Background/Purpose

Lupus nephritis (LN) has a higher prevalence among African Americans, Hispanics, and Asians compared to Caucasians. Significant differences in SLE severity also exist within continental groups, with northern European genetic ancestry conferring protection against autoantibody production and renal disease, which we have previously shown to be independent of socioeconomic status (SES). The goal of our study was to test whether the effect of northern European ancestry is mediated by known SLE risk alleles or recently identified LN susceptibility loci.

Methods

We studied 1142 SLE patients from four independent case collections with genotype data obtained from a previous genome-wide association study (GWAS). A set of continental and intra-European ancestry informative markers (AIMs) was analyzed using the program STRUCTURE to define percent European and northern European ancestry. Subjects with <90% European ancestry were excluded. Multivariate logistic regression of LN risk was performed including percent northern European and other covariates (Table 1). Susceptibility loci were incorporated as potential mediators of the effect of genetic ancestry on the risk of LN. Forty-nine established SLE susceptibility loci and 12 single nucleotide polymorphisms (SNPs) with the strongest association with LN in a recent renal GWAS of SLE subjects were tested for association with LN. A p<0.05 was required for SNPs in multivariate logistic regression with other putative risk SNPs to be included in the model of LN risk. A polygenic risk score (PRS), a statistical method for calculating the effect of many common variants in aggregate, was generated from a random 2/3 of individuals using the program PLINK to select 12,935 SNPs with evidence of cumulative association with LN (p<0.05).

Results

The overall rate of LN in the study population was 27.3%. A 25% increase in the proportion of northern European ancestry was associated with a 16% reduction in the odds of having renal disease, after adjustment for disease duration and gender (OR 0.84, 95% CI 0.72-0.99, p=0.04). Two previously reported SLE susceptibility loci (BANK1, HLA-DR3) and 7 of 12 LN risk SNPs were significantly associated with LN in our dataset. Adjustment for all 9 putative LN susceptibility loci did not substantially alter the association between northern European ancestry and LN (Table 1). Exploratory analyses incorporating the PRS were underpowered in our study but suggested that a more comprehensive set of genetic variants, as captured by the PRS, may explain more of the effect of Northern European ancestry on the risk of LN.

Conclusion

Northern European ancestry has a significant protective effect for renal disease among SLE patients of European ancestry; this appears to be independent of currently known SLE risk alleles and LN susceptibility loci, but may be partially explained by a PRS.