title: High-Throughput Characterization of Blood Serum Proteomics of IBD Patients with Respect to Aging and Genetic Factors.
abstract: To date, no large scale, systematic description of the blood serum proteome has been performed in inflammatory bowel disease (IBD) patients. By using microarray technology, a more complete description of the blood proteome of IBD patients is feasible. It may help to achieve a better understanding of the disease. We analyzed blood serum profiles of 1128 proteins in IBD patients of European descent (84 Crohn's Disease (CD) subjects and 88 Ulcerative Colitis (UC) subjects) as well as 15 healthy control subjects, and linked protein variability to patient age (all cohorts) and genetic components (genotype data generated from CD patients). We discovered new, previously unreported aging-associated proteomic traits (such as serum Albumin level), confirmed previously reported results from different tissues (i.e., upregulation of APOE with aging), and found loss of regulation of MMP7 in CD patients. In carrying out a genome wide genotype-protein association study (proteomic Quantitative Trait Loci, pQTL) within the CD patients, we identified 41 distinct proteomic traits influenced by cis pQTLs (underlying SNPs are referred to as pSNPs). Significant overlaps between pQTLs and cis eQTLs corresponding to the same gene were observed and in some cases the QTL were related to inflammatory disease susceptibility. Importantly, we discovered that serum protein levels of MST1 (Macrophage Stimulating 1) were regulated by SNP rs3197999 (p = 5.96E-10, FDR<5%), an accepted GWAS locus for IBD. Filling the knowledge gap of molecular mechanisms between GWAS hits and disease susceptibility requires systematically dissecting the impact of the locus at the cell, mRNA expression, and protein levels. The technology and analysis tools that are now available for large-scale molecular studies can elucidate how alterations in the proteome driven by genetic polymorphisms cause or provide protection against disease. Herein, we demonstrated this directly by integrating proteomic and pQTLs with existing GWAS, mRNA expression, and eQTL datasets to provide insights into the biological processes underlying IBD and pinpoint causal genetic variants along with their downstream molecular consequences.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Antonio F
authors.identifier: 0000-0002-4033-5038
authors.initials: AF
authors.lastname: Di Narzo
authors.affiliation: Janssen R&D, LLC, Spring House, Pennsylvania, United States of America.
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Telesco
authors.affiliation: Janssen R&D, LLC, Spring House, Pennsylvania, United States of America.
authors.forename: Carrie
authors.initials: C
authors.lastname: Brodmerkel
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Carmen
authors.initials: C
authors.lastname: Argmann
authors.affiliation: Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Lauren A
authors.identifier: 0000-0002-3747-0474
authors.initials: LA
authors.lastname: Peters
authors.affiliation: Janssen R&D, LLC, Spring House, Pennsylvania, United States of America.
authors.forename: Katherine
authors.identifier: 0000-0002-1578-5029
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Brian
authors.identifier: 0000-0003-2110-1145
authors.initials: B
authors.lastname: Kidd
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Joel
authors.initials: J
authors.lastname: Dudley
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Judy
authors.initials: J
authors.lastname: Cho
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kasarskis
authors.affiliation: Janssen R&D, LLC, Spring House, Pennsylvania, United States of America.
authors.forename: Radu
authors.identifier: 0000-0002-3336-0091
authors.initials: R
authors.lastname: Dobrin
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
mesh_terms: D000328:Adult; D000375:Aging / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D017228:Hepatocyte Growth Factor / Q000097:blood; D057166:High-Throughput Screening Assays; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000097:blood* / Q000453:epidemiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000097:blood; D040641:Quantitative Trait Loci
chemical_list: D015415:Biomarkers; D020543:Proteome; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor