title: The dichotomy between disease phenotype databases and the implications for understanding complex diseases involving the major histocompatibility complex.
abstract: Many genes related to innate and adaptive immunity reside within the major histocompatibility complex (MHC) and have been associated with a multitude of complex, immune-related disorders. Despite years of genetic study, this region has seen few causative determinants discovered for immune-mediated diseases. Reported associations have been curated in various databases including the Genetic Association Database, NCBI database of clinically relevant variants (ClinVar) and the Human Gene Mutation Database and together capture genetic associations and annotated pathogenic loci within the MHC and across the genome for a variety of complex, immune-mediated diseases. A review of these three distinct databases reveals disparate annotations between associated genes and pathogenic loci, alluding to the polygenic, multifactorial nature of immune-mediated diseases and the pleiotropic character of genes within the MHC. The technical limitations and inherent biases imposed by current approaches and technologies in studying the MHC create a strong case for the need to perform targeted deep sequencing of the MHC and other immunologically relevant loci in order to fully elucidate and study the causative elements of complex immune-mediated diseases.
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Clark
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kunkel
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Monos
mesh_terms: D002874:Chromosome Mapping; D030541:Databases, Genetic; D004198:Disease Susceptibility; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics* / Q000276:immunology*; D009154:Mutation; D010641:Phenotype