Our laboratory is interested in identifying genes relevant to diseases. Our approach is to use spontaneous mouse mutants with immunological defects and decipher the molecular basis of the phenotypes. In the early 1990s, our attention was focused on the motheaten and viable motheaten mouse mutants. We used these mutant mice as a model system for elucidating the genetic and cellular events contributing to expression of normal hematopoietic and immune function. Our initial goal was to identify the gene responsible for the motheaten and viable motheaten phenotype. In 1993, we and others reported that both motheaten and viable motheaten mice have mutations in the SHP-1 gene. Currently, there are more than 600 publications involving SHP-1. In this review, rather than summarizing all these studies, we highlight work involving SHP-1 that were/are carried out in our and our collaborators' laboratories.

This study shows that one ERAP1 SNP and a haplotype in the ERAP1 and ERAP2 locus are associated with familial AS.

Ankylosing spondylitis (AS) is a complex disease involving multiple risk factors, both genetic and environmental. AS patients are predominantly young men, and the disease is characterized by inflammation and ankylosis, mainly at the cartilage–bone interface and enthesis. HLA-B27 has been known to be the major AS-susceptibility gene for more than 40 years. Despite advances made in the past few years, progress in the search for non-human leukocyte antigen susceptibility genes has been hampered by the heterogeneity of the disease. Compared to other complex diseases, such as inflammatory bowel disease (IBD), fewer susceptibility loci have been identified in AS. Furthermore, non-major histocompatibility-complex susceptibility loci discovered, such as ERAP1 and IL23R, are likely contributors to joint inflammation. Identification and confirmation of functional variants remains a significant challenge of investigations involving genome-wide association studies (GWAS). It remains unclear why none of the AS-susceptibility genes identified in GWAS appear to be directly involved in the ankylosing process. Numerous reviews have recently been published on the genetics of AS. Therefore, aside from a brief summary of what AS GWAS has successfully achieved thus far, this review will focus on directions that could address unanswered questions raised by GWAS.

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