This study shows that genetic substructure within European-derived populations is associated with specific manifestations of SLE. Increased northern European ancestry is associated with an increased risk of photosensitivity and discoid rash (mucocutaneous manifestations), and a decreased risk of autoantibody production. These results support the hypothesis that differences in genetic background between subjects within the same major continental ethnic group (as reflected by northern vs. southern European ancestry in this study) can influence the development of specific SLE phenotypes. Of note, ancestry associations with autoantibody production are in some instances stronger than the associations with mucocutaneous manifestations. This finding also supports the theory that genetic factors may be more relevant to the production of autoantibodies (which are implicated in disease pathogenesis), than other SLE manifestations such as arthritis or serositis.
The associations between photosensitivity and discoid rash with increased northern European ancestry are particularly intriguing, since exposure to sunlight and ultraviolet radiation has been shown to precipitate various SLE manifestations, including cutaneous reactions (30
). One can hypothesize an evolutionary mechanism for this finding. In general, populations in northern Europe are exposed to less sunlight than those in southern Europe. Over time, northern European populations may have developed increased capacity for sunlight absorption than their southern counterparts. However, this increased absorption may become detrimental if the person moves to a more sun-exposed region. The resulting additional sunlight absorption may lead to sun-induced damage (such as discoid rash) and photosensitive reactions. In addition, previous studies have shown that skin damage and inflammation from ultraviolet light exposure has been associated with skin and hair color (33
), suggesting that the association between increased northern European ancestry and the mucocutaneous subphenotypes of photosensitivity and discoid rash may be related to these traits.
The mechanism for increased autoantibody production in those with less northern European (i.e., more southern European ancestry) is not known. This association is likely due, at least in part, to genetic differences between northern and southern Europeans. It is interesting to speculate that natural selection may play a role in explaining this result. Differential exposure to infectious agents in southern compared to northern European population groups may have resulted in selection of genetic variants with consequent differences in immune responses.
Genes previously associated with SLE risk display evidence of geographic variation. One example is the R620W polymorphism of protein tyrosine phosphatase nonreceptor type 22 (PTPN22
). This polymorphism has been associated with multiple autoimmune diseases characterized by autoantibody production, including SLE (19
). The allele frequency of R620W in Europeans decreases substantially from northern Europe to southern Europe (36
). However, the geographic variation seen in this polymorphism is not likely to explain the association between autoantibody production and European substructure seen in our results. The PTPN22 R620W polymorphism is more common in northern Europe, and we found that increased northern European ancestry was protective for autoantibody production. In addition, no associations between the PTPN22 R620W polymorphism and SLE-related autoantibodies have been published.
The human leukocyte antigen (HLA) region on chromosome 6p21 has also shown evidence of geographic variation. HLA alleles (specifically HLA-DRB1*0301 and HLA-DRB1*1501) were the first identified genetic susceptibility risk factors for SLE (37
). In the United Kingdom, allele frequencies for genes in this region have been found to vary on a northwest-southeast cline (38
). HLA class II alleles have also been associated with both anti-dsDNA (39
) and anti-cardiolipin autoantibody production (40
). Further studies are needed to determine the role of the HLA region in the associations between autoantibody production and European population substructure seen in this study.
The strengths of this study include its large sample size of subjects with well-characterized clinical features who were recruited from Europe and multiple sites across the United States. Analyses also adjusted for potential confounding factors such as SLE patient recruitment site, gender, and disease duration (when appropriate). The use of continental ancestry markers ensured that each participant in our study was truly of European ancestry. In addition, the detailed assessment of population substructure in European derived cases has not been previously applied to genetic studies of SLE manifestations.
This study does have limitations. The first limitation is the skewed distribution of the primary predictor, percent northern European ancestry. This skewing may reflect an overall predominately northern European ancestry of many North Americans of European descent. Ideally, the associations identified in this study should be further investigated in a sample of SLE subjects with more southern European ancestry. Secondly, while the north-south cline in Europe is the largest source of population substructure in European Americans (10
), more subtle stratification due to ethnic or regional differences may influence specific phenotypes.
In addition, since these SLE cases are not part of a longitudinal cohort, misclassification of the outcomes may occur. SLE patients may develop additional manifestations as their disease progresses. Since these subphenotypes were not present at study enrollment, the subject would be misclassified as “negative” for this outcome. However, this misclassification error results in biasing our finding towards the null, and thus should not cause false positive results. Further, since most SLE patients in this study had well-established disease at study entry, with a median disease duration of ~7 years, the rate of misclassification should be relatively low.
Lastly, we had limited statistical power to detect association with certain SLE phenotypes (e.g., the neurologic disorder criterion) due to the low frequency in SLE subjects. To fully identify genetic predictors for the rare outcomes, one would need to enrich the case group for these manifestations to achieve a sample size adequate to study these outcomes.
In summary, this study emphasizes the concept that SLE cases descended from the same major continental ethnic group (e.g., European) have measurable genetic differences related to their geographic ancestry (e.g., northern Europe vs. southern Europe) that influence their risk of developing specific SLE manifestations. As an example, we have shown in this study that increased northern European ancestry is associated with photosensitivity and discoid rash, and protective for autoantibody production. These findings also indicate that geographic ancestry, likely reflecting genetic differences between those of northern and southern European ancestry, may contribute to the clinical heterogeneity seen in SLE patients of European descent. Further detailed investigation of the genetic differences among SLE patients with more northern vs. southern European ancestry may provide insight into genetic mechanisms underlying photosensitivity, discoid rash, and autoantibody production. Given the association between SLE-related autoantibodies with potentially severe disease manifestations (e.g., anti-cardiolipin autoantibody with arterial and venous thrombosis), this study also suggests that genetic ancestry can influence life-threatening disease outcomes. Finally, the overall findings of this study also have substantial implications for case-control genetics studies of SLE. Future genetic studies of SLE subphenotypes, even if investigating only a single continental ethnic group, should include assessment for population substructure to avoid confounding by differences in genetic ancestry.