title: Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes.
abstract: Autoimmune disorders constitute a diverse group of phenotypes with overlapping features and a tendency toward familial aggregation. It is likely that common underlying genes are involved in these disorders. Until very recently, no specific alleles--aside from a few common human leukocyte antigen class II genes--had been identified that clearly associate with multiple different autoimmune diseases. In this study, we describe a unique collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium (MADGC). At least two of nine "core" autoimmune diseases are present in each of these families. These core diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), multiple sclerosis (MS), autoimmune thyroid disease (Hashimoto thyroiditis or Graves disease), juvenile RA, inflammatory bowel disease (Crohn disease or ulcerative colitis), psoriasis, and primary Sjogren syndrome. We report that a recently described functional single-nucleotide polymorphism (rs2476601, encoding R620W) in the intracellular tyrosine phosphatase (PTPN22) confers risk of four separate autoimmune phenotypes in these families: T1D, RA, SLE, and Hashimoto thyroiditis. MS did not show association with the PTPN22 risk allele. These findings suggest a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggest that MS may have a pathogenesis that is distinct from RA, SLE, and T1D. DNA and clinical data for the MADGC families are available to the scientific community; these data will provide a valuable resource for the dissection of the complex genetic factors that underlie the various autoimmune phenotypes.
authors.affiliation: Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Kirsten A
authors.initials: KA
authors.lastname: Pfeiffer
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Lum
authors.forename: Bonnie
authors.initials: B
authors.lastname: Gonzales
authors.forename: Jill
authors.initials: J
authors.lastname: Novitzke
authors.forename: Marlena
authors.initials: M
authors.lastname: Kern
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Moser
authors.forename: Ann B
authors.initials: AB
authors.lastname: Begovich
authors.forename: Victoria E H
authors.initials: VE
authors.lastname: Carlton
authors.forename: Wentian
authors.initials: W
authors.lastname: Li
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.forename: Ward
authors.initials: W
authors.lastname: Ortmann
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D012042:Registries; D012737:Sex Factors
chemical_list: D006684:HLA-DR Antigens; C516765:PTPN22 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases
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