Abstract
IntroductionWe aimed to investigate whether the effect size of the systemic lupus erythematosus (SLE) risk alleles varies across European subpopulations.MethodsEuropean SLE patients (n = 1,742) and ethnically matched healthy controls (n = 2,101) were recruited at 17 centres from 10 different countries. Only individuals with self-reported ancestry from the country of origin were included. In addition, participants were genotyped for top ancestry informative markers and for 25 SLE associated SNPs. The results were used to compare effect sizes between the Central Eureopan and Southern European subgroups.ResultsTwenty of the 25 SNPs showed independent association with SLE, These SNPs showed a significant bias to larger effect sizes in the Southern subgroup, with 15/20 showing this trend (P = 0.019) and a larger mean odds ratio of the 20 SNPs (1.46 vs. 1.34, P = 0.02) as well as a larger difference in the number of risk alleles (2.06 vs. 1.63, P = 0.027) between SLE patients and controls than for Central Europeans. This bias was reflected in a very significant difference in the cumulative genetic risk score (4.31 vs. 3.48, P = 1.8 × 10-32). Effect size bias was accompanied by a lower number of SLE risk alleles in the Southern subjects, both patients and controls, the difference being more marked between the controls (P = 1.1 × 10-8) than between the Southern and Central European patients (P = 0.016). Seven of these SNPs showed significant allele frequency clines.ConclusionOur findings showed a bias to larger effect sizes of SLE loci in the Southern Europeans relative to the Central Europeans together with clines of SLE risk allele frequencies. These results indicate the need to study risk allele clines and the implications of the polygenic model of inheritance in SLE.
Highlights
We aimed to investigate whether the effect size of the systemic lupus erythematosus (SLE) risk alleles varies across European subpopulations
These latter loci can be due to the absence or rarity of the polymorphism in one of the ethnic groups, but other SLE loci show a similar frequency in discordant populations
Nine SLE susceptibility loci with a Southern bias We have already replicated association of top single nucleotide polymorphism (SNP) in nine SLE susceptibility loci in the samples included in this study (Table 2) [24]. When these SNPs were analysed separately in the two subgroups, Central European and Southern European, we found a bias for stronger association in the latter (Figure 1A)
Summary
We aimed to investigate whether the effect size of the systemic lupus erythematosus (SLE) risk alleles varies across European subpopulations. The systemic lupus erythematosus (SLE) genetic component has been partially elucidated thanks to large studies that have uncovered more than 30 loci reaching very convincing disease association [1,2,3,4,5,6,7,8,9,10,11,12] These studies have shown that a large fraction of the SLE loci (such as STAT4, TNFSF4 or BLK) are shared in the different ethnic groups; other loci are not (such as PTPN22, which is exclusive of Europeans). We wondered whether genetic heterogeneity of this type could exist among European subjects Support for this hypothesis is provided by the recent evidence of differences in SLE clinical features among Europeans [15,16,17] and by opposed results of SLE association with PDCD1 [18,19]. These two observations showed a North-South axis of variations, which is the main axis of European population differentiation [20,21,22,23]
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