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.

High-density SNP analysis of 642 Caucasian families with rheumatoid arthritis identifies two new linkage regions on 11p12 and 2q33

“…A candidate gene association approach was also used to identify the PTPN22 association with type 1 diabetes 19 and subsequently other related autoimmune disorders. 21,45 Although the utility of linkage for disease mapping in complex autoimmune disorders remains uncertain, the data reported here are likely to reinvigorate efforts to map susceptibility genes for RA based on positional information. Our analysis indicates that the improved linkage signals we observed using the Illumina SNP marker set resulted from the fact that the information content across the entire genome was 44% higher using the SNP panel as opposed to the microsatellite marker set from Marshfield.…”

PTPN22 and rheumatoid arthritis: Gratifying replication

“…Working independently and combining a broad screen of functional single-nucleotide polymorphisms guided by previously published linkage studies, Begovich et al (4) reported a similar association with RA, in the summer of 2004. These studies were followed by several confirmations of the PTPN22 association with type 1 diabetes (5-7) as well as convincing associations with systemic lupus erythematosus (8), Graves' disease, and Hashimoto thyroiditis (9,10). More recently, several confirmations of the RA association have been reported (11,12).…”

“…Autoantibodies are not a prominent feature of either of these disorders. In addition, results of studies in familial clustering of autoimmune disease suggest that the PTPN22-associated disorders (i.e., RA, type 1 diabetes, autoimmune thyroid disease, and lupus) may form a related group (10). In contrast, support is much more limited for clustering of multiple sclerosis and Crohn's disease with this group of disorders, although admittedly, the epidemiologic data are rather sparse.…”

Familial association between type 1 diabetes and other autoimmune and related diseases

“…Genetic and epidemiological data indicate that certain autoimmune diseases aggregate in type 1 diabetes families [10,11,[14][15][16][17][18][19][20][21][22][23][24][25]. Reported associated autoimmune and related diseases include coeliac disease, multiple sclerosis, rheumatoid arthritis and autoimmune polyendocrine syndrome [14,21,[26][27][28].…”