Association of a promoter polymorphism mapping to the FCRL3
gene with RA has recently been reported in a Japanese population [7
]. The gene is likely to play a role in immune regulation, and functional data showed that the associated polymorphism controls the levels of gene expression. The association was replicated in the same study in another cohort of RA patients, with systemic lupus erythematosus and autoimmune thyroid disease. Furthermore, association has since been replicated by a separate group of investigators in an independent cohort of RA patients and controls from Japan [14
]. Hence, strong evidence exists to support the hypothesis that variation within the gene may be disease causal. In this well-powered study, however, we have failed to demonstrate a similar association with RA in a UK population.
Our result may represent a false-negative finding, but this is unlikely for several reasons. Firstly, we had 100% power to detect a similar effect size to that reported in the original study (effect size in test group, 2.15) and 90% power to detect the effect size of 1.3 reported in their replication cohort [7
]. Secondly, false-negative findings can also occur as a result of population stratification, but our control allele frequencies are similar to those reported previously in populations of Northern European descent and no difference in allele frequencies was observed between control or case samples from different regions of the United Kingdom (data not shown). Finally, previous studies from US and Spanish populations have also failed to demonstrate association with RA at this locus [15
It seems probable, then, that the association of this polymorphism with RA may be population specific. This is analogous to the association of the PTPN22*R620W
polymorphism with RA in European, Northern and Southern American populations but not in Far Eastern populations (summarised in [2
]). In this case, the population specificity arises from the fact that the polymorphism is common in European and Northern American populations (approximately 10% minor allele frequency) but very rare in Japan. For the FCRL3
gene, however, the putative disease causal allele is common in both the UK and Japanese cohorts (45% and 35% minor allele frequency, respectively) so this cannot explain the population differences found. Similarly, the same haplotypes exist, albeit at slightly different frequencies.
Association of the PADI4
gene with RA also shows variation between populations and, like the FCRL3-169*C/T
gene polymorphism, the susceptibility haplotype is common in all populations. A functional haplotype of the PADI4
gene has been consistently associated with RA in Far Eastern populations [4
]. While most studies in patients of Northern European descent have failed to demonstrate any association [9
], one study in a US population did recently report that this gene may have a very small effect [19
]. This finding has yet to be confirmed but, if it is, it may be argued that the effect size for the FCRL3
gene may also simply be much smaller in populations of Northern European descent, possibly reflecting differences in exposure to environmental susceptibility factors between populations. In support of this, a study in the UK population has replicated association of the FCRL3-169*C/T
gene polymorphism with Graves' disease but with a smaller effect size [20
]. Our study was sufficiently powered, however, to detect an effect size of 1.24. Indeed, by combining our data with those reported from a North American population, an effect size of 1.18 can be excluded with 80% power [15
The differences in the association of disease in different populations highlights the importance of accounting for ethnic origin when performing association studies, particularly in populations where considerable ethnic mixing may have occurred, such as that found in the United States.