of Genomics and Bioinformatics, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.|Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
authors.forename: Stephen Kwok-Wing
authors.initials: SK
authors.lastname: Tsui
authors.affiliation: Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
authors.forename: Si
authors.initials: S
authors.lastname: Lok
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
authors.forename: Risa
authors.initials: R
authors.lastname: Ozaki
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
authors.forename: Andrea O
authors.initials: AO
authors.lastname: Luk
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
authors.forename: Alice P S
authors.initials: AP
authors.lastname: Kong
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
authors.forename: Wing-Yee
authors.initials: WY
authors.lastname: So
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
authors.forename: Ronald C W
authors.initials: RC
authors.lastname: Ma
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
authors.forename: Juliana C N
authors.initials: JC
authors.lastname: Chan
authors.affiliation: Hong Kong Bioinformatics Centre, School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.|Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.|Department of Computer Science and Engineering, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Ting-Fung
authors.initials: TF
authors.lastname: Chan
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D059467:Transcriptome / Q000235:genetics*