Author: Chee-Seng Ku
Position: PhD student
Institution: Center for Molecular Epidemiology, Yong Loo Lin School of Medicine, National University of Singapore
E-mail: cmekcs@nus.edu.sg
Additional Authors: CHIA Kee Seng
Submitted Date: September 26, 2007
Published Date: September 26, 2007
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

I read with interest the article published by Kurreeman and colleagues (1). This study is most welcome because their findings further substantiate the evidence of association of TRAF1-C5 locus with rheumatoid arthritis (RA) that recently identified by a genome wide association (GWA) study (2).

RA is one of the most common autoimmune diseases which is well-characterized by chronic inflammation of synovial tissue and cause the destruction of joint. This chronic and debilitating disease is a polygenic disease attributed to combination and complex interaction of multiple genetic and environment factors. Although RA has been described for decades; the complete patho-physiology and etiological factors are still largely vague; and yet to be elucidated. The association of HLA-DRB1 shared epitope (SE) alleles and susceptibility to RA (i.e. the shared epitope hypothesis) was first described in late 1980s (3). HLA-DRB1 locus only accounts for ~30% of the total genetic component; therefore, it does not explain entirely the genetic susceptibility to RA. Thereafter, no much success has been achieved in dissecting the genetic basis of RA. Prior to 2004, no other candidate gene located outside major histocompatibility complex (MHC) was found and identifying genetic variant with modest effect has been proven both difficult and challenging. PTPN22 was the first non-HLA gene identified for RA in 2004 and the association was consistently replicated in Caucasian populations (4). The failure in identifying more candidate genes was largely attributed to lack of an efficient and powerful genetic design such as GWA approach that only became feasible after the completion of the International HapMap Project in 2005.

Two prominent studies were published in the September issue of New England Journal of Medicine must have excited the genetics and rheumatology community (2, 5). The findings from these studies started to shed some new lights into the genetic basis of RA. Plenge and colleagues conducted the first GWA study in North American Rheumatoid Arthritis Consortium (NARAC) and Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) cohorts and these excellent works lead to a remarkable discovery that a common genetic variant at the TRAF1-C5 locus is associated with an increased risk of anti-cyclic citrullinated peptide positive RA. The ability to demonstrate the reproducibility of the results from GWA study is paramount for investigator to declare the finding of bona-fide association (6). The TRAF1-C5 association was further verified by Kurreeman and colleagues in their candidate gene studies in three independent sample sets from the Netherlands, Sweden and US. This consistent replication has provided firm evidence beyond the statistical doubt to suggest that TRAF1-C5 is a genuine RA locus.

The second study was also conducted by investigators from NARAC and EIRA through the fine mapping of chromosome 2q region that previously identified by linkage analysis. Thirteen candidate genes within this region were tested for association with RA; and a haplotype of STAT4 is associated with increased risk for RA. This is not uncommon from the literature that the genetic associations reported in Caucasians were hardly replicated in Asians; the notable examples were PTPN22 and FCRL3 genes. The former gene was failed to be replicated in Japanese (7); conversely, a meta-analysis found no reliable evidence of the genetic association (-169T>C) of FCRL3 in populations of European descent (8). However, STAT4 haplotype is the first genetic association in RA that was confirmed across the boundary of ethnicities; it was successfully replicated in Korean population with similar magnitude of genetic effect (9) and thus indicates that the STAT4 haplotype was common and associated with increased risk of RA in both Caucasian and Asian populations. Therefore, this is essential to conduct replication studies for TRAF1-C5 locus in Asian populations; nevertheless, non-replication in well-powered studies in other populations with different ancestry background does not necessary refute or invalidate the original findings, this might indicate true population or genetic heterogeneity. MHC2TA is another well-studied candidate gene in RA; unfortunately, results from a lately meta-analysis did not support the association of this gene (10). Meta-analysis is a very power ‘tool’ to combine and analyze the results from many small genetic association studies; this will ensure adequate statistical power to detect the genetic association and hence resolve the conflicting results in the literature review.

The major breakthrough achieved by both the NARAC and EIRA is commendable; this highlights the significance of scientific collaboration and the importance of replication as the gold standard to validate the findings from GWA studies. This also demonstrated the promise of GWA approach in unraveling novel genetic variants for complex diseases e.g. the discovery of TRAF1-C5 locus. Furthermore, a well-designed linkage study follow by fine mapping of the linkage region is also promising in identifying the genetic variant and gene for complex disease like the study conducted by Remmers and colleagues that had lead to discovery of STAT4 haplotype for RA.

References

1. Kurreeman FA, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M et al. (2007) A candidate gene approach identifies the TRAF1/C5 region as a risk factor for rheumatoid arthritis. PLoS Med 18: e278.
2. Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF et al. (2007) TRAF1-C5 as a risk locus for rheumatoid arthritis - a genome wide study. N Engl J Med 357: 1199-1209.
3. Gregersen PK, Silver J, Winchester RJ. (1987) The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 30: 1205-1213.
4. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP et al. (2004) A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 75: 330-337.
5. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G et al. (2007) STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 357: 977-986.
6. NCI-NHGRI Working Group on Replication in Association Studies (2007) Replicating genotype-phenotype associations. Nature 447: 655-660.
7. Ikari K, Momohara S, Inoue E, Tomatsu T, Hara M et al. (2006) Haplotype analysis revealed no association between the PTPN22 gene and RA in a Japanese population. Rheumatology (Oxford) 45: 1345-1348.
8. Begovich AB, Chang M, Schrodi SJ. (2007) Meta-analysis evidence of a differential risk of the FCRL3 -169T>C polymorphism in white and East Asian rheumatoid arthritis patients. Arthritis Rheum 56: 3168-3171.
9. Lee HS, Remmers EF, Le JM, Kastner DL, Bae SC et al. (2007) Association of STAT4 with rheumatoid arthritis in the Korean population. Available: http://www.pubmedcentral....
10. Bronson PG, criswell LA, Barcellos LF. The MHC2TA -168A/G polymorphism and risk for rheumatoid arthritis: a meta-analysis of 6,861 patients and 9,270 controls reveals no evidence for association. Available: http://ard.bmj.com.libpro...