Multi-Ancestral Genomic Approach to SLE-Precision Medicine
Abstract
We hypothesized that clinical heterogeneity in systemic lupus erythematosus (SLE) is partially due to genetic heterogeneity associated with SLE-risk single nucleotide polymorphisms (SNPs). We have observed considerable differences in SLE-risk allele frequencies across various race/ethnic groups, reflecting their unique microevolutionary histories. As a component of our hypothesis, we posit that unique genetic profiles across ancestral backgrounds will manifest as differences in the relative impact of key biological pathways on SLE-risk; pathways shared by all races/ethnicities but having differing magnitudes of impact at the population level. We have composed a race/ethnicity-specific and trans-race/ethnicity list of SLE-risk polymorphisms from public SLE Immunochip and GWAS studies. We have linked them to genes by function and computed intensive in silico systems biology and bioinformatic analyses across three ancestral groups (European, African, Asian). We have completed similar work using DNA methylation data. Although some pathways are shared (e.g., interferon) between SNP-associated and DNA methylation genes, the nucleic acid sensing pathway was identified in our DNA methylation study. We observed pathway differences by race/ethnicity in the SNP-associated studies; EA-dominant pathways included innate immune, myeloid cell function, and robust interferon response, AA-dominant pathways included aberrant B cell activity accompanied by ER stress and metabolic dysfunction, and Asian-dominant pathways include elevated oxidative stress, altered metabolism and mitochondrial dysfunction. Focused on these hypotheses and corresponding results, we have published two manuscripts, submitted one manuscript, and are preparing two manuscripts.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2021
- Accession Number
- AD1162344
Entities
People
- Carl D. Langefeld
Organizations
- Wake Forest University