In the present association study, we investigated the relevance of the classification of HLA-DRB1
alleles proposed by Tezenas du Montcel and colleagues [11
] regarding susceptibility to RA, across various Caucasoid and non-Caucasoid population samples, using publicly available data from the 13th IHWG RA studies. Across these various population samples, our approach strengthens the relevance of this classification, exhibiting an overall positive association with RA susceptibility for S2
alleles and an overall negative association with RA susceptibility for S1
and X alleles. The genotype analysis performed in the present study fits with the genotype risk hierarchy previously reported in Caucasoid RA sporadic cases [11
] and families [12
The present combined analysis included 10 samples from different genetic backgrounds. Although we did not observe significant heterogeneity for S1, S2, S3D and S3P allele groups, we observed significant heterogeneity for the X allele group across the different population samples. The fixed effect model of the Mantel-Haenszel method, used for the overall effect analysis of the HLA-DRB1 allele and genotype groups on RA susceptibility in the present study, assumes that each allele group carries out a homogeneous effect on RA susceptibility across the various Caucasoid and non-Caucasoid samples. The heterogeneity observed for the X allele group may be questioned according the heterogeneity of the HLA-DRB1 allele and genotype groups at two levels across the different population samples: the effect level and the frequency level. Our data suggest that there is a differential effect of the S1, S2, S3D and S3P allele groups on RA susceptibility. Each of these effects seems homogenous across the various population samples. Because the SE allele distribution varies across these populations, the resulting effect of the X allele group on RA susceptibility depends both on the frequency of the S1, S2, S3D and S3P allele groups, and their respective effects on RA susceptibility, which might explain the observed heterogeneity of the effect of the X allele group in our study.
The contribution of SE alleles to RA susceptibility has been confirmed by numerous studies on different populations. For example, a recent meta-analysis on Latin American RA patients has shown the important role played by SE in RA susceptibility [15
]. However, RA prevalence studies have shown differences in frequency estimations between populations with different genetic backgrounds. The highest prevalence rates have been found in Native American populations with estimation ranges of 32 to 48 per 1,000 men and 59 to 70 per 1,000 women. In Afro-Caribbean people who live in the UK, RA prevalence appeared to be lower than that in the general population. In urban African populations, RA prevalence was estimated around 10 per 1,000 and was found to be significantly higher than in rural populations. Studies on Chinese populations have reported lower prevalence estimations than in European ones. Molokhia and McKeigue previously pointed out the difficulty brought up by admixture in investigating the etiology of rheumatic diseases, notably for RA [16
]. The significant variations observed in the incidence and prevalence of RA among different populations or ethnic groups could be explained, in part, by genetic variations in the HLA region, especially variations in the prevalence of SE in different populations [17
]. In addition, as no consideration of environmental exposure variations between the population samples studied was made, the heterogeneity could be explained by the different impact of environmental factors on RA susceptibility in each different sample, such as nutrition as previously suggested, in particular in the Greek population [18
]. In addition to nutrition, environmental factors such as exposure to cigarette smoking [20
] or individual factors such as gender [22
] may influence susceptibility to RA by interacting with genetic factors such as HLA-DRB1
The classification proposed by Tezenas du Montcel and colleagues [11
], based on amino acid sequence at positions 70 to 74, does not aim to account for all previously reported associations between particular HLA-DRB1 alleles and RA susceptibility in specific ethnic backgrounds. For example, the previously reported association between the HLA-DRB1
*0901 allele and RA susceptibility in East Asian populations could not be tested in the present study, as this particular allele was classified together with many others as an X allele [23
]. The high frequency of the HLA-DRB1
*0901 allele in the Javanese population could contribute both to the association found between X alleles and susceptibility to RA in this particular population sample and to the observed heterogeneity of the X allele group.
The contribution of the HLA-DRB1
allele classification in accounting for the genetic contribution of the HLA-DRB1
gene was previously analyzed in terms of RA severity and in terms of autoantibody production such as anti-cyclic citrullinated peptide (anti-CCP) antibodies and anti-deiminated human fibrinogen autoantibodies. As RA severity outcomes as well as anti-CPP information were not collected in the framework of the 13th IHWG, we were not able to discuss the relevance of the classification of HLA-DRB1 alleles proposed by Tezenas du Montcel and colleagues [8
] regarding RA severity or autoantibody production in the various Caucasoid and non-Caucasoid population samples included in the present study.