Background More tan 30 reproducible SLE susceptibility loci have been identified in the last years. Some of these loci are specific of particular ethnic groups, like PXK or FCGR2A, due to unknown causes1. Independently, it has become clear that there are gradients of prevalence of some SLE clinical features among Europeans2,3, and it is known that there are frequency clines of polymorphisms in the Europeans along a dominant North-South axis4. Therefore, we have hypothesized that there could be heterogeneity in the effect sizes of SLE loci among Europeans.
Objectives We aimed to know if the effect size of the SLE susceptibility loci varies across Europe.
Methods European SLE patients, 1742, and ethnically matched healthy controls, 2101, were recruited at 17 centres from 10 different countries. Only individuals with uniform self-reported ancestry from the country of origin were included. In addition, they were genotyped for top ancestry informative markers and for 25 SLE susceptibility loci. The results were used to compare association effect sizes between the Central and Southern European subgroups.
Results Twenty of the 25 loci showed significant association with SLE in our samples. There was a significant bias to larger effect sizes in the Southern subgroup with 15/20 associated SNPs showing this trend (P=0.019), two of them with significant differences. There was also a larger mean O.R. of the 20 SNPs (1.46 vs.1.34; P=0.02) in patients from the South than from Central Europeans., as well as, a larger difference in the number of risk alleles between SLE patients and controls (2.06 vs. 1.63; P=0.027). This bias was accompanied by a lower number of SLE risk alleles in the Southern subjects, both patients and controls, being the difference more marked between the controls (12.0 vs. 12.8; P=1.1×10-8) than between the Southern and Central European patients (14.0 vs. 14.4; P=0.016).
Conclusions Our study has shown a bias in effect sizes of the SLE susceptibility loci towards a stronger association in Southern Europeans relative to Central Europeans. This bias is related with a lower frequency of risk alleles in the Southern subgroup, with a more marked difference in healthy controls than in SLE patients. These results have implications for the design and interpretation of genetic studies and for the understanding of the SLE genetic structure. They also suggest that selective forces have shaped the genetic epidemiology of SLE differentially in Europeans and reinforce the need to investigate the proposed interplay between infection resistance and susceptibility to autoimmunity.
Han JW, et al. Nat Genet. 2009;41:1234-7
Chung SA, et al. Arthritis Rheum. 2009;60:2448-56
Alonso-Perez E, et al. PLoS One. 2011;6:e29033
Seldin MF, et al. PLoS Genet. 2006;2:e143
Disclosure of Interest None Declared