Background/Purpose: Systemic lupus erythematosus (SLE) disproportionately affects minority patients. Non-European ancestry is associated with more severe disease, and conversely, European ancestry is associated with a lower risk of developing renal disease in SLE. Large genetic studies have identified 58 single nucleotide polymorphisms (SNPs) that influence risk of SLE. Separately, the Human Genome Diversity Project (HGDP) has characterized the allele frequency of 650,000 SNPs in 938 people from 53 different populations worldwide. We hypothesized that SLE SNPs with the greatest allele frequency differences across populations compared to Europeans could identify risk alleles that are associated with severe disease manifestations.

Methods: We analyzed the frequency distribution of the 58 SLE SNPs across populations in the HGDP database grouped into 6 geographic regions; 50 SNPs or proxies had available data. For each SNP, we determined the maximum absolute difference (max diff) in mean frequency between each region and Europe. SNPs were selected whose max diff was greater than 4 standard deviations of the distribution of intra-European frequencies. We tested these SNPs in our multiethnic cohort of 1588 SLE patients for severe disease outcomes (renal disease by ACR renal criterion, severe renal disease including severe forms of lupus nephritis on biopsy or end-stage renal disease, and production of double-stranded DNA antibodies) stratified by ethnicity: Caucasian, African American, Hispanic, and Asians. Logistic regression was performed for these 3 outcomes, adjusting for disease duration and gender.

Results: The max diff approach identified 19 SNPs; 13 had been genotyped in our SLE collection. Analysis identified a strong association between renal disease and Hispanic ethnicity: the number of these 13 risk alleles cumulatively increased the risk of renal disease among Hispanic patients (OR=1.2 per allele, p=0.006). Three of the 13 SNPs were individually associated (p ≤ 0.05) with renal disease or severe renal disease. The strongest single allele associations were rs2205960/TNFSF4 (OR=2.2, p=0.0014 for renal disease), rs2736340/BLK (OR 2.1, p=0.006 for severe renal disease and OR 1.6, p=0.05 for renal disease) and rs9888739/ITGAM (OR 1.8, p=0.04 for renal disease). In HGDP data, the Central/South American region was the first or second greatest max diff compared to Europeans for these alleles. 

Conclusion: Using worldwide genetic ancestry data, we identified SLE risk SNPs with high allele frequency variability across populations, postulating that these variants might influence severe disease phenotypes. Indeed, in a multiethnic SLE cohort, these 13 SNPs cumulatively increased the risk of renal disease in Hispanics, and 3 of these 13 alleles were individually associated with renal disease outcomes. This approach may be useful for identifying genetic variants that influence disease severity in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lupus-risk-alleles-with-high-ethnic-variability-worldwide-are-associated-with-renal-disease-in-hispanic-patients/