Join us for the next instalment of the STAGE International Speaker Seminar Series (ISSS) with
Carl Langefeld
Professor
Department of Biostatistical Sciences
Co-Director
Bioinformatics Core
Wake Forest Comprehensive Cancer Center
Talk Title:
Predictive Ability of SLE Genetic Risk Factors Varies Across Ethnicities
Abstract:
Systemic lupus erythematosus (SLE) exhibits marked ethnic disparities. The SLE Immunochip Consortium’s transancestral association study of SLE (27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry) raised the number of common risk variants to >100 (Langefeld 2017). Previously, we proposed the cumulative hit hypothesis, where the cumulative effect of individual risk loci is greater than if each locus acted independently. Here, we explore the joint contribution of SLE-susceptibility loci, how it varies by ethnicity, and whether there are distinct genetic risk profiles. Specifically, penalized regression (i.e., Lasso regression) and support vector machines identified EA risk SNPs that maximally predict SLE status in EA. We then applied these predictions to an independent set of EA, AA and HA. The odds ratio comparing lowest versus highest 10% of risk allele count was ~30, ~6, and ~3 for EA, HA and AA, respectively, showing EA risk loci were not highly predictive of SLE risk in HA and AA. Lasso regression identified 51 risk alleles that maximally predicted SLE in EA, and a factor analysis identified seven uncorrelated risk profiles (one driven by HLA alleles and six by non-HLA loci). Using predicted probabilities from the lasso in EA, the area under the ROC curve was 0.75 for EA, 0.72 for HA, and 0.60 for AA. Thus, EA SLE risk loci are highly predictive in EA, modestly predictive in HA, and weakly predictive in AA. We posit that the genetic architecture of SLE in AA is meaningfully different from EA and HA, merit increased study, and will require ethnicity-informed treatment strategies.
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