The search for rheumatoid arthritis susceptibility genes: A call for global collaboration

In this issue of Arthritis & Rheumatism, MacKay and colleagues from the UK report the results of a major genome-wide screen for rheumatoid arthritis (RA) susceptibility genes (1). This study required a sustained effort by a large group of collaborating investigators, led by Dr. Jane Worthington at the University of Manchester. The results emphasize the complexity of the genetics of RA, and the publication of this report offers an opportunity to take stock of what we have learned and where we need to go. Since the early 1990s, there has been a flurry of interest in applying genome-wide approaches to the genetic analysis of autoimmune disorders as well as a variety of other complex traits. Early on, the level of enthusiasm was high (2). Type 1 diabetes mellitus was the first autoimmune disorder to which genome screening for linkage was applied in a serious way, with the initial reports appearing in 1994 (3,4); the research community eagerly anticipated identification of the genes involved. Now, nearly 8 years later, the magnitude of the challenge is apparent. Other than HLA and the insulin locus, no specific genes in type 1 diabetes mellitus have been identified, although up to 20 different loci have been suggested as being involved in genetic susceptibility. Some investigators are expressing outright skepticism about the feasibility of using this approach to identify genes for complex disorders (5). Given the enormous investment of time, money, and careers in these studies, scientists (and interested editorialists!) may be motivated to interpret interim results in the most favorable light. Is treasure within reach, or are we mining the genome with the wrong tools? Is there, in fact, any treasure to be found? For at least some autoimmune disorders, the answer to the last question is a resounding “yes!” The recent discovery of NOD2 mutations in Crohn’s disease is a welcome success story in this regard. Similar to the situation with type 1 diabetes, RA, and other autoimmune diseases (6), linkage with numerous different chromosomal regions has been reported in Crohn’s disease, one of which is on chromosome 16q. Two different strategies were used independently to show that NOD2 is the relevant susceptibility gene in this region. In one study, an informed guess led investigators to identify NOD2 as a likely candidate gene in the region, with the subsequent identification of a frameshift mutation in NOD2 in patients from families showing linkage at marker D16S3396 (7). Using the transmission disequilibrium test (TDT) and a case–control analysis, it was shown that this mutation was strongly associated with Crohn’s disease. A second study used a highly labor-intensive positional cloning approach (8). Singlenucleotide polymorphisms were identified by DNA sequencing in the region of linkage, followed by linkage disequilibrium mapping, and the ultimate identification of strong associations with rare NOD2 alleles. These studies demonstrated that it is now possible to move from identification of a gene location by genome screening to identification of a specific susceptibility gene, using either a positional cloning approach or a focused candidate gene approach. Why has this type of success been so difficult to achieve in other autoimmune disorders? It is likely that the answer lies in the extraordinary complexity and heterogeneity of these diseases, at both the phenotypic and genetic levels (9). In the case of RA, there is no doubt that the HLA region confers considerable genetic risk. Indeed, linkage to HLA has been observed in all major genome-wide screens for linkage (10,11), including the study by MacKay et al (1). This is encouraging Supported by NIH grants R01-AR-44222 and N01-AR-7-2232 and the National Arthritis Foundation. Damini Jawaheer, PhD, Peter K. Gregersen, MD: Center for Genomics and Human Genetics, North Shore Long Island Jewish Research Institute, Manhasset, New York. Address correspondence and reprint requests to Peter K. Gregersen, MD, Center for Genomics and Human Genetics, North Shore Long Island Jewish Research Institute, North Shore University Hospital, 350 Community Drive, Manhasset, NY 11030. E-mail: peterg@nshs.edu. Submitted for publication October 24, 2001; accepted in revised form November 2, 2001.